Materiały źródłowe

• #1 Anthrax Pathogenesis – PubMed

  https://pubmed.ncbi.nlm.nih.gov/26195305/

  Anthrax is caused by the spore-forming, gram-positive bacterium Bacillus anthracis. The bacterium’s major virulence factors are (a) the anthrax toxins and (b) an antiphagocytic polyglutamic capsule. These are encoded by two large plasmids, the former by pXO1 and the latter by pXO2. The expression of both is controlled by the bicarbonate-responsive transcriptional regulator, AtxA. The anthrax toxins are three polypeptides-protective antigen (PA), lethal factor (LF), and edema factor (EF)-that come together in binary combinations to form lethal toxin and edema toxin. PA binds to cellular receptors to translocate LF (a protease) and EF (an adenylate cyclase) into cells. The toxins alter cell signaling pathways in the host to interfere with innate immune responses in early stages of infection and to induce vascular collapse at late stages. This review focuses on the role of anthrax toxins in pathogenesis. […] Other virulence determinants, as well as vaccines and therapeutics, are briefly discussed.

• #1 Anthrax toxin – Wikipedia

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

  Anthrax toxin is a three-protein exotoxin secreted by virulent strains of the bacterium, Bacillus anthracis, the causative agent of anthrax. […] Anthrax toxin is composed of a cell-binding protein, known as protective antigen (PA), and two enzyme components, called edema factor (EF) and lethal factor (LF). […] Assembled complexes containing the toxin components are endocytosed. In the endosome, the enzymatic components of the toxin translocate into the cytoplasm of a target cell. Once in the cytosol, the enzymatic components of the toxin disrupt various immune cell functions, namely cellular signaling and cell migration. […] The toxin may even induce cell lysis, as is observed for macrophage cells. […] Anthrax toxin allows the bacteria to evade the immune system, proliferate, and ultimately kill the host animal.

• #1 Anthrax – Wikipedia

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

  The lethality of the anthrax disease is due to the bacterium’s two principal virulence factors: the poly-D-glutamic acid capsule, which protects the bacterium from phagocytosis by host neutrophils; and the tripartite protein toxin, called anthrax toxin, consisting of protective antigen (PA), edema factor (EF), and lethal factor (LF). PA plus LF produces lethal toxin, and PA plus EF produces edema toxin. These toxins cause death and tissue swelling (edema), respectively. To enter the cells, the edema and lethal factors use another protein produced by B. anthracis called protective antigen, which binds to two surface receptors on the host cell. A cell protease then cleaves PA into two fragments: PA20 and PA63. PA20 dissociates into the extracellular medium, playing no further role in the toxic cycle. PA63 then oligomerizes with six other PA63 fragments forming a heptameric ring-shaped structure named a prepore. Once in this shape, the complex can competitively bind up to three EFs or LFs, forming a resistant complex. Receptor-mediated endocytosis occurs next, providing the newly formed toxic complex access to the interior of the host cell. The acidified environment within the endosome triggers the heptamer to release the LF and/or EF into the cytosol. It is unknown how exactly the complex results in the death of the cell.

• #1 Anthrax: Transmission, Pathogenesis, Prevention and Treatment

  https://www.mdpi.com/2072-6651/17/2/56

  The lethal toxin consists of PA protein and an enzymatic moiety, LF, whereas edema toxin contains PA protein and the EF enzymatic moiety. […] The intrinsic activity of native LF involves inactivation of mitogen-activated protein kinase kinases (MEKs), which shuts down the RAS-RAF-MEK-ERK (Rat Sarcoma—Rapidly Accelerated Fibrosarcoma—Mitogen-Activated Protein Kinase Kinase—Extracellular Signal-Regulated Kinase) signalling pathway. […] In the beginning of infection, anthrax toxin complex (LT and ET) weakens the immune system, which helps in the establishment of the disease. In later stages, toxins, together with bacterial infection, cause death by targeting the liver and other vital organs of the host. […] Protein phosphorylation plays a pivotal role in regulating bacterial pathogenesis, a concept that traces its origins to the groundbreaking discovery by Edmond Fischer and Edwin Krebs in 1955.

