Materiały źródłowe

• #1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4134018/

  The agent of Q fever, Coxiella burnetii, is an obligate intracellular bacterium that causes acute and chronic infections. […] In this Review, we describe how these recent advances have improved our understanding of C. burnetii invasion and host cell modulation, including the formation of replication-permissive Coxiella-containing vacuoles. […] As an intra-cellular pathogen, this organism has evolved a range of mechanisms to invade and survive within host cells. C. burnetii has a tropism for professional phagocytes and invades such cells using classic phagocytic mechanisms that rely on specific receptor-ligand interactions. […] However, C. burnetii does not follow this paradigm, but instead actively directs the maturation of a phagolysosome-like compartment known as the Coxiella-containing vacuole (CCV).

• #2 Q Fever – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556095/

  Q fever is a zoonotic febrile disease affecting workers involved in farming livestock. […] The microorganism causing Q fever is Coxiella burnetii, a gram-negative pleomorphic intracellular coccobacillus, phylogenetically related to Legionella. It can survive in the low pH of the host cell, which is also essential for its survival. It transforms into a spore-like form to survive in the rigid external environment for long periods. It undergoes two types of phase variation in response to its environmental changes. First is a virulent phase in lab animals and nature, associated with a delayed IgG response. The second is an avirulent phase (via alterations in capsular lipopolysaccharide) seen in culture media after repeated passage. […] Inhalation of aerosols from an infected animal placenta at parturition, animal excreta, straw, or dust from a farm or farm vehicle is the suspected mode of transmission. The digestive route of transmission is another mode suspected in humans. The average incubation period is 20 days for acute Q fever. Inhaled Coxiella bacteria multiply in the lungs, resulting in bacteremia, during which systemic manifestations occur. The virulence of the bacterial strain and the infecting dose determine illness severity, eg, the QPH1 plasmid-containing strain is more virulent than the QPRS plasmid strain. Based on the host’s immune response, the primary infection can be symptomatic (Q fever) or asymptomatic. Both can progress to endocarditis, depending on host characteristics. […] Chronic infection results in an aberrant immune response, possibly explaining Q fever fatigue syndrome.

• #3 Q Fever: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/227156-overview

  As noted earlier, Q fever is a ubiquitous zoonotic disease caused by C burnetii, with protean clinical manifestations that are not fully understood. […] C burnetii is a strict, intracellular, pleomorphic, gram-negative coccobacillus with an incubation period of 9-40 days; the average incubation period is 20 days (range, 18-21 d). Q fever is primarily transmitted by: (1) aerosolization from newborn animals, their placentas, and contaminated hides and fur; (2) ingestion of raw milk and goat cheese; (3) transfusions of blood products; (4) mother to offspring (ie, vertical) transmission; and (5) tick bites. Even wind patterns may make a difference by spreading aerosolized organisms downwind. […] C burnetii lives inside acidic lysosomes, a point that has therapeutic implications, and it has 2 morphologic variants: the small-cell variant (SCV) (0.2 x 0.7 microns), which survives well in the environment because of its resistance to heat and desiccation, pressure, and chemical agents; and the large-cell variant (LCV), which multiplies in the host monocyte and macrophage.

• #4 Q Fever: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/227156-overview

  The small-cell variant is a sporelike structure, enabling the organism to persist on fomites for more than 1 year. After passive entry into the host-cell phagosome, the organism delays the fusion of the phagosome with lysosomes, presumably using this delay to transform from the small-cell variant into the large-cell variant. […] C burnetii attaches to host macrophages by means of spectrin-binding proteins called ankyrin and is internalized into the cell, where it fuses with lysosomes to form phagolysosomes. The acidic environment of the phagolysosomes has little effect in defending the host against the invading organism, which multiplies and disseminates itself from this environment. […] Proliferation of organisms within the phagolysosome eventually ruptures the host cell. The infected pulmonary macrophages also are transported systemically, with the reticuloendothelial system (liver, spleen, bone marrow [most commonly]) being the most heavily infected.

• #5 Q Fever: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/227156-overview

  Like other gram-negative bacteria, C burnetii possesses a lipopolysaccharide as a virulence factor that also is responsible for an antigenic phase variation, an important property that first was utilized for serologic diagnosis by Bengtson in 1941. […] The infection has 2 phases, which are analogous to the lipopolysaccharide rough and smooth phase of Enterobacteriaceae organisms. Bacterial isolates from naturally infected and laboratory-infected eukaryotic cell hosts are virulent and have a phase I (smooth) lipopolysaccharide that helps protect the microorganism from the hosts defense mechanisms. […] The phase 1 form is responsible for acute Q fever infections. The phase 2 form has been identified during transmission of C burnetii in immunoincompetent hosts, such as embryonated hen eggs or cell-culture systems.

• #6 Q Fever—A Neglected Zoonosis

  https://www.mdpi.com/2076-2607/10/8/1530

  C. burnetii possesses a distinct characteristic called phase variation of the cell wall. Phase I bacteria have a complete LPS molecule and are highly virulent. This virulent form of bacteria can be isolated from infected animals, human beings and ticks. However, Phase II bacteria are avirulent and can be obtained after serial passages of Phase I bacteria in cell culture or embryonated chicken eggs. LPS of Phase II is rough and truncated. Besides LPS, the two antigenic forms of C. burnetii also differ in cell density, surface charge and surface protein configuration. Morphologically, there are two different forms of C. burnetii: the large cell variant (LCV) and the small cell variant (SCV). The LCV is larger in size with a less electron-dense center, while SCV is a metabolically inactive and less replicating form, with a compact rod shape and dense central region. These SCVs are excreted by infected animals, leading to environmental contamination.

• #7

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4134018/

  The agent of Q fever, Coxiella burnetii, is an obligate intracellular bacterium that causes acute and chronic infections. […] In this Review, we describe how these recent advances have improved our understanding of C. burnetii invasion and host cell modulation, including the formation of replication-permissive Coxiella-containing vacuoles. […] As an intra-cellular pathogen, this organism has evolved a range of mechanisms to invade and survive within host cells. C. burnetii has a tropism for professional phagocytes and invades such cells using classic phagocytic mechanisms that rely on specific receptor-ligand interactions. […] However, C. burnetii does not follow this paradigm, but instead actively directs the maturation of a phagolysosome-like compartment known as the Coxiella-containing vacuole (CCV).

• #8 Q Fever—A Neglected Zoonosis

  https://www.mdpi.com/2076-2607/10/8/1530

  The main route for C. burnetii transmission in both animals and humans is inhalation and to a lesser extent by ingestion of contaminated milk and milk products. Once the organism enters the body, it attaches to the cell membranes of phagocytes (monocytes/macrophages). Attachment of virulent bacteria to the phagocytic cells is triggered by avb3 integrin, while for avirulent bacteria, avb3 and complement receptor CR3 mediate the attachment. Phase I bacteria survive inside the phagocytic cells, whereas Phase II bacteria are eliminated. Additionally, Phase I bacteria are phagocytosed by the host cells in a considerably lower amount than Phase II bacteria. […] The SCVs are phagocytosed by monocytes and macrophages, and enter the phagolysosomes. Here, SCVs fuse with the lysosomal contents, change into the metabolically active form, undergo vegetative growth and ultimately transform into LCVs. Normally, both antigenic forms of C. burnetii are present within this phagolysosome niche. However, Phase II bacteria are quickly eliminated. The acidic environment of phagolysosomes is highly conducive for the growth of C. burnetii. Most important is the organism’s ability to propagate and multiply within the acidic phagolysosome and its tendency to develop persistent infection. The entire developmental cycle of a metabolically active Phase I bacterium occurs within this acidic niche.

• #9 Q fever immunology: the quest for a safe and effective vaccine | npj Vaccines

  https://www.nature.com/articles/s41541-023-00727-6

  The pathogenesis of Q fever is a convergence of Coxiella burnetii virulence with host cell resistance. Following inhalation of SCVs, Coxiella burnetii primarily targets alveolar macrophages. They are internalized by both phagocytotic and non-phagocytotic cells. Phase I and phase II enter phagocytic cells through the engagement of different receptors. The uptake of Coxiella burnetii by non-phagocytotic cells is through a zippering mechanism. The interaction of surface ligands with cognate receptors on host cells such as fibroblasts and HeLa cells passively encloses them in a zipper-like manner, accompanied by remodeling of the actin cytoskeleton. Recent studies by multi-phenotypic high-content screening identify OmpA as an essential PAMP of Coxiella burnetii that enables its entry into non-phagocytic cells. Complement receptor CR3 and leukocyte response integrin (v3) are receptors present on monocytes, involved in the uptake. The avirulent variant is readily recognized by both CR3 and integrin receptors after which it is efficiently eliminated following phagocytosis. In contrast phase I uptake is mediated by v3 alone. This difference in receptor recognition lies in the LPS structure variation. The resistance of the phase I variant to serum complement-mediated attack suggests that steric hindrance provided by LPS might mask its opsonization by the complement system, hence the lack of recognition by its cognate CR3 receptor. Furthermore, impaired spatial rearrangement of CR3 outside membrane protrusions inhibits its essential crosstalk with the integrin receptor resulting in impaired uptake of phase I bacteria. Internalization of phase I Coxiella burnetii by the integrin receptor v3, initiates extensive membrane ruffling through rearrangement of the filamentous (F)-actin cytoskeleton controlled by the Rho family of GTPases. Once contained in the early phagosome, now referred to as a Coxiella containing Vacuole (CCV), it fuses with early endosomes. This process is similar to the usual canonical pathway and regulated by GTPase Rab5, which recruits early endosome antigen EEA1 that promotes the fusion of the endosome with the CCV. The maturing CCV increases in size as it enters the late phagosome stage. Rab7 replaces Rab5, while vacuolar ATPase on the CCV membrane pumps protons into the CCV reducing the pH to 5.56. Lysosome associated membrane glycoprotein (LAMP) LAMP1 and LAMP 2 are recruited to the late endosome stage. The phagosomes that house phase II Coxiella burnetii transition to a phagolysosome where it is destroyed by the action of lysosomal enzymes such as cathepsins and hydrolases. Remarkably, studies with THP-1 cells demonstrate that vacuoles that shelter virulent Coxiella burnetii do not acquire lysosomal markers and therefore do not transition to a phagolysosome, escaping their degradation. Contradicting this theory, later studies reveal that fusion of CCV containing the virulent phase I with lysosome does occur but is halted due to its interaction with the autophagy pathway. The overexpression of the autophagic proteins GFP-LC3 or GFP-Rab24 increases CCV maturation after early infection. The CCV membrane equips itself with LC3 markers a few minutes after infection. The fusion of lysosome protein with CCV is further delayed by starvation-induced autophagy. Autophagy is a homeostatic process that degrades and recycles molecular components of damaged organelles and proteins inside a cell. It involves the recruitment of Atg8 proteins such as LC3, which enclose the ubiquitinated cargo in the autophagosome. Fusion with the lysosome to generate the autophagolysosome mediates the degradation of the cargo by lysosomal enzymes. The CCV is known to interfere with the host autophagic pathway to favor its enlargement and survival inside the host cell. Diverted phagolysosomal maturation is speculated to provide time for the differentiation of metabolically inactive SCV inside the CCV to the metabolically active LCV form and the autophagy cargo acts as a source of nutrients to initiate replication and metabolic development to LCV. The transition of SCV to LCV in mature CCVs halts the late CCV endosome maturation, retains the LC3 markers, and acquires the lysosomal glycoproteins LAMP1, and LAMP2. The acidic pH in the CCV lumen sustains their survival as acidity is required for the assimilation of nutrients required for the synthesis of nucleic acids and amino acids. Homotypic fusions with multiple small CCVs and heterotypic fusions with autophagic vesicles result in a large parasitophorous vacuole (PV) that occupies half the volume of the cell. The PV is surrounded by a cholesterol-rich membrane and lipid raft proteins flotillin-1 and flotillin-2 that enables membrane fusions and is filled with LCV and SCV variants. Six days post-infection the LCV reverts back to the SCV form, retaining the features of late CCV. The fate of the host cell at this point is exploited in two ways by Coxiella burnetii: (1) it can inhibit apoptosis by actively inhibiting signaling pathways or (2) Induction of pro-survival factors such as the ERKI, ERK2, and AKT family. The need for prolonged survival of host cells could be crucial for the establishment of chronic disease and continued survival of Coxiella burnetii. Similarly, Coxiella burnetii can also initiate apoptosis of invaded host cells in a caspase-independent pathway, disseminating replicating bacteria to infect other susceptible cells.

