Materiały źródłowe

• #1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10619736/

  Chlamydia trachomatis is a strict intracellular human pathogen. It is the main bacterial cause of sexually transmitted infections and the etiologic agent of trachoma, which is the leading cause of preventable blindness. […] However in recent years, the advancement of genetic manipulation approaches for C. trachomatis has increased our understanding of the molecular pathogenesis of C. trachomatis and progress towards a vaccine. […] We highlight the factors known to be critical for developmental cycle stages, gene expression regulatory factors, type III secretion system and their effectors, and individual virulence factors with known impacts. […] The Chlamydia developmental cycle is characterised as biphasic, relying on specific interactions with the host cell for nutrients in order to survive and replicate due to the reduced chlamydial genome. There are two main morphological bacterial phases; the extracellular infectious elementary body (EB) and the intracellular, non-infectious, replicative reticulate body (RB). The infectious EBs are robust formations with spore-like structures that consist of disulphide cross-linked outer membrane protein complex on the surface. The development cycle of CT can be impacted by environmental factors and stresses. Known stressors include nutrient deprivation, exposure to host cytokines, and cell wall synthesis-targeting antibiotics. Under these conditions, RBs transition to altered morphological forms of non-culturable, non-dividing, aberrantly enlarged persistent forms, called aberrant bodies (ABs). These forms remain viable and can revert into an active infection once conditions are favourable.

• #2 Chlamydia Trachomatis Infections: Screening, Diagnosis, and Management | AAFP

  https://www.aafp.org/pubs/afp/issues/2012/1215/p1127.html

  Chlamydia trachomatis is a gram-negative bacterium that infects the columnar epithelium of the cervix, urethra, and rectum, as well as nongenital sites such as the lungs and eyes. […] The bacterium is the cause of the most frequently reported sexually transmitted disease in the United States, which is responsible for more than 1 million infections annually. […] Untreated infection can result in serious complications such as pelvic inflammatory disease, infertility, and ectopic pregnancy in women, and epididymitis and orchitis in men. […] Men and women can experience chlamydia-induced reactive arthritis. […] Chlamydia infections put women at an increased risk of developing pelvic inflammatory disease, infertility, or perihepatitis (Fitz-Hugh-Curtis syndrome). […] Infection during pregnancy increases the risk of poor outcomes for the fetus.

• #3 Better In Vitro Tools for Exploring Chlamydia trachomatis Pathogenesis

  https://www.mdpi.com/2075-1729/12/7/1065

  Chlamydia trachomatis is an obligate intracellular human pathogen responsible for a range of diseases of public health importance. Indeed, this pathogen is the leading cause of sexually transmitted bacterial infection worldwide, with more than 130 million new cases each year; the prevalence and incidence estimates are highest for both women and men in the Western Pacific Region, and rates peak in the region of the Americas, although the real prevalence of C. trachomatis genital infection remains unknown and probably underestimated, due to the high proportion of asymptomatic infections. […] Over the past decades, pathogenic mechanisms underlying C. trachomatis mediated complications have received significant research attention. Specifically, several in vitro cellular models, based on two-dimensional (2D) cultures of immortalized cells, have been employed for investigating C. trachomatis host–cell interaction, focusing on the characteristics of chlamydial developmental cycle and its intracellular survival strategies.

• #4 Chlamydia trachomatis – Wikipedia

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

  C. trachomatis exists in two forms, an extracellular infectious elementary body (EB) and an intracellular non-infectious reticulate body (RB). […] The EB attaches to host cells and enter the cell using effector proteins, where it transforms into the metabolically active RB. […] Inside the cell, RBs rapidly replicate before transitioning back to EBs, which are then released to infect new host cells. […] Once attached, the bacteria inject various effector proteins into the host cell using a type three secretion system. […] These effectors trigger the host cell to take up the elementary bodies and prevent the cell from triggering apoptosis. […] Within 6 to 8 hours after infection, the elementary bodies transition to reticulate bodies and a number of new effectors are synthesized.

• #5 Core Concepts – Chlamydial Infections – Self-Study Lessons – National STD Curriculum

  https://www.std.uw.edu/go/comprehensive-study/chlamydial-infections/core-concept/all

  Chlamydia trachomatis is an obligate intracellular bacterium with a cell wall and ribosomes similar to those of gram-negative organisms. The C. trachomatis cell wall is unique in that it contains an outer lipopolysaccharide membrane, but it lacks peptidoglycan; within the cell wall, cysteine-rich proteins act as the functional peptidoglycan equivalent. The absence of peptidoglycan explains why the organism is not seen with a standard Gram stain. Chlamydia trachomatis infects columnar epithelial cells at mucosal sites, often becoming a chronic infection that may last months or even longer than a year if untreated. Chlamydia trachomatis has a complex replicative cycle, typically requiring 48 to 72 hours to complete. The organisms replicate within a host cell, frequently causing eventual death of the host cell. The life cycle of C. trachomatis involves five key steps: The elementary body, a small, infectious, but nonreplicating particle found in secretions, attaches to and enters a host cell, such as an endocervical or urethral columnar epithelial cell. The contact with the host cell membrane causes the elementary body to induce its own endocytosis. Within 8 hours, the now-intracellular elementary body interacts with glycogen and transforms into a reticulate body, which begins to multiply within an isolated intracellular structure referred to as an inclusion. The reticulate bodies are the noninfectious replicating form. Within 48 hours, some reticulate bodies begin to reorganize back to elementary bodies. Within 72 hours, most of the reticulate bodies have transitioned back to elementary bodies, and the inclusion either undergoes lysis at the host cell wall or the intact inclusion (containing numerous elementary bodies) is released into the extracellular space, a process called extrusion. Regardless of whether the inclusion undergoes lysis or extrusion, the elementary bodies are released to infect adjacent cells or to be transmitted to and infect another person. Chlamydia trachomatis is highly transmissible via sexual contact. The overall rate of C. trachomatis transmission between sex partners is approximately 55%, with a per-act transmission of urogenital infection of about 10%. The transmission rate per sex act for rectal and oropharyngeal infection is unknown. Sexual transmission rates per sex act are thought to be slightly higher from men to women than from women to men, but given the number of asymptomatic carriers in the general population, estimates for rates of transmission remain imprecise. Transmission of C. trachomatis can also occur from mother to infant via the infants contact with the mothers genital tract during birth. Among mothers with untreated chlamydial infection, the rate of transmission to the neonate is estimated at 20-50%.