• #1 Anthrax – Wikipedia

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

  Edema factor is a calmodulin-dependent adenylate cyclase. Adenylate cyclase catalyzes the conversion of ATP into cyclic AMP (cAMP) and pyrophosphate. The complexation of adenylate cyclase with calmodulin removes calmodulin from stimulating calcium-triggered signaling, thus inhibiting the immune response. To be specific, LF inactivates neutrophils (a type of phagocytic cell) by the process just described so they cannot phagocytose bacteria. Throughout history, lethal factor was presumed to cause macrophages to make TNF-alpha and interleukin 1 beta (IL1B). TNF-alpha is a cytokine whose primary role is to regulate immune cells, as well as to induce inflammation and apoptosis or programmed cell death. Interleukin 1 beta is another cytokine that also regulates inflammation and apoptosis. The overproduction of TNF-alpha and IL1B ultimately leads to septic shock and death. However, recent evidence indicates anthrax also targets endothelial cells that line serious cavities such as the pericardial cavity, pleural cavity, and peritoneal cavity, lymph vessels, and blood vessels, causing vascular leakage of fluid and cells, and ultimately hypovolemic shock and septic shock.

• #1 Anthrax toxin – Wikipedia

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

  EF acts as a Ca2+ and calmodulin dependent adenylate cyclase that greatly increases the level of cAMP in the cell. […] LF also helps the bacteria evade the immune system through killing macrophages. […] Thus, the synergistic effect of these three proteins leads to cellular death through a cascade of events that allow the proteins to enter the cell and disrupt cellular function. […] The mechanism of anthrax toxin action is the result of the molecular structures of the three toxin proteins in combination with biomolecules of the host cell. […] The formation of the -barrel pore is facilitated with a drop in pH. […] PA is endocytosed as a soluble heptamer attached to its receptors, with LF or EF attached to the heptamer as cargo. […] The first step after endocytosis is the acidification of the endocytotic vesicle.

• #1 The pathogenesis of Bacillus anthracis – microbewiki

  https://microbewiki.kenyon.edu/index.php/The_pathogenesis_of_Bacillus_anthracis

  The edema factor is a cyclase that causes an imbalance of water homeostasis. […] The lethal factor is a metalloprotease that cleaves major pathways to surface receptors for the transcription of certain genes within the nucleus [12] while the capsule enhances the virulence by inhibiting the phagocytosis ofBacillus anthracis.

• #1 Understanding anthrax virulence | Nature Reviews Microbiology

  https://www.nature.com/articles/nrmicro1106

  The virulence of B. anthracis has been ascribed to the production of two secreted toxins as well as the presence of the DPGA capsule. […] B. anthracis strains that lack pXO2 show reduced virulence compared with wild-type bacteria. […] The virulence and the dissemination potential of these capsule-defective strains were compared with that of the virulent parent strain UT500, using a mouse inhalation model of anthrax. […] Although large numbers of UT500 bacteria disseminated from the lung to the spleen of infected mice and caused both pulmonary damage and necrotizing splenitis, the capBCAD mutant and the acpA acpB double mutant were completely attenuated. […] Neither of these capsule-deficient strains caused systemic disease. […] Furthermore, vegetative cells of the capBCAD mutant and acpA acpB double mutant were not visualized in the lungs of mice post-infection and 16S rRNA transcripts were also not detected, indicating a lack of replication with possible clearance of the non-encapsulated mutants from pulmonary tissue.

• #1 Anthrax – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK507773/

  The pathogenesis of anthrax follows the route of infection with three primary forms in humans: cutaneous, GI, and inhalational. […] Inhalational anthrax leads to accumulation of B. anthracis spores within the lung alveoli. The spores are engulfed by immune cells (macrophages, neutrophils, dendritic cells) and transported to regional lymph nodes where the bacteria germinate, multiply, and begin toxin production. This results in systemic clinical illness, and pathologically to toxin-induced cell damage and cell death. As the disease progresses, bloodstream infection occurs leading to septic shock. Patients can present suddenly and may deteriorate rapidly. […] Cutaneous anthrax results from inoculation of B. anthracis spores through the abraded skin into subcutaneous tissues. The bacteria subsequently germinate and multiply locally and begin toxin production. This leads to the characteristic edema and cutaneous ulceration.