• #10 Coxiella burnetii Pathogenesis: Emphasizing the Role of the Autophagic Pathway

  https://archrazi.areeo.ac.ir/article_129090.html

  Coxiella burnetii strains are the primary cause of acute and chronic forms of Q fever with distinct pathotypes, according to phylogenetic analysis. The pathogenicity and virulence of C. burnetii are determined by the kind of infected animal species, the C. burnetii strain, the route of infection, and the pathogen inoculum size. […] Following aerosol transmission, pathogens infiltrate professional phagocyte cells via RAC1-dependent phagocytosis. It enters the host cell passively via actin-dependent phagocytosis (v3 integrin, as the primary receptor), which is implicated in actin-cytoskeletal ruffling. […] The bacterial ligand for v3 integrin is yet to be adequately characterized in phagocytic cells. In contrast, the OmpA protein in non-professional phagocyte cells has been identified as a bacterial invasin that enables active entrance into the host cells via a zipper-like mechanism.

• #11

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4134018/

  The agent of Q fever, Coxiella burnetii, is an obligate intracellular bacterium that causes acute and chronic infections. […] In this Review, we describe how these recent advances have improved our understanding of C. burnetii invasion and host cell modulation, including the formation of replication-permissive Coxiella-containing vacuoles. […] As an intra-cellular pathogen, this organism has evolved a range of mechanisms to invade and survive within host cells. C. burnetii has a tropism for professional phagocytes and invades such cells using classic phagocytic mechanisms that rely on specific receptor-ligand interactions. […] However, C. burnetii does not follow this paradigm, but instead actively directs the maturation of a phagolysosome-like compartment known as the Coxiella-containing vacuole (CCV).

• #12 Q fever immunology: the quest for a safe and effective vaccine | npj Vaccines

  https://www.nature.com/articles/s41541-023-00727-6

  The pathogenesis of Q fever is a convergence of Coxiella burnetii virulence with host cell resistance. Following inhalation of SCVs, Coxiella burnetii primarily targets alveolar macrophages. They are internalized by both phagocytotic and non-phagocytotic cells. Phase I and phase II enter phagocytic cells through the engagement of different receptors. The uptake of Coxiella burnetii by non-phagocytotic cells is through a zippering mechanism. The interaction of surface ligands with cognate receptors on host cells such as fibroblasts and HeLa cells passively encloses them in a zipper-like manner, accompanied by remodeling of the actin cytoskeleton. Recent studies by multi-phenotypic high-content screening identify OmpA as an essential PAMP of Coxiella burnetii that enables its entry into non-phagocytic cells. Complement receptor CR3 and leukocyte response integrin (v3) are receptors present on monocytes, involved in the uptake. The avirulent variant is readily recognized by both CR3 and integrin receptors after which it is efficiently eliminated following phagocytosis. In contrast phase I uptake is mediated by v3 alone. This difference in receptor recognition lies in the LPS structure variation. The resistance of the phase I variant to serum complement-mediated attack suggests that steric hindrance provided by LPS might mask its opsonization by the complement system, hence the lack of recognition by its cognate CR3 receptor. Furthermore, impaired spatial rearrangement of CR3 outside membrane protrusions inhibits its essential crosstalk with the integrin receptor resulting in impaired uptake of phase I bacteria. Internalization of phase I Coxiella burnetii by the integrin receptor v3, initiates extensive membrane ruffling through rearrangement of the filamentous (F)-actin cytoskeleton controlled by the Rho family of GTPases. Once contained in the early phagosome, now referred to as a Coxiella containing Vacuole (CCV), it fuses with early endosomes. This process is similar to the usual canonical pathway and regulated by GTPase Rab5, which recruits early endosome antigen EEA1 that promotes the fusion of the endosome with the CCV. The maturing CCV increases in size as it enters the late phagosome stage. Rab7 replaces Rab5, while vacuolar ATPase on the CCV membrane pumps protons into the CCV reducing the pH to 5.56. Lysosome associated membrane glycoprotein (LAMP) LAMP1 and LAMP 2 are recruited to the late endosome stage. The phagosomes that house phase II Coxiella burnetii transition to a phagolysosome where it is destroyed by the action of lysosomal enzymes such as cathepsins and hydrolases. Remarkably, studies with THP-1 cells demonstrate that vacuoles that shelter virulent Coxiella burnetii do not acquire lysosomal markers and therefore do not transition to a phagolysosome, escaping their degradation. Contradicting this theory, later studies reveal that fusion of CCV containing the virulent phase I with lysosome does occur but is halted due to its interaction with the autophagy pathway. The overexpression of the autophagic proteins GFP-LC3 or GFP-Rab24 increases CCV maturation after early infection. The CCV membrane equips itself with LC3 markers a few minutes after infection. The fusion of lysosome protein with CCV is further delayed by starvation-induced autophagy. Autophagy is a homeostatic process that degrades and recycles molecular components of damaged organelles and proteins inside a cell. It involves the recruitment of Atg8 proteins such as LC3, which enclose the ubiquitinated cargo in the autophagosome. Fusion with the lysosome to generate the autophagolysosome mediates the degradation of the cargo by lysosomal enzymes. The CCV is known to interfere with the host autophagic pathway to favor its enlargement and survival inside the host cell. Diverted phagolysosomal maturation is speculated to provide time for the differentiation of metabolically inactive SCV inside the CCV to the metabolically active LCV form and the autophagy cargo acts as a source of nutrients to initiate replication and metabolic development to LCV. The transition of SCV to LCV in mature CCVs halts the late CCV endosome maturation, retains the LC3 markers, and acquires the lysosomal glycoproteins LAMP1, and LAMP2. The acidic pH in the CCV lumen sustains their survival as acidity is required for the assimilation of nutrients required for the synthesis of nucleic acids and amino acids. Homotypic fusions with multiple small CCVs and heterotypic fusions with autophagic vesicles result in a large parasitophorous vacuole (PV) that occupies half the volume of the cell. The PV is surrounded by a cholesterol-rich membrane and lipid raft proteins flotillin-1 and flotillin-2 that enables membrane fusions and is filled with LCV and SCV variants. Six days post-infection the LCV reverts back to the SCV form, retaining the features of late CCV. The fate of the host cell at this point is exploited in two ways by Coxiella burnetii: (1) it can inhibit apoptosis by actively inhibiting signaling pathways or (2) Induction of pro-survival factors such as the ERKI, ERK2, and AKT family. The need for prolonged survival of host cells could be crucial for the establishment of chronic disease and continued survival of Coxiella burnetii. Similarly, Coxiella burnetii can also initiate apoptosis of invaded host cells in a caspase-independent pathway, disseminating replicating bacteria to infect other susceptible cells.

• #13

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4134018/

  The maturation of the CCV essentially follows the canonical endosomal pathway described above, but there are a number of important differences that rely on specific bacterial proteins. […] Most intracellular pathogens subvert the endosomal cascade and arrest maturation of the phagosome at an early stage to avoid fusion with lysosomes. However, in C. burnetii, lysosomal enzymes, including cathepsin D (CTSD) and lysosomal acid phosphatase (ACP2), accumulate in the CCV, although this is delayed until 2 hours after infection. […] The large CCV forms as a result of homotypic fusion of multiple smaller CCVs, and it can continue to expand through heterotypic fusion with autophagic, endocytic and lysosome vesicles. […] C. burnetii prolongs host cell viability in two ways: it actively inhibits apoptotic signalling pathways, and it induces pro-survival factors.

• #14

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4134018/

  The ability to prevent apoptosis and stimulate pro-survival pathways would also be beneficial for persistent infection, as this activity maintains the host cell to allow continued replication of the bacterium. […] The T4SS of C. burnetii is unlikely to be involved, as translocation of effectors does not occur until at least 8 hours after infection, suggesting that the bacterial proteins which interact with the autophagy pathway remain to be identified. […] The ability of C. burnetii to evade detection by pathogen recognition receptors prevents the activation of infected macrophages and provides a replication-permissive intracellular niche. […] C. burnetii actively recruits autophagy components to the CCV, and the induction of autophagy actually promotes C. burnetii intracellular replication.

• #15 Coxiella burnetii: Characteristics, Pathogenesis, Diagnosis

  https://microbenotes.com/coxiella-burnetii-characteristics-pathogenesis-diagnosis/

  C. burnetii has also been known to enter the body via other mucous membranes, abrasions, and the gastrointestinal tract through consumption of milk from infected animals. […] C. burnetii exists in two antigenic forms called phase I and phase II. […] Phase I is the virulent form that is found in humans with Q fever and infected vertebrate animals, and it is the infectious form, whereas Phase II is the avirulent form. […] Entry into the lungs results in infection of the alveolar macrophages. […] C. burnetii escapes intracellular killing in macrophages by: […] Inhibiting the final phagosome maturation step (cathepsin fusion) […] Resistant to the acidic environment of phagolysosome by producing superoxide dismutase. […] The normal progression after phagocytosis of most organisms is fusion of the phagosome with a series of endosomes (intracellular vesicles), resulting in a drop in intracellular pH, followed by fusion with lysosomes containing hydrolytic enzymes and resultant bacterial death which occurs with C. burnetii if phase II organisms are ingested; however, phase I Coxiella is able to arrest this process before lysosomal fusion.