• #6 Chlamydia (Chlamydial Genitourinary Infections): Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/214823-overview

  Chlamydiae have a unique biphasic life cycle that is adaptable to both intracellular and extracellular environments. In the extracellular milieu, the so-called elementary body (EB) is found. EBs are metabolically inactive infectious particles; functionally, they are spore-type structures. Once inside a susceptible host cell, the EB prevents phagosome-lysozyme fusion and then undergoes reorganization to form a reticulate body (RB). […] The RB synthesizes its own DNA, RNA, and proteins but requires energy in the form of adenosine triphosphate (ATP) from the host cell. After a sufficient amount of RBs have formed, some transform back into EBs, exiting the cell to infect others.

• #7 Better In Vitro Tools for Exploring Chlamydia trachomatis Pathogenesis

  https://www.mdpi.com/2075-1729/12/7/1065

  Unlike most bacteria, C. trachomatis developmental cycle occurs entirely within a cell-derived membrane bound vesicle where it undergoes dramatic physiological and morphological changes, alternating between two functionally distinct forms: the elementary body (EB) and the reticulate body (RB). […] Soon after attachment to the host cell, EBs are internalized and confined to a parasitophorous vacuole termed inclusion, through a process requiring the secretion of Type III secretion system (T3SS) effector proteins, such as the translocated actin-recruiting phosphoprotein (TarP), the translocated early phosphoprotein (TepP) and inclusion membrane (Inc) proteins. […] A further survival strategy of C. trachomatis is the development of persistent forms. Indeed, under stressful conditions (e.g., antibiotic or IFN-γ treatment, iron deficiency, coinfection with HSV-2, etc.), C. trachomatis has been shown to stop its developmental cycle, generating persistent forms that remain inside the host cell for a long time due to their ability to evade the immune system, leading to a chronic inflammatory state responsible for the tissue damage.

• #8 Chlamydia Trachomatis | British Society for Immunology

  https://www.immunology.org/public-information/bitesized-immunology/pathogens-disease/chlamydia-trachomatis

  Chlamydia trachomatis (Ct) infection is the commonest bacterial sexually transmitted infection worldwide. […] Ct is a Gram-negative bacterium which exists in two forms: the infectious elementary body (EB) and the intracellular reticulate body (RB), which is able to replicate and multiply. Infection begins when EBs attach to the membrane of a cell of the inner layer (epithelium) of the urogenital tract. EBs enter the cell and two hours later are transformed into RBs which grow and divide over the next hours, resulting in a rapid increase in number. At this point RBs transform into EBs. Usually, 48–72 hours after infection, the host cell bursts to release the infectious EBs. […] Ct has a number of serovars which cause different types of pathology; A–C are responsible for ocular infections (trachoma) and are a major cause of blindness particularly in the developing world; D–K cause the common sexually transmitted infection and L1 and L2 cause the severe pathology of lymphogranuloma venereum.

• #9 Contribution of the Exit Mechanism Extrusion in Chlamydia trachomatis Pathogenesis

  https://escholarship.org/uc/item/4f22r0nb

  Chlamydia trachomatis is an obligate intracellular bacterium that is a public health burden worldwide. The precise strategies that intracellular pathogens use to exit host cells have a direct impact on their ability to disseminate within a host, transmit to new hosts, and manipulate immune responses. Chlamydia exits the host cell by two distinct strategies, lysis and extrusion. Lysis is a sequential rupture of vacuole, nuclear and plasma membranes, culminating in the release of free infectious bacteria. Extrusion is a packaged release of Chlamydia that begins with invagination of the chlamydial inclusion, followed by the pinching of the cell plasma membrane, resulting in a double membrane compartment containing Chlamydia, chlamydial inclusion, host cell cytoplasm, and host plasma membrane.

• #10

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10619736/

  As an obligate intracellular organism, virulence and pathogenic features interplay critically with host cellular factors and the host immune system which can also contribute to disease pathology. The intracellular nature and unusual bi-phasic developmental cycle has, until recently, hampered progress on biological investigations and genetic manipulation of Chlamydia. Recently, genetic methods have rapidly progressed and accordingly our understanding of pathogenic mechanisms has increased. […] A well-known pathogenic feature of C. trachomatis is the T3SS and their associated effector proteins. The T3SS is composed of a needle-like injectosome apparatus, which secretes effector proteins directly from the chlamydial cytoplasm into the host cell. Specific chlamydial chaperone 4 (Scc4; formerly CT663) precisely regulates T3SS function through gene expression and effector networks. There are 80 speculated anti-host T3SS-secreted effectors. The secreted effectors have a variety of functions, including; disrupting the cytoskeletal structure, evasion of host defences, and prevention of host cell apoptosis.

• #11 Male genital tract immune response against Chlamydia trachomatis infection in: Reproduction Volume 154 Issue 4 (2017)

  https://rep.bioscientifica.com/view/journals/rep/154/4/REP-16-0561.xml

  Chlamydia trachomatis is the most commonly reported agent of sexually transmitted bacterial infections worldwide. This pathogen frequently leads to persistent, long-term, subclinical infections, which in turn may cause severe pathology in susceptible hosts. This is in part due to the strategies that Chlamydia trachomatis uses to survive within epithelial cells and to evade the host immune response, such as subverting intracellular trafficking, interfering signaling pathways and preventing apoptosis. […] Understanding the molecular mechanisms developed by Chlamydia trachomatis to avoid killing and host immune response would be crucial for designing new therapeutic approaches and developing protective vaccines. […] CT has developed several molecular mechanisms to subvert or dampen the host immune response. Among them, CT prevents nuclear translocation of nuclear factor B (NFB) by the release of the chlamydial proteins ChlaDub1 and ChlaDub2 (deubiquitinating enzymes) that in turn interfere with inhibitor of NF-kB (IkB) ubiquitination.