• #1 Convergent evolution of diverse Bacillus anthracis outbreak strains toward altered surface oligosaccharides that modulate anthrax pathogenesis | PLOS Biology

  https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001052

  The evidence is mounting that dendritic cell-mediated spore transport to local lymph nodes, during which they are triggered to germinate and begin vegetative cell growth, is an important mechanism of anthrax pathogenesis. […] The spore surface, or exosporium, is coated with the glycoprotein BclA. […] Anthrose is a unique monosaccharide rarely found in nature. […] The biosynthetic operon is well characterized, and the genes essential for anthrose production have been identified. […] The uniqueness and antigenicity of anthrose identify it as a potential serodiagnostic target. […] Evidence suggests that anthrose is a major Sterne live spore vaccine epitope and is currently being developed as a glycoconjugate vaccine. […] The larger picture emerging is representative of several lineages of B. anthracis, via multiple genetic mechanisms, undergoing convergent evolution toward anthrose deficiency.

• #1 Anthrax – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/gram-positive-bacilli/anthrax

  Anthrax is caused by the gram-positive Bacillus anthracis, which are toxin-producing, encapsulated, facultative anaerobic organisms. […] Spores germinate and begin multiplying rapidly when they enter an environment rich in amino acids and glucose (eg, tissue, blood). […] After entering the body, spores germinate inside macrophages, which migrate to regional lymph nodes where the bacteria multiply. In inhalation anthrax, spores are deposited in alveolar spaces, where they are ingested by macrophages, which migrate to mediastinal lymph nodes, usually causing a hemorrhagic mediastinitis. […] The virulence of B. anthracis is due to its antiphagocytic capsule, toxins (factors), and rapid replication capability. […] The predominant toxins are edema toxin and lethal toxin. A cell-binding protein, called protective antigen (PA), binds to target cells and facilitates cellular entry of edema toxin and lethal toxin. Edema toxin causes massive local edema. Lethal toxin triggers a massive release of cytokines from macrophages, which is responsible for the sudden death common among people with anthrax infection.

• #1 What Is Anthrax?

  https://www.mdpi.com/2076-0817/11/6/690

  By disabling these critical innate immune responses at the site of infection, the bacteria can evade the immune response, disseminate throughout the infected host, and produce massive amounts of toxin. Studies in animal models show that both LF and EF induce vascular shock, but through different mechanisms. LF induces a cytokine-independent, nonhemorrhagic vascular collapse resulting in hypoxic necrosis, while EF induces cAMP-mediated vascular dysfunction and hemorrhage. […] The clinical presentation of these metal workers with pulmonary infections has differed from those of patients with inhalation anthrax, who instead usually present with a mediastinitis. The metal workers consistently had necrotizing and suppurative bronchopneumonias. While acute bronchopneumonia occurs in half of inhalation anthrax cases, it is not necrotizing and is felt to be of hematogenous origin. […] These findings imply that patients infected with B. cereus group bacteria containing anthrax toxin genes should receive anthrax antitoxin in addition to antimicrobials with activity against the B. cereus group.

• #1 The Relationship Between Cutaneous Anthrax and Melanogenesis: A Toxic Affair

  https://escholarship.org/uc/item/074423h9

  The severe and often lethal disease Anthrax has been known since antiquity, and is caused by the spore-forming, gram-positive bacterium, Bacillus anthracis (B. a). […] Interestingly, the cause of the black eschars is not understood nor has their role in anthrax pathogenesis or host defense been adequately investigated. […] Bacillus anthracis secretes two toxic factors, Edema Factor (EF) and Lethal factor (LF), both paralyze the immune response in the early phase of infection and promote alarming symptoms in the later stages of the disease. […] Edema Factor is a potent Adenylate Cyclase, that leads to an uncontrolled rise in cAMP concentration, and is responsible for edema; whereas lethal toxin is a zinc metalloprotease that cleaves MAPKK ultimately inhibiting cell growth and division.