• #16 Q fever immunology: the quest for a safe and effective vaccine | npj Vaccines

  https://www.nature.com/articles/s41541-023-00727-6

  The pathogenesis of Q fever is a convergence of Coxiella burnetii virulence with host cell resistance. Following inhalation of SCVs, Coxiella burnetii primarily targets alveolar macrophages. They are internalized by both phagocytotic and non-phagocytotic cells. Phase I and phase II enter phagocytic cells through the engagement of different receptors. The uptake of Coxiella burnetii by non-phagocytotic cells is through a zippering mechanism. The interaction of surface ligands with cognate receptors on host cells such as fibroblasts and HeLa cells passively encloses them in a zipper-like manner, accompanied by remodeling of the actin cytoskeleton. Recent studies by multi-phenotypic high-content screening identify OmpA as an essential PAMP of Coxiella burnetii that enables its entry into non-phagocytic cells. Complement receptor CR3 and leukocyte response integrin (v3) are receptors present on monocytes, involved in the uptake. The avirulent variant is readily recognized by both CR3 and integrin receptors after which it is efficiently eliminated following phagocytosis. In contrast phase I uptake is mediated by v3 alone. This difference in receptor recognition lies in the LPS structure variation. The resistance of the phase I variant to serum complement-mediated attack suggests that steric hindrance provided by LPS might mask its opsonization by the complement system, hence the lack of recognition by its cognate CR3 receptor. Furthermore, impaired spatial rearrangement of CR3 outside membrane protrusions inhibits its essential crosstalk with the integrin receptor resulting in impaired uptake of phase I bacteria. Internalization of phase I Coxiella burnetii by the integrin receptor v3, initiates extensive membrane ruffling through rearrangement of the filamentous (F)-actin cytoskeleton controlled by the Rho family of GTPases. Once contained in the early phagosome, now referred to as a Coxiella containing Vacuole (CCV), it fuses with early endosomes. This process is similar to the usual canonical pathway and regulated by GTPase Rab5, which recruits early endosome antigen EEA1 that promotes the fusion of the endosome with the CCV. The maturing CCV increases in size as it enters the late phagosome stage. Rab7 replaces Rab5, while vacuolar ATPase on the CCV membrane pumps protons into the CCV reducing the pH to 5.56. Lysosome associated membrane glycoprotein (LAMP) LAMP1 and LAMP 2 are recruited to the late endosome stage. The phagosomes that house phase II Coxiella burnetii transition to a phagolysosome where it is destroyed by the action of lysosomal enzymes such as cathepsins and hydrolases. Remarkably, studies with THP-1 cells demonstrate that vacuoles that shelter virulent Coxiella burnetii do not acquire lysosomal markers and therefore do not transition to a phagolysosome, escaping their degradation. Contradicting this theory, later studies reveal that fusion of CCV containing the virulent phase I with lysosome does occur but is halted due to its interaction with the autophagy pathway. The overexpression of the autophagic proteins GFP-LC3 or GFP-Rab24 increases CCV maturation after early infection. The CCV membrane equips itself with LC3 markers a few minutes after infection. The fusion of lysosome protein with CCV is further delayed by starvation-induced autophagy. Autophagy is a homeostatic process that degrades and recycles molecular components of damaged organelles and proteins inside a cell. It involves the recruitment of Atg8 proteins such as LC3, which enclose the ubiquitinated cargo in the autophagosome. Fusion with the lysosome to generate the autophagolysosome mediates the degradation of the cargo by lysosomal enzymes. The CCV is known to interfere with the host autophagic pathway to favor its enlargement and survival inside the host cell. Diverted phagolysosomal maturation is speculated to provide time for the differentiation of metabolically inactive SCV inside the CCV to the metabolically active LCV form and the autophagy cargo acts as a source of nutrients to initiate replication and metabolic development to LCV. The transition of SCV to LCV in mature CCVs halts the late CCV endosome maturation, retains the LC3 markers, and acquires the lysosomal glycoproteins LAMP1, and LAMP2. The acidic pH in the CCV lumen sustains their survival as acidity is required for the assimilation of nutrients required for the synthesis of nucleic acids and amino acids. Homotypic fusions with multiple small CCVs and heterotypic fusions with autophagic vesicles result in a large parasitophorous vacuole (PV) that occupies half the volume of the cell. The PV is surrounded by a cholesterol-rich membrane and lipid raft proteins flotillin-1 and flotillin-2 that enables membrane fusions and is filled with LCV and SCV variants. Six days post-infection the LCV reverts back to the SCV form, retaining the features of late CCV. The fate of the host cell at this point is exploited in two ways by Coxiella burnetii: (1) it can inhibit apoptosis by actively inhibiting signaling pathways or (2) Induction of pro-survival factors such as the ERKI, ERK2, and AKT family. The need for prolonged survival of host cells could be crucial for the establishment of chronic disease and continued survival of Coxiella burnetii. Similarly, Coxiella burnetii can also initiate apoptosis of invaded host cells in a caspase-independent pathway, disseminating replicating bacteria to infect other susceptible cells.

• #17 Q fever immunology: the quest for a safe and effective vaccine | npj Vaccines

  https://www.nature.com/articles/s41541-023-00727-6

  The pathogenesis of Q fever is a convergence of Coxiella burnetii virulence with host cell resistance. Following inhalation of SCVs, Coxiella burnetii primarily targets alveolar macrophages. They are internalized by both phagocytotic and non-phagocytotic cells. Phase I and phase II enter phagocytic cells through the engagement of different receptors. The uptake of Coxiella burnetii by non-phagocytotic cells is through a zippering mechanism. The interaction of surface ligands with cognate receptors on host cells such as fibroblasts and HeLa cells passively encloses them in a zipper-like manner, accompanied by remodeling of the actin cytoskeleton. Recent studies by multi-phenotypic high-content screening identify OmpA as an essential PAMP of Coxiella burnetii that enables its entry into non-phagocytic cells. Complement receptor CR3 and leukocyte response integrin (v3) are receptors present on monocytes, involved in the uptake. The avirulent variant is readily recognized by both CR3 and integrin receptors after which it is efficiently eliminated following phagocytosis. In contrast phase I uptake is mediated by v3 alone. This difference in receptor recognition lies in the LPS structure variation. The resistance of the phase I variant to serum complement-mediated attack suggests that steric hindrance provided by LPS might mask its opsonization by the complement system, hence the lack of recognition by its cognate CR3 receptor. Furthermore, impaired spatial rearrangement of CR3 outside membrane protrusions inhibits its essential crosstalk with the integrin receptor resulting in impaired uptake of phase I bacteria. Internalization of phase I Coxiella burnetii by the integrin receptor v3, initiates extensive membrane ruffling through rearrangement of the filamentous (F)-actin cytoskeleton controlled by the Rho family of GTPases. Once contained in the early phagosome, now referred to as a Coxiella containing Vacuole (CCV), it fuses with early endosomes. This process is similar to the usual canonical pathway and regulated by GTPase Rab5, which recruits early endosome antigen EEA1 that promotes the fusion of the endosome with the CCV. The maturing CCV increases in size as it enters the late phagosome stage. Rab7 replaces Rab5, while vacuolar ATPase on the CCV membrane pumps protons into the CCV reducing the pH to 5.56. Lysosome associated membrane glycoprotein (LAMP) LAMP1 and LAMP 2 are recruited to the late endosome stage. The phagosomes that house phase II Coxiella burnetii transition to a phagolysosome where it is destroyed by the action of lysosomal enzymes such as cathepsins and hydrolases. Remarkably, studies with THP-1 cells demonstrate that vacuoles that shelter virulent Coxiella burnetii do not acquire lysosomal markers and therefore do not transition to a phagolysosome, escaping their degradation. Contradicting this theory, later studies reveal that fusion of CCV containing the virulent phase I with lysosome does occur but is halted due to its interaction with the autophagy pathway. The overexpression of the autophagic proteins GFP-LC3 or GFP-Rab24 increases CCV maturation after early infection. The CCV membrane equips itself with LC3 markers a few minutes after infection. The fusion of lysosome protein with CCV is further delayed by starvation-induced autophagy. Autophagy is a homeostatic process that degrades and recycles molecular components of damaged organelles and proteins inside a cell. It involves the recruitment of Atg8 proteins such as LC3, which enclose the ubiquitinated cargo in the autophagosome. Fusion with the lysosome to generate the autophagolysosome mediates the degradation of the cargo by lysosomal enzymes. The CCV is known to interfere with the host autophagic pathway to favor its enlargement and survival inside the host cell. Diverted phagolysosomal maturation is speculated to provide time for the differentiation of metabolically inactive SCV inside the CCV to the metabolically active LCV form and the autophagy cargo acts as a source of nutrients to initiate replication and metabolic development to LCV. The transition of SCV to LCV in mature CCVs halts the late CCV endosome maturation, retains the LC3 markers, and acquires the lysosomal glycoproteins LAMP1, and LAMP2. The acidic pH in the CCV lumen sustains their survival as acidity is required for the assimilation of nutrients required for the synthesis of nucleic acids and amino acids. Homotypic fusions with multiple small CCVs and heterotypic fusions with autophagic vesicles result in a large parasitophorous vacuole (PV) that occupies half the volume of the cell. The PV is surrounded by a cholesterol-rich membrane and lipid raft proteins flotillin-1 and flotillin-2 that enables membrane fusions and is filled with LCV and SCV variants. Six days post-infection the LCV reverts back to the SCV form, retaining the features of late CCV. The fate of the host cell at this point is exploited in two ways by Coxiella burnetii: (1) it can inhibit apoptosis by actively inhibiting signaling pathways or (2) Induction of pro-survival factors such as the ERKI, ERK2, and AKT family. The need for prolonged survival of host cells could be crucial for the establishment of chronic disease and continued survival of Coxiella burnetii. Similarly, Coxiella burnetii can also initiate apoptosis of invaded host cells in a caspase-independent pathway, disseminating replicating bacteria to infect other susceptible cells.