• #12 The multiple functions of the numerous Chlamydia trachomatis secreted proteins: the tip of the iceberg

  http://microbialcell.com/researcharticles/2019a-bugalhao-microbial-cell/

  Chlamydial outer membrane proteins, such as the Pmps, outer membrane complex protein B (OmcB), MOMP, or C. trachomatis adhesin 1 (Ctad1) are important for the initial contact and adhesion of C. trachomatis with host cells, but they will not be further described here. […] The most prominent group of Chlamydia proteins mediating bacterial-host cell interaction are the inclusion membrane proteins (Incs). […] The lack of a cleavable Sec signal peptide on the first identified Incs and the discovery of homologues of T3S system genes in Chlamydia suggested that Incs could be T3S substrates. […] The interaction with host cell vesicular and non-vesicular transport pathways also enables C. trachomatis to acquire nutrients and lipids required for its growth. […] Completion of the developmental cycle and subversion of host cells processes by C. trachomatis involves the timely secretion of many chlamydial proteins.

• #13 Chlamydia trachomatis – Wikipedia

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

  These effectors include a number of proteins that modify the inclusion membrane (Inc proteins), as well as proteins that redirect host vesicles to the inclusion. […] 8 to 16 hours after infection, another set of effectors are synthesized, driving acquisition of nutrients from the host cell. […] If several elementary bodies have infected a single cell, their inclusions will fuse at this point to create a single large inclusion in the host cell. […] From 24 to 72 hours after infection, reticulate bodies transition to elementary bodies which are released either by lysis of the host cell or extrusion of the entire inclusion into the host genital tract. […] The chlamydial plasmid, a DNA molecule existing separately from the genome of C. trachomatis, functions to enhance genetic diversity via the genes encoded.

• #14 Chlamydia trachomatis- An Overview – Microbe Notes

  https://microbenotes.com/chlamydia-trachomatis/

  Chlamydia are acquired by direct contact with mucous membranes or abraded skin, that is, by sexual contact or by direct inoculation into the eye in the case of trachoma or neonatal conjunctivitis. […] Two forms of the organism are needed for infection and disease to occur: the infectious, extracellular form called an elementary body (EB) and the noninfectious but metabolically active intracellular form called a reticulate body (RB). […] Infection is initiated by attachment of EBs to the apical surfaces of epithelial cells of the conjunctiva, respiratory, gastrointestinal, or urogenital tracts, followed by entry by receptor-mediated endocytosis. […] The EBs quickly modify their early endosomal membrane to exit the endosomal pathway, thereby avoiding fusion with lysosomes and traffic on microtubules to the peri-Golgi/ nuclear hof region.

• #15 Male genital tract immune response against Chlamydia trachomatis infection in: Reproduction Volume 154 Issue 4 (2017)

  https://rep.bioscientifica.com/view/journals/rep/154/4/REP-16-0561.xml

  CT drives modifications in host vesicular transport by selective exclusion or retention of Rab GTPases (family of small Ras-like GTPases) on the chlamydial inclusion membrane. […] Current evidence indicates that CT acquires lipids not only by hijacking Golgi-derived exocytic vesicles or multivesicular bodies (MVBs). […] CT has the ability to recruit lipid droplets (LDs, neutral lipid rich organelles) by the interaction with chlamydial protein Lda3. […] The induction of indoleamine-2,3-dioxygenase 1 (IDO1) by this cytokine results in depletion of intracellular tryptophan, which in turn imposes nutritional stress to CT, given that these bacteria are tryptophan auxotrophs. […] In summary, current knowledge supports the concept that CT ensures its survival, development and replication by hijacking multiple vesicle pathways to seize host cells for its own benefit.

• #16 Recruitment of BAD by the Chlamydia trachomatis Vacuole Correlates with Host-Cell Survival | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.0020045

  Thus, the PI3K pathway plays a prominent role in protecting C. trachomatis-infected cells from apoptosis. […] The PI3K pathway leads to phosphorylation of AKT, which in C. trachomatis-infected cells remains phosphorylated even after treatment with STS. […] As 14-3-3 co-localizes with the chlamydial protein IncG on the surface of the inclusion, these results suggest that this IncG-14-3-3 interaction allows the inclusion to sequester BAD away from mitochondria, where it could stimulate release of cytochrome c.

• #17 Persistence in Chlamydia | IntechOpen

  https://www.intechopen.com/chapters/85386

  The ability of Chlamydiae to induce host-cell apoptosis under some circumstances and actively inhibit apoptosis to complete their obligate intracellular growth has been extensively studied for decades. […] Various mechanisms of interference with pro-apoptotic BCL-2 family proteins have been described in Chlamydia. […] Chlamydia trachomatis expresses distinct patterns of ncRNAs during normal development.

• #18

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10619736/

  The extracellular translocated actin-recruiting phosphoprotein (TarP, CT456) is required in the early developmental stages. TarP is Slc-1-dependent and involved in chlamydial internalisation, and invasion of host cell. TarP binds to the host cells major cytoskeletal component, actin. Phosphorylated TarP interacts with a multitude of host cell signalling molecules, as well as phosphatidylinositol 3-kinase (PI3K) and SHC-transforming protein 1 (SHC1), involved in diverse cell functions (e.g. growth, differentiation, motility, survival). […] The early translocator phosphoprotein, TepP, is the second Slc-1-dependent effector and one of the few T3SS effectors where null mutants have been characterised. TepP is secreted by the T3SS to enhance CT infectivity and dampen host immune activation. TepP is localised near the inclusion in the eukaryotic cells cytosol, where it is phosphorylated by the host kinases. It then targets host factors CRK, PI3K and GSK3B to locally synthesise phosphoinositide-(3,4,5)-triphosphate (PIP3) and modulate host cell signalling in nascent infections.