• #1 Anthrax – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK507773/

  GI anthrax occurs due to ingestion of contaminated meat, with spores introduced into the gastrointestinal tract, causing bacterial replication, mucosal ulcerations, and bleeding. […] The damage to tissues is caused by the anthrax toxins, of which the edema toxin is most lethal. […] Humans are relatively resistant to cutaneous anthrax but any break in the skin can allow the organism to enter the skin. Once inside the circulation, the organism spreads rapidly and affects the lungs, kidney, and spleen. The organism can also enter the brain and cause meningitis which is universally fatal.

• #1 Anthrax | Iowa State University

  https://vetmed.iastate.edu/vdpam/about/focus-areas/swine/swine-disease-manual/index-diseases/anthrax

  During infection the anthrax bacilli produce a complex exotoxin. A lethal factor in the exotoxin is responsible for the death of experimental animals and, presumably, of swine. Lethal factor causes depression of the central nervous system (CNS) and has a harmful effect on mitochondria. […] Invasion of the anthrax bacilli usually is through defects in the pharyngeal mucosa or the tonsils. Invasion often is followed by lymphangitis and localization of B. anthracis in tonsils and/or cervical lymph nodes. Alternatively, there can be focal or multifocal localization in the intestine followed by spread to one or more mesenteric lymph nodes. Localizations tend to be necrotizing. Frequently both pharyngeal and intestinal lesions develop. There seldom is a septicemic form of anthrax in swine except, perhaps, in young pigs.

• #1 Structure of S-layer protein Sap reveals a mechanism for therapeutic intervention in anthrax | Nature Microbiology

  https://www.nature.com/articles/s41564-019-0499-1

  Anthrax is an ancient and deadly disease caused by the spore-forming bacterial pathogen Bacillus anthracis. […] The cell surface of B. anthracis is covered by a protective paracrystalline monolayer known as surface layer or S-layer that is composed of the S-layer proteins Sap or EA1. […] Here, we generate nanobodies to inhibit the self-assembly of Sap, determine the structure of the Sap S-layer assembly domain (SapAD) and show that the disintegration of the S-layer attenuates the growth of B. anthracis and the pathology of anthrax in vivo. […] Sap-inhibitory nanobodies prevented the assembly of Sap and depolymerized existing Sap S-layers in vitro. […] In vivo, nanobody-mediated disruption of the Sap S-layer resulted in severe morphological defects and attenuated bacterial growth. […] Subcutaneous delivery of Sap inhibitory nanobodies cleared B. anthracis infection and prevented lethality in a mouse model of anthrax disease. […] These findings highlight disruption of S-layer integrity as a mechanism that has therapeutic potential in S-layer-carrying pathogens.

• #1 Convergent evolution of diverse Bacillus anthracis outbreak strains toward altered surface oligosaccharides that modulate anthrax pathogenesis | PLOS Biology

  https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001052

  Bacillus anthracis, a spore-forming gram-positive bacterium, causes anthrax. The external surface of the exosporium is coated with glycosylated proteins. The sugar additions are capped with the unique monosaccharide anthrose. […] Loss of anthrose delayed spore germination and enhanced sporulation. Spores without anthrose were phagocytized at higher rates than spores with anthrose, indicating that anthrose may serve an antiphagocytic function on the spore surface. […] The absence of the BclA glycoprotein results in enhanced attachment to epithelial cells. […] Mutational removal of anthrose increased binding of host cell phagocytic receptor CD14 with exosporium rhamnose residues, directly implicating anthrose as an antiphagocytic exosporium residue. […] The importance of glycosylated BclA in targeting spores to integrin CD11b-expressing cells (macrophages and classical dendritic cells) was demonstrated by BclA knockout.