• #18 Q fever pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Q_fever_pathophysiology

  The small cell form is often described as the spore form of C. burnetii. It can resist external environmental factors such as heat, pressure, and disinfectants for long periods of time. […] The large cell form is the active form of the organism. It persists in macrophages inside acidic vacuoles. […] The genome of C. burnetii was analyzed in 1995. Multiple genes encoding for Na+ ion proton exchange have been discovered, explaining the ability of the organism to survive in a low pH environment. […] There is a delay between the entry of the organism into the host cell and the fusion with lysosomes. This delay is thought to be due to the transformation from the small cell variant into the large cell variant. […] The acidic environment inside the lysosome has little effect on the large cell form of the organism.

• #19 Coxiella burnetii – Wikipedia

  https://en.wikipedia.org/wiki/Coxiella_burnetii

  The bacteria use a type IVB secretion system known as Icm/Dot (intracellular multiplication / defect in organelle trafficking genes) to inject over 100 effector proteins into the host. These effectors increase the bacteria’s ability to survive and grow inside the host cell by modulating many host cell pathways, including blocking cell death, inhibiting immune reactions, and altering vesicle trafficking.

• #20 Coxiella burnetii Pathogenesis: Emphasizing the Role of the Autophagic Pathway

  https://archrazi.areeo.ac.ir/article_129090.html

  C. burnetii replicates within this membrane-bound compartment, known as a „parasitophorous vacuole (PV)”, and may withstand lysosomal hydrolases while utilizing the acidic pH for metabolic activation. Furthermore, PV interacts with secretory and autophagic processes implicated in C. burnetii replication. […] C. burnetii has a T4BSS system similar to the Dot/Icm secretion system of L. pneumophila that acts as a surrogate host for the production of putative C. burnetii T4SS effectors, which is critical for C. burnetii intracellular survival. […] Several Cvps have been found in endosomes and CCVs, diverting autophagy and preparing a favorable intracellular replication environment for C. burnetii. These proteins are crucial in modifying the autophagy pathway to induce autophagy for Coxiella vacuole formation, as well as supplying sufficient nutrients for C. burnetii replication and the expansion and maturation of CCV compartments. […] C. burnetii was found to be one of these bacteria that survived and replicated within AM cells via the xenophagy pathway. C. burnetii remains in endosome vesicles after internalization and goes through the host endosomal network, but it does not impede the fusion of the pathogen-containing phagosome with lysosomes. The acidification of the phagosome activates T4SS on C. burnetii, facilitating the formation of highly fusogenic CCVs.

• #21 Coxiella burnetii Pathogenesis: Emphasizing the Role of the Autophagic Pathway

  https://archrazi.areeo.ac.ir/article_129090.html

  The induction of the autophagy pathway in Chinese hamster ovary cells increased the number of infected cells with C. burnetii, the bacterial load, and the size of the CCVs, according to Gutierrez, Vzquez. […] Furthermore, they claimed that activating and using the autophagy pathway improves C. burnetii replication and viability. Another study discovered that autophagosomes fuse with CCVs in a clathrin heavy chain dependent way whose expression and autophagy in CCVs have a substantial relationship. […] CvpB protein (also known as Cig2) is a 93.1 kDa effector protein that interacts with phosphatidylinositol 3-phosphate (PI3P) and phosphatidylserine on vacuolar structures. […] This observation implies that CvpB is required for the fusion and biogenesis of the large CCV. The C. burnetii CvpB mutant-infected Galleria mellonella (G. mellonella, wax moth) model indicated that the wax moth was more tolerant of the CvpB mutants, and that CvpB mutant replication was unaffected by infection with HeLa cells. […] Collectively, this evidence proposes a critical function for CvpA in C. burnetii growth and CCV biogenesis via the subversion of clathrin-mediated vesicular trafficking of the host cells.

• #22

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4134018/

  The ability to prevent apoptosis and stimulate pro-survival pathways would also be beneficial for persistent infection, as this activity maintains the host cell to allow continued replication of the bacterium. […] The T4SS of C. burnetii is unlikely to be involved, as translocation of effectors does not occur until at least 8 hours after infection, suggesting that the bacterial proteins which interact with the autophagy pathway remain to be identified. […] The ability of C. burnetii to evade detection by pathogen recognition receptors prevents the activation of infected macrophages and provides a replication-permissive intracellular niche. […] C. burnetii actively recruits autophagy components to the CCV, and the induction of autophagy actually promotes C. burnetii intracellular replication.

• #23 Q fever immunology: the quest for a safe and effective vaccine | npj Vaccines

  https://www.nature.com/articles/s41541-023-00727-6

  The pathogenesis of Q fever is a convergence of Coxiella burnetii virulence with host cell resistance. Following inhalation of SCVs, Coxiella burnetii primarily targets alveolar macrophages. They are internalized by both phagocytotic and non-phagocytotic cells. Phase I and phase II enter phagocytic cells through the engagement of different receptors. The uptake of Coxiella burnetii by non-phagocytotic cells is through a zippering mechanism. The interaction of surface ligands with cognate receptors on host cells such as fibroblasts and HeLa cells passively encloses them in a zipper-like manner, accompanied by remodeling of the actin cytoskeleton. Recent studies by multi-phenotypic high-content screening identify OmpA as an essential PAMP of Coxiella burnetii that enables its entry into non-phagocytic cells. Complement receptor CR3 and leukocyte response integrin (v3) are receptors present on monocytes, involved in the uptake. The avirulent variant is readily recognized by both CR3 and integrin receptors after which it is efficiently eliminated following phagocytosis. In contrast phase I uptake is mediated by v3 alone. This difference in receptor recognition lies in the LPS structure variation. The resistance of the phase I variant to serum complement-mediated attack suggests that steric hindrance provided by LPS might mask its opsonization by the complement system, hence the lack of recognition by its cognate CR3 receptor. Furthermore, impaired spatial rearrangement of CR3 outside membrane protrusions inhibits its essential crosstalk with the integrin receptor resulting in impaired uptake of phase I bacteria. Internalization of phase I Coxiella burnetii by the integrin receptor v3, initiates extensive membrane ruffling through rearrangement of the filamentous (F)-actin cytoskeleton controlled by the Rho family of GTPases. Once contained in the early phagosome, now referred to as a Coxiella containing Vacuole (CCV), it fuses with early endosomes. This process is similar to the usual canonical pathway and regulated by GTPase Rab5, which recruits early endosome antigen EEA1 that promotes the fusion of the endosome with the CCV. The maturing CCV increases in size as it enters the late phagosome stage. Rab7 replaces Rab5, while vacuolar ATPase on the CCV membrane pumps protons into the CCV reducing the pH to 5.56. Lysosome associated membrane glycoprotein (LAMP) LAMP1 and LAMP 2 are recruited to the late endosome stage. The phagosomes that house phase II Coxiella burnetii transition to a phagolysosome where it is destroyed by the action of lysosomal enzymes such as cathepsins and hydrolases. Remarkably, studies with THP-1 cells demonstrate that vacuoles that shelter virulent Coxiella burnetii do not acquire lysosomal markers and therefore do not transition to a phagolysosome, escaping their degradation. Contradicting this theory, later studies reveal that fusion of CCV containing the virulent phase I with lysosome does occur but is halted due to its interaction with the autophagy pathway. The overexpression of the autophagic proteins GFP-LC3 or GFP-Rab24 increases CCV maturation after early infection. The CCV membrane equips itself with LC3 markers a few minutes after infection. The fusion of lysosome protein with CCV is further delayed by starvation-induced autophagy. Autophagy is a homeostatic process that degrades and recycles molecular components of damaged organelles and proteins inside a cell. It involves the recruitment of Atg8 proteins such as LC3, which enclose the ubiquitinated cargo in the autophagosome. Fusion with the lysosome to generate the autophagolysosome mediates the degradation of the cargo by lysosomal enzymes. The CCV is known to interfere with the host autophagic pathway to favor its enlargement and survival inside the host cell. Diverted phagolysosomal maturation is speculated to provide time for the differentiation of metabolically inactive SCV inside the CCV to the metabolically active LCV form and the autophagy cargo acts as a source of nutrients to initiate replication and metabolic development to LCV. The transition of SCV to LCV in mature CCVs halts the late CCV endosome maturation, retains the LC3 markers, and acquires the lysosomal glycoproteins LAMP1, and LAMP2. The acidic pH in the CCV lumen sustains their survival as acidity is required for the assimilation of nutrients required for the synthesis of nucleic acids and amino acids. Homotypic fusions with multiple small CCVs and heterotypic fusions with autophagic vesicles result in a large parasitophorous vacuole (PV) that occupies half the volume of the cell. The PV is surrounded by a cholesterol-rich membrane and lipid raft proteins flotillin-1 and flotillin-2 that enables membrane fusions and is filled with LCV and SCV variants. Six days post-infection the LCV reverts back to the SCV form, retaining the features of late CCV. The fate of the host cell at this point is exploited in two ways by Coxiella burnetii: (1) it can inhibit apoptosis by actively inhibiting signaling pathways or (2) Induction of pro-survival factors such as the ERKI, ERK2, and AKT family. The need for prolonged survival of host cells could be crucial for the establishment of chronic disease and continued survival of Coxiella burnetii. Similarly, Coxiella burnetii can also initiate apoptosis of invaded host cells in a caspase-independent pathway, disseminating replicating bacteria to infect other susceptible cells.

• #24

  https://www.aaem.pl/Q-fever-selected-issues,71917,0,2.html

  Q fever is an infectious disease of humans and animals caused by Gram-negative coccobacillus Coxiella burnetii, belonging to the Legionellales order, Coxiellaceae family. The pathomechanism of infection starting from internalization of the bacteria to its release from infected cell are thoroughly described. […] In molecular diagnostics of C. burnetii infection, the most frequently used method is PCR and its modifications; namely, nested PCR and real time PCR which detect target sequences, such as htpAB and IS1111, chromosome genes (com1), genes specific for different types of plasmids and transposase genes. […] Natural history and pathophysiology of Q fever. […] Coxiella burnetii modulates Beclin 1 and BCL-2, preventing host cell apoptosis to generate a persistent bacterial infection.