• #19

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10619736/

  The human CT urogenital serovars (D-K) encode a partial 73 kDa cytotoxin (CT166). This cytotoxin was found to contain a functional glycosyltransferase DXD domain and UDP-glucose binding domain with significant homology to the large cytotoxins (LCT) from Clostridioides difficile. The chlamydial cytotoxin is responsible for the cytopathic ballooning effects seen in infected host cells by glucosylating the Rho-GTPase protein, Rac1. This inactivates Rac1 leading to actin remodelling. […] Chlamydia retains a highly conserved ~7.5 kb virulence plasmid that was found to be significant in vivo. The plasmid encodes 8 glycoproteins (pGP1-8) that have a variety of functions including promoting infection ascension, inducing pro-inflammatory responses, and promoting extrusion processes. Virulence plasmid-deficient or pGP3-deficient strains resulted in attenuated infections.

• #20

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10619736/

  CTs pathogenesis is additionally mediated by various proteases and membrane proteins. HtrA (DegP) is a periplasmic serine protease with chaperone functions, including proteolysis of abnormal or misfolded proteins, and serves as a stress response protein that is upregulated in some persistence and stress models. Chlamydia Protease-like Activity Factor (CPAF) is a secreted protease that was initially thought to degrade dozens of host proteins involved in Golgi reorganisation, apoptosis, cytoskeleton remodelling and immune regulation. […] Genetic approaches to investigate CT are still time consuming and technically difficult. Genome wide genetic manipulation and screening approaches remain challenging. Therefore, selective approaches to genetic manipulation guided by current knowledge of virulence functions, homolog functions, etc. has been used to target loci for genetic manipulation. These genetic approaches in CT have already confirmed the role of several established virulence factors while also overturning or disputing other widely-held understandings in Chlamydia pathogenesis such as the role of the T3SS in secreting plasmid regulated chromosomally-encoded proteins and the role of CPAF.

• #21 Chlamydia trachomatis – Wikipedia

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

  The plasmid gene protein 3 (pgp3) has been linked to the establishment of persistent infection within the genital tract by suppressing the host immune response. […] Polymorphic outer membrane proteins (Pmp proteins) on the surface of C. trachomatis use tropism to bind specific host cell receptors, which in turn initiates infection. […] CPAF (Chlamydia Protease-like Activity Factor) functions by preventing the host from triggering the proper immune response. […] C. trachomatis use of CPAF targets and cleaves proteins that restructure the Golgi apparatus and activate DNA repair so that C. trachomatis is able to use the host cell machinery and proteins to its advantage.

• #22 Chlamydia (Chlamydial Genitourinary Infections): Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/214823-overview

  Chlamydia infects columnar epithelial cells, which places the adolescent female at particular risk because of the presence of the squamocolumnar junction on the ectocervix until early adulthood. […] The initial response of epithelial cells to infection is a neutrophilic infiltration, followed by lymphocytes, macrophages, plasma cells, and eosinophilic invasion. The release of cytokines and interferons by the infected epithelial cell initializes this inflammatory cascade. […] Infection with chlamydial organisms invokes a humoral cell response, resulting in secretory immunoglobulin A (IgA) and circulatory immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies and a cellular immune response. A 40-kd major outer membrane protein (MOMP) and 10- and 60-kd chlamydial heat-shock proteins (cHSPs) have been implicated in the immunopathologic response, but further studies are needed to provide a better understanding of these cell-mediated immune responses.

• #23 Chlamydia – Medical Microbiology – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK8091/

  Chlamydiae have a hemagglutinin that may facilitate attachment to cells. The cell-mediated immune response is largely responsible for tissue damage during inflammation, although an endotoxin-like toxin has been described. […] Chlamydial agents are intracytoplasmic obligate parasites of mammalian cells and can damage infected cells in tissues. The elementary bodies are infectious particles that can be transmitted from the infected tissues to uninfected tissues in the same person (transfer of C trachomatis elementary bodies from an infected genital tract to the eyes and vice versa) or from a person with atypical pneumonia (caused by C psittaci or C pneumoniae) to healthy individuals (respiratory release of elementary bodies). In the infected individuals the chlamydial agent causes tissue damage and induction of interleukin-1, interleukin-1, and tumor necrosis factor alpha, which are cytokines involved in the inflammation process. Ocular infections by C trachomatis and sometimes C pneumoniae strains cause acute purulent conjunctivitis either due to infection of the neonate during passage through the birth canal or due to subsequent infections leading to scarring of the conjunctiva and to blindness subsequent to mucopurulent follicular conjunctivitis. C trachomatis infection also spreads through sexual contact when urethritis or cervicitis is present. The genital tract infection serves as a source of infectious elementary bodies for the eyes.

• #24 Chlamydia trachomatis- An Overview – Microbe Notes

  https://microbenotes.com/chlamydia-trachomatis/

  The inclusion membrane may then fuse with the host plasma membrane to release chlamydiae, or the host cell, depleted of nutrients and energy, may lyse. […] Infection of epithelial mucosal cells with C. trachomatis has been shown to generate several cytokines, including interleukin-1 (IL-1), IL-6, IL-8, GRO- and granulocytemacrophage colony stimulating factor (GMCSF), which generate and sustain an inflammatory response. […] Infected epithelial cells and early infiltrating natural killer cells activate antigen presenting cells into programming the cell-mediated immune response. […] As the host immune response develops, active sites of infection show an infiltration of lymphocytes, plasma cells, and macrophages. […] IFNs, in particular IFN-, play an important part in the immune response to chlamydial infection by inhibiting intracellular replication at the RB stage through tryptophan depletion.

• #25 Immunology of Chlamydia infection: implications for a Chlamydia trachomatis vaccine | Nature Reviews Immunology

  https://www.nature.com/articles/nri1551

  Sexually transmitted diseases caused by Chlamydia trachomatis are an important public-health concern worldwide. Infection causes pelvic inflammatory disease (PID), fallopian-tube scarring and sequelae that include infertility and ectopic pregnancy. […] The upper compartment of the female genital tract strongly responds to infection with Chlamydia spp. Infected epithelial and immune cells in this compartment secrete pro-inflammatory cytokines, which trigger immune effector functions that clear infection but can damage tissue. […] Persistent forms of C. trachomatis that are generated in response to low concentrations of IFN- are metabolically active and seem to promote continuous secretion of pro-inflammatory cytokines, a condition that might contribute to tissue scarring. […] These authors show that chlamydial infection of cervical epithelium upregulates the expression of several pro-inflammatory cytokines, including CXCL1, CXCL8, GM-CSF, IL-1 and IL-6. Induction of these mediators was shown to persist throughout the chlamydial life cycle, indicating that they might be involved in disease exacerbation.