• #25 Q fever immunology: the quest for a safe and effective vaccine | npj Vaccines

  https://www.nature.com/articles/s41541-023-00727-6

  The pathogenesis of Q fever is a convergence of Coxiella burnetii virulence with host cell resistance. Following inhalation of SCVs, Coxiella burnetii primarily targets alveolar macrophages. They are internalized by both phagocytotic and non-phagocytotic cells. Phase I and phase II enter phagocytic cells through the engagement of different receptors. The uptake of Coxiella burnetii by non-phagocytotic cells is through a zippering mechanism. The interaction of surface ligands with cognate receptors on host cells such as fibroblasts and HeLa cells passively encloses them in a zipper-like manner, accompanied by remodeling of the actin cytoskeleton. Recent studies by multi-phenotypic high-content screening identify OmpA as an essential PAMP of Coxiella burnetii that enables its entry into non-phagocytic cells. Complement receptor CR3 and leukocyte response integrin (v3) are receptors present on monocytes, involved in the uptake. The avirulent variant is readily recognized by both CR3 and integrin receptors after which it is efficiently eliminated following phagocytosis. In contrast phase I uptake is mediated by v3 alone. This difference in receptor recognition lies in the LPS structure variation. The resistance of the phase I variant to serum complement-mediated attack suggests that steric hindrance provided by LPS might mask its opsonization by the complement system, hence the lack of recognition by its cognate CR3 receptor. Furthermore, impaired spatial rearrangement of CR3 outside membrane protrusions inhibits its essential crosstalk with the integrin receptor resulting in impaired uptake of phase I bacteria. Internalization of phase I Coxiella burnetii by the integrin receptor v3, initiates extensive membrane ruffling through rearrangement of the filamentous (F)-actin cytoskeleton controlled by the Rho family of GTPases. Once contained in the early phagosome, now referred to as a Coxiella containing Vacuole (CCV), it fuses with early endosomes. This process is similar to the usual canonical pathway and regulated by GTPase Rab5, which recruits early endosome antigen EEA1 that promotes the fusion of the endosome with the CCV. The maturing CCV increases in size as it enters the late phagosome stage. Rab7 replaces Rab5, while vacuolar ATPase on the CCV membrane pumps protons into the CCV reducing the pH to 5.56. Lysosome associated membrane glycoprotein (LAMP) LAMP1 and LAMP 2 are recruited to the late endosome stage. The phagosomes that house phase II Coxiella burnetii transition to a phagolysosome where it is destroyed by the action of lysosomal enzymes such as cathepsins and hydrolases. Remarkably, studies with THP-1 cells demonstrate that vacuoles that shelter virulent Coxiella burnetii do not acquire lysosomal markers and therefore do not transition to a phagolysosome, escaping their degradation. Contradicting this theory, later studies reveal that fusion of CCV containing the virulent phase I with lysosome does occur but is halted due to its interaction with the autophagy pathway. The overexpression of the autophagic proteins GFP-LC3 or GFP-Rab24 increases CCV maturation after early infection. The CCV membrane equips itself with LC3 markers a few minutes after infection. The fusion of lysosome protein with CCV is further delayed by starvation-induced autophagy. Autophagy is a homeostatic process that degrades and recycles molecular components of damaged organelles and proteins inside a cell. It involves the recruitment of Atg8 proteins such as LC3, which enclose the ubiquitinated cargo in the autophagosome. Fusion with the lysosome to generate the autophagolysosome mediates the degradation of the cargo by lysosomal enzymes. The CCV is known to interfere with the host autophagic pathway to favor its enlargement and survival inside the host cell. Diverted phagolysosomal maturation is speculated to provide time for the differentiation of metabolically inactive SCV inside the CCV to the metabolically active LCV form and the autophagy cargo acts as a source of nutrients to initiate replication and metabolic development to LCV. The transition of SCV to LCV in mature CCVs halts the late CCV endosome maturation, retains the LC3 markers, and acquires the lysosomal glycoproteins LAMP1, and LAMP2. The acidic pH in the CCV lumen sustains their survival as acidity is required for the assimilation of nutrients required for the synthesis of nucleic acids and amino acids. Homotypic fusions with multiple small CCVs and heterotypic fusions with autophagic vesicles result in a large parasitophorous vacuole (PV) that occupies half the volume of the cell. The PV is surrounded by a cholesterol-rich membrane and lipid raft proteins flotillin-1 and flotillin-2 that enables membrane fusions and is filled with LCV and SCV variants. Six days post-infection the LCV reverts back to the SCV form, retaining the features of late CCV. The fate of the host cell at this point is exploited in two ways by Coxiella burnetii: (1) it can inhibit apoptosis by actively inhibiting signaling pathways or (2) Induction of pro-survival factors such as the ERKI, ERK2, and AKT family. The need for prolonged survival of host cells could be crucial for the establishment of chronic disease and continued survival of Coxiella burnetii. Similarly, Coxiella burnetii can also initiate apoptosis of invaded host cells in a caspase-independent pathway, disseminating replicating bacteria to infect other susceptible cells.

• #26

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4134018/

  The ability to prevent apoptosis and stimulate pro-survival pathways would also be beneficial for persistent infection, as this activity maintains the host cell to allow continued replication of the bacterium. […] The T4SS of C. burnetii is unlikely to be involved, as translocation of effectors does not occur until at least 8 hours after infection, suggesting that the bacterial proteins which interact with the autophagy pathway remain to be identified. […] The ability of C. burnetii to evade detection by pathogen recognition receptors prevents the activation of infected macrophages and provides a replication-permissive intracellular niche. […] C. burnetii actively recruits autophagy components to the CCV, and the induction of autophagy actually promotes C. burnetii intracellular replication.

• #27 Coxiella burnetii: Characteristics, Pathogenesis, Diagnosis

  https://microbenotes.com/coxiella-burnetii-characteristics-pathogenesis-diagnosis/

  In addition, the organisms require acid pH for their metabolic activities, which, in turn, protects them from the killing activities of most antibiotics. […] Coxiella is able to regulate the cell signaling pathways in its phagocytic home so that cell death is delayed. […] The ability of C. burnetii to cause either acute or chronic disease is determined in part by the organisms ability to survive intracellularly. […] In acute cases, in the presence of interferon-, phagosomelysosome fusion occurs, leading to bacterial death; however, in chronic infections interleukin-10 is overproduced by the host cell, which interferes with fusion and allows intracellular survival of C. burnetii. […] Infection with C. bumetii induces autoantibodies, particularly to cardiac and smooth muscles. […] Chronic form leads to disseminated cases affecting various organs with pathological condition.

• #28 Q fever pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Q_fever_pathophysiology

  The lipopolysaccharide capsule is one of the most important virulence factors of the organism. […] The different phases of infection are associated with changes in the lipopolysaccharide capsule. […] Lipopolysaccharide phase I (smooth polysaccharide) is associated with protection against the host’s immune response. […] Lipopolysaccharide phase II (rough polysaccharide) is isolated from avirulent, non-infectious host cells and is not associated with protection of the virus from the host cell. […] Both humoral and cell mediated immunity are involved in the immune response against C. burnetii. However, cell mediated immunity is more important in defending against the organism and people with deficient cell mediated immunity are more susceptible to developing chronic infection.

• #29 BIOLOGICAL AGENTS Q Fever – JMVH

  https://jmvh.org/article/biological-agents-q-fever/

  Q Fever is caused by the rickettsial pathogen Coxiella burnetii, a minute bacterium-like organism which may vary in size and shape. […] The molecular basis of Q fever pathogenesis is still poorly understood. It appears that different isolates of C. burnetii possess surface lipopolysaccharides (LPS) which vary antigenically and cause different host cell responses and clinical manifestations Host characteristics (immune status, predisposing factors such as cardiac or immunological anomalies) may also be important in the clinical manifestations of Q fever. […] Correlations have been found between the LPS type and the form of the disease either chronic or acute. Virulent Phase I pathogens possess a smooth LPS, whereas LPS of avirulent Phase II organisms is truncated or rough. […] Phase I LPS has been shown to induce toxic responses, such as hyperthermia, weight loss, hepatomegaly, lipid infiltration of the liver, and leukocytosis.

• #30 BIOLOGICAL AGENTS Q Fever – JMVH

  https://jmvh.org/article/biological-agents-q-fever/

  The precise role of LPS in pathogenesis is not known, but it may involve toxicity, attachment to host cells or influence on the immune response. […] Other virulence factors are probably involved in pathogenesis but have not yet been identified. […] Q fever can occur either as a short-term acute disease, or as a chronic illness which may last for months or years. Approximately five percent of patients with acute Q fever will develop chronic disease. There is some evidence to suggest that the form of the disease is very much dependent on the particular strain of C. burnetii involved. […] Coxiella burnetii is an obligate intracellular parasite which can grow in monocytes, macrophages and pneumocytes. The pathogens enter the cell passively by endocytosis (they are engulfed by the phagocyte) and grow in the highly acidic phagolysosomes, where huge colonies may form.

• #31 SciELO Brazil – Overview of Q fever in Brazil: an underestimated zoonosis Overview of Q fever in Brazil: an underestimated zoonosis

  https://www.scielo.br/j/rimtsp/a/TLHJX3cK9dKqwyQyNFRYRcR/

  As Toman et al. described, C. burnetii has particular mechanisms that give it versatility and the ability to survive and replicate in different hosts. These mechanisms are modulated by effector proteins released by a type IVB secretion system with unique functions and features to evade the immune system. Among these mechanisms, we can highlight: […] Action against the activation of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), the main mechanisms of innate immunity capable of fighting intracellular C. burnetii; […] Growth restricted to a low oxygen environment; […] Release of cations and DNA repair enzymes, allowing the genome to be as small as possible to survive in the environment; […] Bacterial LPS can antagonize TLR4 receptors and limit immune activity in several ways, including penetrating cells through the interaction between the O-chain and lipid rafts;

• #32 SciELO Brazil – Overview of Q fever in Brazil: an underestimated zoonosis Overview of Q fever in Brazil: an underestimated zoonosis

  https://www.scielo.br/j/rimtsp/a/TLHJX3cK9dKqwyQyNFRYRcR/

  As Toman et al. described, C. burnetii has particular mechanisms that give it versatility and the ability to survive and replicate in different hosts. These mechanisms are modulated by effector proteins released by a type IVB secretion system with unique functions and features to evade the immune system. Among these mechanisms, we can highlight: […] Action against the activation of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), the main mechanisms of innate immunity capable of fighting intracellular C. burnetii; […] Growth restricted to a low oxygen environment; […] Release of cations and DNA repair enzymes, allowing the genome to be as small as possible to survive in the environment; […] Bacterial LPS can antagonize TLR4 receptors and limit immune activity in several ways, including penetrating cells through the interaction between the O-chain and lipid rafts;

• #33 SciELO Brazil – Overview of Q fever in Brazil: an underestimated zoonosis Overview of Q fever in Brazil: an underestimated zoonosis

  https://www.scielo.br/j/rimtsp/a/TLHJX3cK9dKqwyQyNFRYRcR/

  As Toman et al. described, C. burnetii has particular mechanisms that give it versatility and the ability to survive and replicate in different hosts. These mechanisms are modulated by effector proteins released by a type IVB secretion system with unique functions and features to evade the immune system. Among these mechanisms, we can highlight: […] Action against the activation of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), the main mechanisms of innate immunity capable of fighting intracellular C. burnetii; […] Growth restricted to a low oxygen environment; […] Release of cations and DNA repair enzymes, allowing the genome to be as small as possible to survive in the environment; […] Bacterial LPS can antagonize TLR4 receptors and limit immune activity in several ways, including penetrating cells through the interaction between the O-chain and lipid rafts;

• #34 SciELO Brazil – Overview of Q fever in Brazil: an underestimated zoonosis Overview of Q fever in Brazil: an underestimated zoonosis

  https://www.scielo.br/j/rimtsp/a/TLHJX3cK9dKqwyQyNFRYRcR/

  As Toman et al. described, C. burnetii has particular mechanisms that give it versatility and the ability to survive and replicate in different hosts. These mechanisms are modulated by effector proteins released by a type IVB secretion system with unique functions and features to evade the immune system. Among these mechanisms, we can highlight: […] Action against the activation of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), the main mechanisms of innate immunity capable of fighting intracellular C. burnetii; […] Growth restricted to a low oxygen environment; […] Release of cations and DNA repair enzymes, allowing the genome to be as small as possible to survive in the environment; […] Bacterial LPS can antagonize TLR4 receptors and limit immune activity in several ways, including penetrating cells through the interaction between the O-chain and lipid rafts;

• #35 SciELO Brazil – Overview of Q fever in Brazil: an underestimated zoonosis Overview of Q fever in Brazil: an underestimated zoonosis

  https://www.scielo.br/j/rimtsp/a/TLHJX3cK9dKqwyQyNFRYRcR/

  As Toman et al. described, C. burnetii has particular mechanisms that give it versatility and the ability to survive and replicate in different hosts. These mechanisms are modulated by effector proteins released by a type IVB secretion system with unique functions and features to evade the immune system. Among these mechanisms, we can highlight: […] Action against the activation of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), the main mechanisms of innate immunity capable of fighting intracellular C. burnetii; […] Growth restricted to a low oxygen environment; […] Release of cations and DNA repair enzymes, allowing the genome to be as small as possible to survive in the environment; […] Bacterial LPS can antagonize TLR4 receptors and limit immune activity in several ways, including penetrating cells through the interaction between the O-chain and lipid rafts;

• #36 SciELO Brazil – Overview of Q fever in Brazil: an underestimated zoonosis Overview of Q fever in Brazil: an underestimated zoonosis

  https://www.scielo.br/j/rimtsp/a/TLHJX3cK9dKqwyQyNFRYRcR/

  Manipulation of signaling mechanisms of infected host cell, preventing its action against C. burnetii; […] Use of cellular kinases and cytoplasmic lipids for the biogenesis of the parasitophorous vacuole (PV) for replication. C. burnetii resists the degradative functions of the vacuole and exploits the acidic pH for metabolic activities; […] Anti-apoptosis activity with the secretion of Bcl-2 protein; […] Autophagic cell recycling activity by the secretion of the Beclin-1 protein; […] Tropism by adipose and placental tissues, strategic for escaping immune surveillance and establishing replicative activity. It is suggested that inhaled bacteria tend to generate pulmonary complications, while ingestion of contaminated raw milk tends to generate hepatopathies; however, this may also be related to the strain involved. The acute disease occurs as a consequence of the genotype involved, while the bacterial persistence is linked to predisposing factors of the individual.

• #37 SciELO Brazil – Overview of Q fever in Brazil: an underestimated zoonosis Overview of Q fever in Brazil: an underestimated zoonosis

  https://www.scielo.br/j/rimtsp/a/TLHJX3cK9dKqwyQyNFRYRcR/

  Manipulation of signaling mechanisms of infected host cell, preventing its action against C. burnetii; […] Use of cellular kinases and cytoplasmic lipids for the biogenesis of the parasitophorous vacuole (PV) for replication. C. burnetii resists the degradative functions of the vacuole and exploits the acidic pH for metabolic activities; […] Anti-apoptosis activity with the secretion of Bcl-2 protein; […] Autophagic cell recycling activity by the secretion of the Beclin-1 protein; […] Tropism by adipose and placental tissues, strategic for escaping immune surveillance and establishing replicative activity. It is suggested that inhaled bacteria tend to generate pulmonary complications, while ingestion of contaminated raw milk tends to generate hepatopathies; however, this may also be related to the strain involved. The acute disease occurs as a consequence of the genotype involved, while the bacterial persistence is linked to predisposing factors of the individual.

• #38 SciELO Brazil – Overview of Q fever in Brazil: an underestimated zoonosis Overview of Q fever in Brazil: an underestimated zoonosis

  https://www.scielo.br/j/rimtsp/a/TLHJX3cK9dKqwyQyNFRYRcR/

  Manipulation of signaling mechanisms of infected host cell, preventing its action against C. burnetii; […] Use of cellular kinases and cytoplasmic lipids for the biogenesis of the parasitophorous vacuole (PV) for replication. C. burnetii resists the degradative functions of the vacuole and exploits the acidic pH for metabolic activities; […] Anti-apoptosis activity with the secretion of Bcl-2 protein; […] Autophagic cell recycling activity by the secretion of the Beclin-1 protein; […] Tropism by adipose and placental tissues, strategic for escaping immune surveillance and establishing replicative activity. It is suggested that inhaled bacteria tend to generate pulmonary complications, while ingestion of contaminated raw milk tends to generate hepatopathies; however, this may also be related to the strain involved. The acute disease occurs as a consequence of the genotype involved, while the bacterial persistence is linked to predisposing factors of the individual.

• #39 SciELO Brazil – Overview of Q fever in Brazil: an underestimated zoonosis Overview of Q fever in Brazil: an underestimated zoonosis

  https://www.scielo.br/j/rimtsp/a/TLHJX3cK9dKqwyQyNFRYRcR/

  Manipulation of signaling mechanisms of infected host cell, preventing its action against C. burnetii; […] Use of cellular kinases and cytoplasmic lipids for the biogenesis of the parasitophorous vacuole (PV) for replication. C. burnetii resists the degradative functions of the vacuole and exploits the acidic pH for metabolic activities; […] Anti-apoptosis activity with the secretion of Bcl-2 protein; […] Autophagic cell recycling activity by the secretion of the Beclin-1 protein; […] Tropism by adipose and placental tissues, strategic for escaping immune surveillance and establishing replicative activity. It is suggested that inhaled bacteria tend to generate pulmonary complications, while ingestion of contaminated raw milk tends to generate hepatopathies; however, this may also be related to the strain involved. The acute disease occurs as a consequence of the genotype involved, while the bacterial persistence is linked to predisposing factors of the individual.

• #40 SciELO Brazil – Overview of Q fever in Brazil: an underestimated zoonosis Overview of Q fever in Brazil: an underestimated zoonosis

  https://www.scielo.br/j/rimtsp/a/TLHJX3cK9dKqwyQyNFRYRcR/

  Manipulation of signaling mechanisms of infected host cell, preventing its action against C. burnetii; […] Use of cellular kinases and cytoplasmic lipids for the biogenesis of the parasitophorous vacuole (PV) for replication. C. burnetii resists the degradative functions of the vacuole and exploits the acidic pH for metabolic activities; […] Anti-apoptosis activity with the secretion of Bcl-2 protein; […] Autophagic cell recycling activity by the secretion of the Beclin-1 protein; […] Tropism by adipose and placental tissues, strategic for escaping immune surveillance and establishing replicative activity. It is suggested that inhaled bacteria tend to generate pulmonary complications, while ingestion of contaminated raw milk tends to generate hepatopathies; however, this may also be related to the strain involved. The acute disease occurs as a consequence of the genotype involved, while the bacterial persistence is linked to predisposing factors of the individual.

• #41 Q fever pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Q_fever_pathophysiology

  The lipopolysaccharide capsule is one of the most important virulence factors of the organism. […] The different phases of infection are associated with changes in the lipopolysaccharide capsule. […] Lipopolysaccharide phase I (smooth polysaccharide) is associated with protection against the host’s immune response. […] Lipopolysaccharide phase II (rough polysaccharide) is isolated from avirulent, non-infectious host cells and is not associated with protection of the virus from the host cell. […] Both humoral and cell mediated immunity are involved in the immune response against C. burnetii. However, cell mediated immunity is more important in defending against the organism and people with deficient cell mediated immunity are more susceptible to developing chronic infection.

• #42 BIOLOGICAL AGENTS Q Fever – JMVH

  https://jmvh.org/article/biological-agents-q-fever/

  The organism is able to resist degradation by lysosomal enzymes and requires acidic conditions for the metabolism and transport of nutrients such as sugars and amino acids. […] Pathogens which are able to persist in the body may cause chronic illness, although the physiological mechanism of persistence is not well understood. […] It has been demonstrated in vitro that C. burnetii is able to induce the presentation of antigens on the surface of the host cell, and that the degree of presentation varies with different isolates. […] Strains which are associated with acute disease cause more antigen presentation than those strains implicated in chronic infection. If this is also relevant in vivo, chronic isolates may be able to survive for a longer period in the host because they are not as visible to the immune system.

• #43 Microorganisms | Special Issue : Pathogenesis and Pathophysiology of Coxiella burnetii Infection

  https://www.mdpi.com/journal/microorganisms/special_issues/W338EC898P

  Coxiella burnetii is the causative agent of Q fever, a zoonosis with significant outbreaks worldwide. Given its very low infectious dose, mode of contamination, ease of dissemination and environmental resistance, C. burnetii has been classified as a category B critical biologic agent by the Centre for Disease Control and Prevention, and the disease is included in the World Organisation for Animal Health list of notifiable diseases. In Humans, the primary infection which may be symptomatic resolves spontaneously in most of the cases. Efficient host defense relies on cell-mediated immunity, with a critical role for Th1 response and interferon-gamma. Progression to persistent infection reflects failure of the Th1 response and results from a combination of intrinsic and extrinsic parameters, in which interleukin-10 plays a significant role.

• #44 Q fever in pregnant goats: humoral and cellular immune responses | Veterinary Research | Full Text

  https://veterinaryresearch.biomedcentral.com/articles/10.1186/1297-9716-44-67

  Q fever is a zoonosis caused by the intracellular bacterium Coxiella burnetii. Both humoral and cellular immunity are important in the host defence against intracellular bacteria. […] The role of cellular immunity in the host defence against C. burnetii infections is not well established. In mice it is suggested that T cells are particularly important for the clearance of the bacterium after infection. Interferon-gamma (IFN-) and tumour necrosis factor-alpha (TNF-) seem to be essential for the early control of Coxiella proliferation. […] Cellular immune responses after C. burnetii infection of domestic ruminants have not been investigated, although this may provide potential tools to investigate the pathogenesis of C. burnetii infection in ruminants and to improve its diagnosis. […] The cell-mediated immune response during the first weeks after inoculation was minimal, as indicated by the results of the IFN- Elispot and the apparent absence of a systemic cytokine mRNA responses. This might indicate that the PBMCs have not been in contact with C. burnetii.