• #26 Chlamydia Trachomatis | British Society for Immunology

  https://www.immunology.org/public-information/bitesized-immunology/pathogens-disease/chlamydia-trachomatis

  In women infection can have devastating and long-term effects on reproductive health. Ct has been associated with urethritis, pelvic inflammatory disease, scarring in the pelvis (such as adhesions), and fertility complications including ectopic pregnancy, infertility, miscarriage and premature rupture of membranes. […] Ct infection usually occurs in the lower genital tract and attracts different types of immune cells such as lymphocytes, macrophages and dendritic cells to infiltrate the epithelium. At the site of infection there is a strong inflammatory reaction mediated mainly by CD4+ T cells with a Th1 phenotype to clear the infection. These cells produce interferon-γ (IFN-γ) which is known to inhibit chlamydial reproduction. However, there is evidence that the concentration of IFN-γ is critical to the outcome of infection; high levels of IFN-γ are associated with the clearance of the infection whilst low levels can allow the bacteria to persist without replicating. Ct infection can persist for several years and reinfection is common. It has been shown that reinfection can result in a strong secondary immune response and the increased inflammation may cause further damage to the reproductive tract. […] If the infection spreads higher up the tract to the uterus and Fallopian tubes, the risk of ectopic pregnancy and infertility due to tubal damage is high. It remains unclear how much damage is caused by Ct and how much by the host immune response.

• #27 Chlamydia trachomatis- An Overview – Microbe Notes

  https://microbenotes.com/chlamydia-trachomatis/

  However, this may result in continuing secretions of chlamydial antigens, leading to further sensitization and also induction of persistent non-replicating infection. […] Resistance to infection and clearance of primary infection are due in large part to T-cell function, with both CD4 and CD8 cells having a protective role. […] A chlamydial heat-shock protein (hsp 60), elicits antibody responses that are associated with the damaging sequelae of C. trachomatis infections in both the eye and genital tract. […] A period of chronic inflammation ensues, with the development of sub-epithelial follicles, and this leads eventually, in some cases, to fibrosis and scarring. […] The inflammatory infiltrate between follicles comprises plasma cells, dendritic cells, macrophages, and polymorphonuclear leucocytes, with T and B lymphocytes.

• #28 Persistence in Chlamydia | IntechOpen

  https://www.intechopen.com/chapters/85386

  Aberrant bodies are capable of remaining viable within the inclusion vacuole for extended period of time. […] Chlamydia employs several mechanisms to interfere with the host innate immune response to persist within the host cell. […] The NFB pathway may be modulated by several different Chlamydial proteins and mechanisms, all of which can interfere with NFB-mediated gene transcription and regulation. […] Various mechanisms of IFN–induced persistence have been proposed. IFN- activates the catabolic depletion of L-tryptophan (Trp) via indoleamine-2,3-dioxygenase (IDO), the enzyme that degrades tryptophan. […] During the persistent state, Chlamydiae can activate pro-survival pathways and inhibit apoptosis to ensure long-term survival inside the cells. […] Chlamydia must protect the host cell from succumbing to stress-induced death before the Chlamydial developmental cycle is complete.

• #29

  https://www.jci.org/articles/view/18770

  Tissue tropism of clinical ocular and genital Chlamydia trachomatis strains is shown to be linked to the tryptophan synthase genotype. It is suggested that, in the presence of IFN-, which depletes available tryptophan, there exist unique host-parasite interactions that may contribute to persistent chlamydial infection. […] A particularly intriguing hypothesis put forth by the authors is that tryptophan synthase genes function as chlamydial virulence factors and may be involved in the maintenance of persistent/chronic chlamydial infection. […] Caldwell et al. propose a mechanism by which genital chlamydial strains may counter the growth inhibitory effects of IFN- by utilizing indole produced by vaginal microbial flora as a substrate for tryptophan synthesis, thus allowing for the continued survival of chlamydiae within a growth-inhibiting environment.

• #30

  https://www.jci.org/articles/view/18770

  Depletion of tryptophan either results in chlamydiae cell death or causes chlamydiae to adopt a noninfectious, nonreplicating form that retains viability (persistence). […] Persistent forms of chlamydiae can redifferentiate into infectious EBs upon removal of IFN- and subsequent replenishing of intracellular tryptophan pools. […] This model is far from complete, and the biological processes involved are likely much more complex and interrelated than depicted here. […] The resistance pattern of the various chlamydial strains to the inhibitory effects of IFN- correlates to polymorphisms in tryptophan synthase genes. […] If persistent or chronic infections are established, then those infections may serve as a reservoir for new infections, contribute to the immunopathological consequences of infection, or require alternative therapeutic approaches.

• #31 Persistence in Chlamydia | IntechOpen

  https://www.intechopen.com/chapters/85386

  Chlamydia spp. are important causes of acute and persistent/chronic infections. All Chlamydia spp. display a unique biphasic developmental cycle alternating between an infectious elementary body (EB) and a replicative form, the reticulate body (RB), followed by the multiplication of RBs by binary fission and progressive differentiation back into EBs. […] During its intracellular life, Chlamydia employs multiple mechanisms to ensure its persistence inside the host. These include evasion of diverse innate immune responses, modulation of host cell structure and endocytosis, inhibition of apoptosis, activation of pro-signaling pathways, and conversion to enlarged, non-replicative but viable aberrant bodies (ABs). […] Chlamydial persistence in vitro is characterized by the presence of a viable but non-cultivable growth stage resulting in a long-term relationship with the infected cell.

• #32 Current Understanding and Gaps in Knowledge of Chlamydia trachomatis Infection

  https://www.scientificarchives.com/article/current-understanding-and-gaps-in-knowledge-of-chlamydia-trachomatis-infection

  The deprivation of tryptophan and cysteine, essential amino acids for the expression of late expression proteins such as MOMP and proteins rich in cysteines that cause the cessation of the division of the reticular bodies as well as dedifferentiation of them in elementary bodies, in other words the persistence of C. trachomatis is a consequence of undifferentiated intracellular particles. […] The resolution of the primary infection, that centered on CD4+Th1 lymphocytes, corresponds to the cellular response. […] There are many aspects to be revealed in terms of pathogenesis, biology of the microbial agent, and treatment, hence the need to generate new knowledge in this regard and to present thematic consolidations as was done in this article.

• #33 Persistence in Chlamydia | IntechOpen

  https://www.intechopen.com/chapters/85386

  Persistence is an important cause of recurrent Chlamydial disease characterized by chronic inflammation and tissue damage in epithelial cells. […] The inclusion represents the ideal protected niche that ensures Chlamydia its survival by evading the endolysosomal pathway and the innate immune responses of the cell and favoring its growth by modulating host cell processes. […] The activity of some of these Incs proteins is important to ensure the Chlamydia long-term survival through the acquisition of nutrients, avoidance of fusion of the inclusion with lysosomes, stability of the inclusion membrane, and modulation of host cell death. […] Under non-bacteriocidal stress conditions, Chlamydia responds by markedly arresting RB division and differentiates into an atypical morphology referred to as aberrant body (AB).

• #34

  https://www.jci.org/articles/view/18770

  Caldwell et al. discuss quite eloquently how genital strains of chlamydiae could utilize indole produced by vaginal microbes to survive in an IFN-rich, tryptophan-limiting environment and how survival under such conditions might facilitate the development of chronic infections. […] Investigating the interplay between chlamydiae and its environment will impart a more thorough understanding of host-microbial interactions and may provide important insight into novel approaches for the treatment and prevention of chlamydial disease.

• #35 Altering the redox status of Chlamydia trachomatis directly impacts its developmental cycle progression

  https://elifesciences.org/reviewed-preprints/98409

  In this valuable study, the authors propose a model wherein the bacterial redox state plays a crucial role in the differentiation of Chlamydia trachomatis into elementary and reticulate bodies. They provide solid evidence to argue that a highly oxidising environment favours the formation of elementary bodies while a reducing condition slows down development. Overall, the study convincingly demonstrates that Chlamydial redox states play a role in differentiation, an observation that may have implications for the study of other bacterial systems. […] Chlamydia trachomatis is an obligate intracellular bacterial pathogen with a unique developmental cycle. It differentiates between two functional and morphological forms: elementary body (EB) and reticulate body (RB). The signals that trigger differentiation from one form to the other are unknown. EBs and RBs have distinctive characteristics that distinguish them, including their size, infectivity, proteome, and transcriptome. Intriguingly, they also differ in their overall redox status as EBs are oxidized and RBs are reduced. We hypothesize that alterations in redox may serve as a trigger for secondary differentiation.

• #36 Cyclic di-AMP drives developmental cycle progression in Chlamydia trachomatis

  https://elifesciences.org/reviewed-preprints/104240

  In this valuable study, ectopic expression and knockdown strategies were used to assess the effects of increasing and decreasing Cyclic di-AMP on the developmental cycle in Chlamydia. The authors convincingly demonstrate that overexpression of the dacA-ybbR operon results in increased production of c-di-AMP and early expression of the transitionary gene hctA and late gene omcB. […] Here, we present evidence cyclic di-AMP (c-di-AMP) is a key factor in triggering the transition from RB to EB (i.e., secondary differentiation) in the chlamydial developmental cycle. […] Based on these data, we conclude there is a threshold level of c-di-AMP needed to trigger secondary differentiation in Chlamydia. This is the first study to identify a mechanism by which secondary differentiation is initiated in Chlamydia and reveals a critical role for the second messenger signaling molecule c-di-AMP in this process.

• #37 Altering the redox status of Chlamydia trachomatis directly impacts its developmental cycle progression

  https://elifesciences.org/reviewed-preprints/98409

  Together, these results indicate that redox potential is a critical factor in developmental cycle progression. For the first time, our study provides a mechanism of chlamydial secondary differentiation dependent on redox status. […] Based on the difference between redox status of EBs and RBs, we hypothesized that changing redox conditions is a critical factor in the process of differentiation from one form to the other. We named this the redox threshold hypothesis. In this scenario, as soon as a given RB has crossed an oxidative threshold, the activity of critical proteins is modified to trigger differentiation to the EB. […] This study establishes the role of AhpC as an antioxidant in Chlamydia, as demonstrated by its ability to counteract different peroxide stresses when overexpressed. Overexpression of AhpC had no negative effect on bacterial replication but delayed the differentiation of RBs to EBs. In contrast, under conditions of ahpC knockdown, the organism was highly sensitive to oxidizing conditions.

• #38 Altering the redox status of Chlamydia trachomatis directly impacts its developmental cycle progression

  https://elifesciences.org/reviewed-preprints/98409

  These data provide mechanistic insight into chlamydial secondary differentiation and are the first to demonstrate redox-regulated differentiation in Chlamydia. […] We detected earlier expression of EB-related genes during ahpC knockdown and were curious if the ahpC knockdown condition could activate these genes under conditions when the chlamydial developmental cycle is blocked. […] Collectively, these data show that post-translational mechanisms drive secondary differentiation in Chlamydia. However, no definitive switch that triggers this step has been identified. […] We propose a simple model to explain this. As secondary differentiation is asynchronous and RBs divide through an asymmetric budding mechanism, AhpC as well as proteins impacted by ROS levels are unevenly distributed between mother and daughter cell. This difference will lead some RBs to breach an oxidative threshold sooner, allowing activation of late genes and secondary differentiation earlier than other RBs. […] These data support our hypothesis that the developmental cycle is delayed in these conditions with a concomitant delay in achieving the oxidative threshold, thus allowing RBs to continue to divide before committing to secondary differentiation.