• #45 Persistent Coxiella burnetii Infection in Mice Overexpressing IL-10: An Efficient Model for Chronic Q Fever Pathogenesis | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.0040023

  Interleukin (IL)-10 increases host susceptibility to microorganisms and is involved in intracellular persistence of bacterial pathogens. IL-10 is associated with chronic Q fever, an infectious disease due to the intracellular bacterium Coxiella burnetii. […] Transgenic mice exhibited sustained tissue infection and strong antibody response in contrast to wild-type mice; thus, bacterial persistence was IL-10-dependent as in chronic Q fever. The overexpression of IL-10 in macrophages prevents anti-infectious competence of host, including the ability to mount granulomatous response and microbicidal pathway in tissues. […] We report an efficient mouse model for chronic Q fever pathogenesis, which associates high levels of specific antibodies, sustained tissue infection, and reduced granuloma formation, as in human Q fever.

• #46 BIOLOGICAL AGENTS Q Fever – JMVH

  https://jmvh.org/article/biological-agents-q-fever/

  The precise role of LPS in pathogenesis is not known, but it may involve toxicity, attachment to host cells or influence on the immune response. […] Other virulence factors are probably involved in pathogenesis but have not yet been identified. […] Q fever can occur either as a short-term acute disease, or as a chronic illness which may last for months or years. Approximately five percent of patients with acute Q fever will develop chronic disease. There is some evidence to suggest that the form of the disease is very much dependent on the particular strain of C. burnetii involved. […] Coxiella burnetii is an obligate intracellular parasite which can grow in monocytes, macrophages and pneumocytes. The pathogens enter the cell passively by endocytosis (they are engulfed by the phagocyte) and grow in the highly acidic phagolysosomes, where huge colonies may form.

• #47 Q Fever – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556095/

  Q fever is a zoonotic febrile disease affecting workers involved in farming livestock. […] The microorganism causing Q fever is Coxiella burnetii, a gram-negative pleomorphic intracellular coccobacillus, phylogenetically related to Legionella. It can survive in the low pH of the host cell, which is also essential for its survival. It transforms into a spore-like form to survive in the rigid external environment for long periods. It undergoes two types of phase variation in response to its environmental changes. First is a virulent phase in lab animals and nature, associated with a delayed IgG response. The second is an avirulent phase (via alterations in capsular lipopolysaccharide) seen in culture media after repeated passage. […] Inhalation of aerosols from an infected animal placenta at parturition, animal excreta, straw, or dust from a farm or farm vehicle is the suspected mode of transmission. The digestive route of transmission is another mode suspected in humans. The average incubation period is 20 days for acute Q fever. Inhaled Coxiella bacteria multiply in the lungs, resulting in bacteremia, during which systemic manifestations occur. The virulence of the bacterial strain and the infecting dose determine illness severity, eg, the QPH1 plasmid-containing strain is more virulent than the QPRS plasmid strain. Based on the host’s immune response, the primary infection can be symptomatic (Q fever) or asymptomatic. Both can progress to endocarditis, depending on host characteristics. […] Chronic infection results in an aberrant immune response, possibly explaining Q fever fatigue syndrome.

• #48 Q Fever: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/227156-overview

  The small-cell variant is a sporelike structure, enabling the organism to persist on fomites for more than 1 year. After passive entry into the host-cell phagosome, the organism delays the fusion of the phagosome with lysosomes, presumably using this delay to transform from the small-cell variant into the large-cell variant. […] C burnetii attaches to host macrophages by means of spectrin-binding proteins called ankyrin and is internalized into the cell, where it fuses with lysosomes to form phagolysosomes. The acidic environment of the phagolysosomes has little effect in defending the host against the invading organism, which multiplies and disseminates itself from this environment. […] Proliferation of organisms within the phagolysosome eventually ruptures the host cell. The infected pulmonary macrophages also are transported systemically, with the reticuloendothelial system (liver, spleen, bone marrow [most commonly]) being the most heavily infected.

• #49 Q fever: etiology, diagnosis, and treatment

  https://jzd.tabrizu.ac.ir/article_16329.html

  In acute infections, the organism can be detected in the host’s blood, liver, spleen, and lungs. In non-pregnant animals, the disease is mainly asymptomatic, while in animals of pregnant, the most important clinical manifestations are abortion, weak offspring, premature birth, and stillbirth. In areas at risk of infection with this agent, there is a correlation between digestive and respiratory problems in apparently healthy children. Although reproductive disorders are not expected C. burnetii infection consequences in domestic animals, infection with this agent can increase the abortion rate by up to 90% in goats. […] Infection with C. burnetii in humans can occur both acutely and chronically. The acute form is often self-limiting with mild flu-like symptoms, but the disease chronic cases are often associated with chronic endocarditis. In cases of abortion caused by infection of C. burnetii, the embryos usually look fresh and normal, but sometimes the embryo is seen as necrotic. The placenta has inflammation and purulent yellow-brown exudates in the inter-cotyledonary spaces. In the microscopic view, the trophoblastic cells in the inter-cotyledonary area of the allantoic-chorion are mostly affected. Epithelial cells in chorionic membranes usually have basophils and vacuolated cytoplasm. A mild granulation can be observed in the liver.

• #50 Q Fever – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556095/

  Q fever is a zoonotic febrile disease affecting workers involved in farming livestock. […] The microorganism causing Q fever is Coxiella burnetii, a gram-negative pleomorphic intracellular coccobacillus, phylogenetically related to Legionella. It can survive in the low pH of the host cell, which is also essential for its survival. It transforms into a spore-like form to survive in the rigid external environment for long periods. It undergoes two types of phase variation in response to its environmental changes. First is a virulent phase in lab animals and nature, associated with a delayed IgG response. The second is an avirulent phase (via alterations in capsular lipopolysaccharide) seen in culture media after repeated passage. […] Inhalation of aerosols from an infected animal placenta at parturition, animal excreta, straw, or dust from a farm or farm vehicle is the suspected mode of transmission. The digestive route of transmission is another mode suspected in humans. The average incubation period is 20 days for acute Q fever. Inhaled Coxiella bacteria multiply in the lungs, resulting in bacteremia, during which systemic manifestations occur. The virulence of the bacterial strain and the infecting dose determine illness severity, eg, the QPH1 plasmid-containing strain is more virulent than the QPRS plasmid strain. Based on the host’s immune response, the primary infection can be symptomatic (Q fever) or asymptomatic. Both can progress to endocarditis, depending on host characteristics. […] Chronic infection results in an aberrant immune response, possibly explaining Q fever fatigue syndrome.

• #51 Q Fever: Causes, Symptoms, Diagnosis, Prevention & Treatment

  https://my.clevelandclinic.org/health/diseases/17883-q-fever

  Chronic Q fever is a serious form of Q fever that can affect your heart, your blood vessels, your bones and other parts of your body. It affects 1 to 5% of people whove had a C. burnetii infection. It can start months or years after your initial symptoms go away and can lead to life-threatening complications. Sometimes people with chronic Q fever had no symptoms with their initial infection. The most common form causes inflammation in your heart (endocarditis). […] Q fever can cause a wide variety of symptoms, but the most common ones are flu-like. The bacterium that causes it, C. burnetii, can infect your lungs, heart, brain, bones or other parts of your body and cause symptoms there. Some people have extreme tiredness (fatigue) and other symptoms for months or years. Chronic Q fever can be life-threatening.

• #52 Q Fever – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/rickettsiae-and-related-organisms/q-fever

  Symptoms do not readily suggest the diagnosis of Q fever. Early on, Q fever resembles many infections (eg, influenza, other viral infections, salmonellosis, malaria, hepatitis, brucellosis). Later, it resembles many forms of bacterial, viral, and mycoplasmal and other atypical pneumonias. Contact with animals or animal products is an important clue. […] Diagnosis of Q fever endocarditis can be difficult because blood cultures are negative and vegetative cardiac valve lesions are small and are visualized by echocardiography in only about 12% of patients. […] For acute Q fever, primary treatment is doxycycline until the patient improves, has been afebrile for about 5 days, and has received treatment for 14 days; longer treatment may be needed for severe disease. […] For endocarditis, treatment needs to be prolonged (months to years to lifelong), typically for at least 18 months. Doxycycline plus hydroxychloroquine is currently recommended. […] For chronic granulomatous hepatitis, the optimal regimen has not been determined.

• #53 Q Fever: Causes, Symptoms, Diagnosis, Prevention & Treatment

  https://my.clevelandclinic.org/health/diseases/17883-q-fever

  A small number of people (1 to 5%), usually those with underlying conditions, go on to develop chronic Q fever. If you have chronic Q fever, youll have to be treated for 18 months or longer. […] Both acute and chronic Q fever can cause complications, though theyre more common and usually more serious in chronic Q fever. Complications include: Weakened, bulging arteries (aneurysm). Arterial fistula, a condition that causes blood to flow incorrectly. Heart inflammation (endocarditis). Scarring in your lungs (fibrosis). Acute respiratory distress syndrome (ARDS). Heart failure. Bone infection (osteomyelitis). Pregnancy loss (miscarriage). Low birth weight. […] The outlook for acute Q fever is usually good when treated with antibiotics. The mortality (death) rate for acute Q fever is 0.5 to 1.5%. Those who go on to develop chronic Q fever are at higher risk for complications and death. The mortality (death) rate for chronic Q fever is 12 to 25%.

• #54 BIOLOGICAL AGENTS Q Fever – JMVH

  https://jmvh.org/article/biological-agents-q-fever/

  Q Fever is caused by the rickettsial pathogen Coxiella burnetii, a minute bacterium-like organism which may vary in size and shape. […] The molecular basis of Q fever pathogenesis is still poorly understood. It appears that different isolates of C. burnetii possess surface lipopolysaccharides (LPS) which vary antigenically and cause different host cell responses and clinical manifestations Host characteristics (immune status, predisposing factors such as cardiac or immunological anomalies) may also be important in the clinical manifestations of Q fever. […] Correlations have been found between the LPS type and the form of the disease either chronic or acute. Virulent Phase I pathogens possess a smooth LPS, whereas LPS of avirulent Phase II organisms is truncated or rough. […] Phase I LPS has been shown to induce toxic responses, such as hyperthermia, weight loss, hepatomegaly, lipid infiltration of the liver, and leukocytosis.