• #39 Cyclic di-AMP drives developmental cycle progression in Chlamydia trachomatis

  https://elifesciences.org/reviewed-preprints/104240

  Given the differences in c-di-AMP levels between EBs and RBs and its function as a diffusible second messenger signaling molecule, we hypothesized that the accumulation of c-di-AMP during the developmental cycle might be a trigger for secondary differentiation in Chlamydia. […] Our data show that higher levels of c-di-AMP are directly linked to increased transcript levels of late genes associated with secondary differentiation as well as the concomitant production of EBs at an earlier stage in the developmental cycle. […] Based on these data, we conclude that there is a threshold level of c-di-AMP necessary to trigger secondary differentiation in C. trachomatis. This is the first study to identify a physiological function for c-di-AMP in Chlamydia as well as a mechanism by which secondary differentiation is initiated in these unique bacteria. […] We conclude that low levels of c-di-AMP are detrimental for secondary differentiation. […] These data support the conclusion that reducing the levels of c-di-AMP delays developmental cycle progression. […] Our data are clear in linking c-di-AMP levels to chlamydial developmental progression.

• #40 Chlamydia trachomatis suppresses host cell store-operated Ca2+ entry and inhibits NFAT/calcineurin signaling | bioRxiv

  https://www.biorxiv.org/content/10.1101/2022.03.15.484523v1.full-text

  The obligate intracellular bacterium, Chlamydia trachomatis, replicates within a parasitophorous vacuole termed an inclusion. […] We find that the SOCE-dependent NFAT/calcineurin signaling pathway is impaired in C. trachomatis L2 infected HeLa cells and likely has major implications on host cell physiology as it relates to C. trachomatis pathogenesis. […] Therefore, we investigated if chlamydial development disrupts host cell Ca2+ homeostasis. Here we provide evidence that SOCE is impaired by the midpoint of the chlamydial developmental cycle and the SOCE-dependent NFAT/calcineurin signaling pathway is concurrently abrogated. […] The impairment of NFAT1 nuclear translocation demonstrate a specific signaling pathway that is affected by suppressing SOCE in C. trachomatis infected cells and likely has a multifaceted impact on host cell physiology and chlamydial pathogenesis.

• #41 Chlamydia trachomatis suppresses host cell store-operated Ca2+ entry and inhibits NFAT/calcineurin signaling | bioRxiv

  https://www.biorxiv.org/content/10.1101/2022.03.15.484523v1.full-text

  Our current working model for C. trachomatis impaired SOCE hypothesizes that the sequestering of the STIM1 CAD domain at the inclusion membrane microdomain prevents STIM1 from interacting with Orai1 to induce SOCE. C. trachomatis suppression of SOCE prevents the SOCE-dependent activation of calcineurin/NFAT signaling of the host cell and likely other SOCE-dependent pathways.

• #42 Current Understanding and Gaps in Knowledge of Chlamydia trachomatis Infection

  https://www.scientificarchives.com/article/current-understanding-and-gaps-in-knowledge-of-chlamydia-trachomatis-infection

  Chlamydia trachomatis is a bacterial infection that most frequently causes sexually transmitted infection in the world, therefore, it is considered a serious public health problem. […] The pathogenic mechanisms involved in them are studied intensely and continuously the genesis of the aforementioned complications. […] Several strategies have been proposed through which C. trachomatis leads to chronic infection, among them: asymptomatic infections by remaining silent that favor bacterial progression towards the most internal tissues. […] The accumulation of heat shock proteins (hsp60) as a consequence of multiple reinfections by C. trachomatis, a protein with a high proportion of identity with the human protein, therefore autoimmunity can occur when human tolerance to its own hsp60 is broken.

• #43 Chlamydia trachomatis- An Overview – Microbe Notes

  https://microbenotes.com/chlamydia-trachomatis/

  The scarring process is responsible for much of the morbidity associated with C. trachomatis, in both the genital tract and the eye. […] Studies of gene expression at the site of ocular infection have shown the importance of innate immune pathways and NK (natural killer) cell activation, and suggest that matrix metalloproteinases 7 and 9 play an important role in the scarring process. […] Polymorphisms in immune response genes encoding tumour necrosis factor-, interferon- and interleukin-10 are associated with the development of severe scarring following ocular C. trachomatis infection. […] Fibrosis is seen at a late stage, typically in trachoma and pelvic inflammatory disease.

• #44 Chlamydiae as Pathogens: New Species and New Issues – Volume 2, Number 4—October 1996 – Emerging Infectious Diseases journal – CDC

  https://wwwnc.cdc.gov/eid/article/2/4/96-0406_article

  In particular, the A*6802 allele was overrepresented among case-patients. It may be that immunopathology is associated with HLA-A*6802 restricted cytotoxic T-lymphocyte responses. […] The association between antibody response to CHSP60 and PID, ectopic pregnancy, tubal infertility, and trachoma has been documented. […] At present, it remains unclear whether antibody to CHSP60 is causally involved in chlamydial immunopathogenesis or is merely a marker of persistent chlamydial infection.

• #45 Chlamydia Trachomatis Infections: Screening, Diagnosis, and Management | AAFP

  https://www.aafp.org/pubs/afp/issues/2012/1215/p1127.html

  In men, consequences may include epididymoorchitis, resulting in infertility. […] A chlamydia infection may also increase a person’s susceptibility to HIV, if exposed. […] Reactive arthritis (Reiter syndrome), a triad of aseptic arthritis, nongonococcal urethritis, and conjunctivitis, can also occur. […] Chlamydia-induced reactive arthritis is believed to be underdiagnosed, and emerging data suggest that asymptomatic chlamydia infections may be a common cause. […] Another sexually transmitted infection caused by C. trachomatis (a different serovar) is lymphogranuloma venereum (LGV). […] Diagnosis is based on clinical symptoms and a genital lesion swab or lymph node sample, similar to those used to diagnose the more typical C. trachomatis genitourinary infection. […] Molecular identification may be needed to differentiate LGV from non-LGV C. trachomatis.