• #55 BIOLOGICAL AGENTS Q Fever – JMVH

  https://jmvh.org/article/biological-agents-q-fever/

  The organism is able to resist degradation by lysosomal enzymes and requires acidic conditions for the metabolism and transport of nutrients such as sugars and amino acids. […] Pathogens which are able to persist in the body may cause chronic illness, although the physiological mechanism of persistence is not well understood. […] It has been demonstrated in vitro that C. burnetii is able to induce the presentation of antigens on the surface of the host cell, and that the degree of presentation varies with different isolates. […] Strains which are associated with acute disease cause more antigen presentation than those strains implicated in chronic infection. If this is also relevant in vivo, chronic isolates may be able to survive for a longer period in the host because they are not as visible to the immune system.

• #56 Q Fever—A Neglected Zoonosis

  https://www.mdpi.com/2076-2607/10/8/1530

  Little is known about the role of the host cellular immunity in infected human patients. The goat’s immune response against C. burnetii infection revealed that both IgG and IgM Phase II specific antibodies can be found within two weeks post-infection and their titers remain elevated in the blood for up to 13 weeks. Phase I antibodies develop after four weeks of Phase II antibodies. The duration of immune response against C. burnetii can persist for several months to years. The metabolically active LCVs are mainly present in the trophoblasts of the placenta. During acute infection, the organism is present in blood, liver, spleen and lungs of the host. The disease is mostly asymptomatic in nonpregnant animals, while in pregnant animals the most important clinical manifestations are abortion, stillbirth, birth of weak offspring and premature delivery. Incidence of respiratory and digestive problems in apparently healthy kids in at-risk areas can be associated with Q fever infection. Although reproductive disorders are not the common consequences of Q fever in domestic animals, increased abortion rates of up to 90% have been reported in goats.

• #57 Q Fever – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/rickettsiae-and-related-organisms/q-fever

  Symptoms do not readily suggest the diagnosis of Q fever. Early on, Q fever resembles many infections (eg, influenza, other viral infections, salmonellosis, malaria, hepatitis, brucellosis). Later, it resembles many forms of bacterial, viral, and mycoplasmal and other atypical pneumonias. Contact with animals or animal products is an important clue. […] Diagnosis of Q fever endocarditis can be difficult because blood cultures are negative and vegetative cardiac valve lesions are small and are visualized by echocardiography in only about 12% of patients. […] For acute Q fever, primary treatment is doxycycline until the patient improves, has been afebrile for about 5 days, and has received treatment for 14 days; longer treatment may be needed for severe disease. […] For endocarditis, treatment needs to be prolonged (months to years to lifelong), typically for at least 18 months. Doxycycline plus hydroxychloroquine is currently recommended. […] For chronic granulomatous hepatitis, the optimal regimen has not been determined.

• #58 Q Fever – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/rickettsiae-and-related-organisms/q-fever

  Symptoms do not readily suggest the diagnosis of Q fever. Early on, Q fever resembles many infections (eg, influenza, other viral infections, salmonellosis, malaria, hepatitis, brucellosis). Later, it resembles many forms of bacterial, viral, and mycoplasmal and other atypical pneumonias. Contact with animals or animal products is an important clue. […] Diagnosis of Q fever endocarditis can be difficult because blood cultures are negative and vegetative cardiac valve lesions are small and are visualized by echocardiography in only about 12% of patients. […] For acute Q fever, primary treatment is doxycycline until the patient improves, has been afebrile for about 5 days, and has received treatment for 14 days; longer treatment may be needed for severe disease. […] For endocarditis, treatment needs to be prolonged (months to years to lifelong), typically for at least 18 months. Doxycycline plus hydroxychloroquine is currently recommended. […] For chronic granulomatous hepatitis, the optimal regimen has not been determined.

• #59 Coxiella burnetii | Mechanisms of Pathogenicity

  https://mechpath.com/2017/12/15/coxiella-burnetii/

  However, C. burnetii is an acidophilic bacterium, meaning its growth is enhanced in acidic conditions. […] Furthermore, the bacteria can create spores which are highly resistant dormant forms of the bacteria to preserve itself and its DNA under extreme conditions or when there is a lack of nutrients. […] Doxycycline and hydroxychloroquine are especially effective as the hydroxychloroquine causes alkalization of the phagolysosome, allowing doxycycline a greater advantage to destroy the bacteria.

• #60 Q Fever program | Research, Innovation & Impact

  https://research.missouri.edu/laboratory-for-infectious-disease-research/q-fever-program

  The infectious dose for Q fever is exceptionally low and it is estimated that only 10 bacterial cells is sufficient to cause disease in humans. […] MU researchers at the LIDR are studying pulmonary Q fever and the mechanism of protective immunity against the disease. […] Their research has identified candidate vaccine approaches that are under development at the LIDR.

• #61 Coxiella Burnetii and Q Fever: A Comprehensive Review of Epidemiology, Pathogenesis, Surveillance, and Control Measures

  https://www.sciqst.com/Coxiella%20Burnetii%20and%20Q%20Fever:%20A%20Comprehensive%20Review%20of%20Epidemiology,%20Pathogenesis,%20Surveillance,%20and%20Control%20Measures

  Coxiella burnetii employs sophisticated mechanisms to survive within the host’s intracellular compartments. By manipulating the host’s autophagy pathway and pH environment, C. burnetii creates a conducive niche within the Coxiella-containing vacuole (CCV) for its replication. […] Understanding these interactions is crucial for developing targeted treatments and vaccines. […] Coxiella burnetii remains a formidable pathogen due to its wide host range, environmental resilience, and sophisticated intracellular survival mechanisms. Recent research underscores the necessity for coordinated epidemiological surveillance, advanced diagnostic tools, and comprehensive control strategies. Integrated efforts under the One Health framework are essential in mitigating the impact of Q fever on both animal and human populations. Continued research and collaboration are paramount for developing effective vaccines, therapeutics, and public health interventions to manage and prevent Coxiella infections globally.

• #62 Airborne geographical dispersal of Q fever from livestock holdings to human communities: a systematic review and critical appraisal of evidence | BMC Infectious Diseases | Full Text

  https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-018-3135-4

  Wind has been implicated as an epidemiological factor in the spread of Q fever in studies from farm and abattoir putative sources. […] Our review suggests that in rural areas, the highest risk of infection occurs within 5 km of infected farms, whereas urban outbreaks generally occur within smaller distances, with the highest risk in areas 2 – 4 km from source farms. […] Our results demonstrate that while geographical distance from livestock sources is a potentially important risk factor in Q fever spatial epidemiology, it has been largely understudied. […] This evidence, along with results from Commandeur et al. implying dairy goat farming should not occur within 3 km of residential dwellings, forms the basis for recommendations by the Robert-Koch Institute to the German planning authorities for a 500 m residential construction exclusion zone around sheep rearing areas.

• #63 Microorganisms | Special Issue : Pathogenesis and Pathophysiology of Coxiella burnetii Infection

  https://www.mdpi.com/journal/microorganisms/special_issues/W338EC898P

  Coxiella burnetii is the causative agent of Q fever, a zoonosis with significant outbreaks worldwide. Given its very low infectious dose, mode of contamination, ease of dissemination and environmental resistance, C. burnetii has been classified as a category B critical biologic agent by the Centre for Disease Control and Prevention, and the disease is included in the World Organisation for Animal Health list of notifiable diseases. In Humans, the primary infection which may be symptomatic resolves spontaneously in most of the cases. Efficient host defense relies on cell-mediated immunity, with a critical role for Th1 response and interferon-gamma. Progression to persistent infection reflects failure of the Th1 response and results from a combination of intrinsic and extrinsic parameters, in which interleukin-10 plays a significant role.

• #64

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4134018/

  The agent of Q fever, Coxiella burnetii, is an obligate intracellular bacterium that causes acute and chronic infections. […] In this Review, we describe how these recent advances have improved our understanding of C. burnetii invasion and host cell modulation, including the formation of replication-permissive Coxiella-containing vacuoles. […] As an intra-cellular pathogen, this organism has evolved a range of mechanisms to invade and survive within host cells. C. burnetii has a tropism for professional phagocytes and invades such cells using classic phagocytic mechanisms that rely on specific receptor-ligand interactions. […] However, C. burnetii does not follow this paradigm, but instead actively directs the maturation of a phagolysosome-like compartment known as the Coxiella-containing vacuole (CCV).

• #65 Coxiella Burnetii and Q Fever: A Comprehensive Review of Epidemiology, Pathogenesis, Surveillance, and Control Measures

  https://www.sciqst.com/Coxiella%20Burnetii%20and%20Q%20Fever:%20A%20Comprehensive%20Review%20of%20Epidemiology,%20Pathogenesis,%20Surveillance,%20and%20Control%20Measures

  Coxiella burnetii employs sophisticated mechanisms to survive within the host’s intracellular compartments. By manipulating the host’s autophagy pathway and pH environment, C. burnetii creates a conducive niche within the Coxiella-containing vacuole (CCV) for its replication. […] Understanding these interactions is crucial for developing targeted treatments and vaccines. […] Coxiella burnetii remains a formidable pathogen due to its wide host range, environmental resilience, and sophisticated intracellular survival mechanisms. Recent research underscores the necessity for coordinated epidemiological surveillance, advanced diagnostic tools, and comprehensive control strategies. Integrated efforts under the One Health framework are essential in mitigating the impact of Q fever on both animal and human populations. Continued research and collaboration are paramount for developing effective vaccines, therapeutics, and public health interventions to manage and prevent Coxiella infections globally.

• #66 Coxiella Burnetii and Q Fever: A Comprehensive Review of Epidemiology, Pathogenesis, Surveillance, and Control Measures

  https://www.sciqst.com/Coxiella%20Burnetii%20and%20Q%20Fever:%20A%20Comprehensive%20Review%20of%20Epidemiology,%20Pathogenesis,%20Surveillance,%20and%20Control%20Measures

  Coxiella burnetii employs sophisticated mechanisms to survive within the host’s intracellular compartments. By manipulating the host’s autophagy pathway and pH environment, C. burnetii creates a conducive niche within the Coxiella-containing vacuole (CCV) for its replication. […] Understanding these interactions is crucial for developing targeted treatments and vaccines. […] Coxiella burnetii remains a formidable pathogen due to its wide host range, environmental resilience, and sophisticated intracellular survival mechanisms. Recent research underscores the necessity for coordinated epidemiological surveillance, advanced diagnostic tools, and comprehensive control strategies. Integrated efforts under the One Health framework are essential in mitigating the impact of Q fever on both animal and human populations. Continued research and collaboration are paramount for developing effective vaccines, therapeutics, and public health interventions to manage and prevent Coxiella infections globally.

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