• #46 Immunology of Chlamydia infection: implications for a Chlamydia trachomatis vaccine | Nature Reviews Immunology

  https://www.nature.com/articles/nri1551

  These authors found that fallopian-tube tissues that are repeatedly infected with C. trachomatis are infiltrated with CD8+ T cells. Furthermore, deposition of fibrotic tissue occurred, as well as production of IFN-, IL-2, IL-6 and IL-10 (but not IL-4), indicating that all of these events might contribute to scarring of the upper genital tract.

• #47 Chlamydia cell biology and pathogenesis | Nature Reviews Microbiology

  https://www.nature.com/articles/nrmicro.2016.30

  In this Review, we summarize the progress in decoding the interactions between Chlamydia spp. and their hosts that has been made possible by recent technological advances in chlamydial proteomics and genetics. The field is now poised to decipher the molecular mechanisms that underlie the intimate interactions between Chlamydia spp. and their hosts, which will open up many exciting avenues of research for these medically important pathogens. […] This study provides the first genetic validation of the role of a C. trachomatis T3SS effector and reveals a hierarchical order in bacterial effector translocation into host cells by differential binding to shared chaperones. […] This study describes the quantitative analysis of the host-cell-derived proteome of inclusions isolated from C. trachomatis and demonstrates that retromer-associated sorting nexins and other components of host cell trafficking are enriched at the inclusion.

• #48 Better In Vitro Tools for Exploring Chlamydia trachomatis Pathogenesis

  https://www.mdpi.com/2075-1729/12/7/1065

  Recently, clinically relevant advances in the knowledge of the pathogenetic mechanisms associated to C. trachomatis genital infection have been provided by in vitro 2D cell-culture models based on primary human cells. […] Three-dimensional (3D) cell-culture models based on primary cells are acquiring great importance as a new and robust platform for studying complex biological processes and might be a promising alternative in C. trachomatis pathogenetic studies. […] Notwithstanding the different 3D cell-culture models, to date, few of them have been utilized in chlamydial research. Amongst them, recent C. trachomatis studies have explored human organoids, produced by embedding primary cell cultures into Matrigel-based scaffold, an animal-derived extra-cellular matrix widely used for organoid cultures.

• #49 Researchers Discover Molecule That Can Kill Chlamydia Without Harming Healthy Bacteria – INDIA New England News

  https://indianewengland.com/researchers-discover-molecule-that-can-kill-chlamydia-without-harming-healthy-bacteria/

  In a significant breakthrough, an international team of scientists has identified a molecule capable of selectively killing Chlamydia trachomatis, the bacterium responsible for the world’s most common bacterial sexually transmitted infection, while leaving beneficial bacteria unharmed. […] The bacterium operates much like a virus, invading human cells and transforming them into safe havens where it can replicate. […] Using large-scale chemical screening methods, the researchers examined thousands of molecules to pinpoint those capable of stopping Chlamydia trachomatis in laboratory-grown human cells. The most promising candidate was found to inhibit the bacterium’s ability to produce fatty acids, a key process for its survival and replication. […] While chlamydia often causes mild or no symptoms, untreated infections can lead to severe complications, particularly in women. Long-term consequences include chronic pelvic pain, infertility, and increased risk of ectopic pregnancy. Research also suggests a possible link between chronic chlamydia infections and cancers of the cervix and ovaries.

• #50 Contribution of the Exit Mechanism Extrusion in Chlamydia trachomatis Pathogenesis

  https://escholarship.org/uc/item/4f22r0nb

  Host cytokinesis proteins are required for the pinching of the chlamydial inclusion just prior to extrusion, but deeper mechanistic understanding of the host requirements that govern the final severing of the extrusion from the host cell have yet to be elucidated. […] Here, we define a role for host abscission proteins in the release of extrusion from the host cell. […] The defining characteristics of extrusions, and advantages gained by Chlamydia within this unique double-membrane structure are not well understood. Results presented here define extrusions as mostly devoid of host organelles, and containing phosphatidylserine on the outer surface of the extrusion membrane. Results further demonstrate that extrusion is highly conserved across Chlamydiae. Extrusions also served as transient, intracellular-like niches for enhanced Chlamydia survival outside the host cell. In addition to enhanced extracellular survival, extrusions are phagocytosed by primary bone marrow-derived macrophages, after which they provide a protective microenvironment for Chlamydia. Extrusion-derived Chlamydia staved off macrophage-based killing, and culminated in the release of infectious EB. Based on these findings, we propose a model in which extrusions serve as trojan horses for Chlamydia, by exploiting macrophages as vehicles for dissemination, immune evasion, and potentially transmission.

• #51 The multiple functions of the numerous Chlamydia trachomatis secreted proteins: the tip of the iceberg

  http://microbialcell.com/researcharticles/2019a-bugalhao-microbial-cell/

  Chlamydia trachomatis interferes with a wide range of host cell processes during its developmental cycle. […] Subversion of host receptor-mediated signalling and of the actin cytoskeleton and its key regulators promotes chlamydial adherence and invasion of host cells. […] The interaction with host cell vesicular and non-vesicular transport pathways also enables C. trachomatis to acquire nutrients and lipids required for its growth. […] In addition, among other aspects, intravacuolar C. trachomatis modulates host cell survival and death and the innate immune signalling. […] Finally, to exit from the host cell, C. trachomatis subverts the host cell cytoskeleton and calcium-signalling.

• #52 OPUS at UTS: Molecular pathogenesis of Chlamydia trachomatis – Open Publications of UTS Scholars

  https://opus.lib.uts.edu.au/handle/10453/172846

  Chlamydia trachomatis is a strict intracellular human pathogen. It is the main bacterial cause of sexually transmitted infections and the etiologic agent of trachoma, which is the leading cause of preventable blindness. […] However in recent years, the advancement of genetic manipulation approaches for C. trachomatis has increased our understanding of the molecular pathogenesis of C. trachomatis and progress towards a vaccine. […] In this mini-review, we aimed to outline the factors related to the developmental cycle phase and specific pathogenesis activity of C. trachomatis in order to focus priorities for future genetic approaches. […] We highlight the factors known to be critical for developmental cycle stages, gene expression regulatory factors, type III secretion system and their effectors, and individual virulence factors with known impacts.

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