• #1 Anthrax–Innate Immunity

  https://www.bio.davidson.edu/people/sosarafova/Assets/Bio307/javaron/Innate%20Immunity.html

  B. anthracis stimulates a the release of a cocktail of cytokines. Because the molecular factors of anthrax pathogenesis all act in concert, it is difficult to study their individual roles, though recent research suggests that anthrax stands to gain from inhibiting cytokine response. […] To add insult to injury, not only does B. anthracis harness the abilities of the macrophage to help kill the host, but it induces apoptosis as well. LeTx induces apoptosis of activated macrophages by destroying MAPK kinases and inhibiting the activation of p38 MAPK. This leads to apoptosis, but only in activated macrophages. […] Yet another way that anthrax disables innate immunity is by paralyzing the dendritic cells. […] B. anthracis has evolved to easily deal with challenges posed by the innate immune system. While there is still a debate as to whether the pathogenic action is the upregulation of cytokines or the inhibition of the cytokine response, there is no disagreement that B. anthracis is able to proliferate in the host without difficulty. It does this by disabling almost every aspect of innate immunity.

• #1 Anthrax: Transmission, Pathogenesis, Prevention and Treatment

  https://www.mdpi.com/2072-6651/17/2/56

  Bacillus anthracis is a deadly pathogen that under unfavourable conditions forms highly resistant spores which enable them to survive for a long period of time. […] The disease is caused by the toxin which is produced by them once they germinate within the host cell. Anthrax toxin is the major virulence factor which has the ability to kill the host cell. […] Lately, it has been reported that protein phosphorylation has a significant role in the pathogenesis of B. anthracis by modulating various cellular processes essential for its survival, virulence and ability to evade host immune responses. […] The pathogenicity of B. anthracis hinges on its ability to subvert the host’s immune defences and establish a systemic infection. This begins with the germination of spores in the infected host and release of two major toxins namely lethal toxin and edema toxin.

• #1 Anthrax: Transmission, Pathogenesis, Prevention and Treatment

  https://www.mdpi.com/2072-6651/17/2/56

  In B. anthracis, the role of protein phosphorylation is especially significant orchestrating essential stages of its life cycle, including toxin production and virulence. […] AtxA contains two phosphotransferase system regulation domains (PRDs) and an EIIB-like domain, which can be phosphorylated at specific histidine residues. […] This regulation is mediated by the phosphoenolpyruvate phosphotransferase system (PEP-PTS), a multicomponent system that serves as a key link between carbon source availability and the regulation of virulence factors. […] By influencing the expression of genes involved in toxin production, this system helps B. anthracis adjust their pathogenic potential according to environmental nutrient conditions. […] In conclusion, protein phosphorylation serves as a central regulatory mechanism that allows B. anthracis to fine-tune its response to environmental signals, optimize energy usage and coordinate virulence factor expression.

• #1 Anthrax pathophysiology – wikidoc

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

  B. anthracis begins to produce toxins within hours of germination. […] After binding to surface receptors, the PA portion of the complexes facilitates translocation of the toxins to the cytosol, in which EF and LF exert their toxic effects. […] Bacillus anthracis disseminate to multiple organs including spleen, liver, intestines, kidneys, adrenal glands, and meninges, affecting their normal functions and leading to systemic infection with a potentially fatal outcome. […] In order to infect the body, Bacillus anthracis must produce toxins. These toxins have 3 main toxic effects: edema, hemorrhage, and necrosis. […] Besides their direct toxic effects responsible for tissue damage, anthrax toxins are also responsible for interfering with cellular pathways, in such way that defense functions of the host’s immune system are affected. This will ultimately allow initial systemic infection by interfering with the immune system.

• #1 Anthrax–Innate Immunity

  https://www.bio.davidson.edu/people/sosarafova/Assets/Bio307/javaron/Innate%20Immunity.html

  To use a historical metaphor, if the macrophages are the brave and noble cavalry of the innate immune system, then bacillus anthracis are the tanks and planes that blind them with superior technology. The complicated interactions between B. anthracis and the innate immune system are some of the most complicated and well researched aspects of the disease. […] The first step of anthrax pathogenesis is the bacterial spores entry into a macrophage via phagocytosis. Once inside the macrophage, the cells become vegetative, rapidly dividing cells. Macrophage-conditioned media has been found to promote transition of B. anthracis from spores to the vegetative state. This process is mediated by the gerH operon, as when this locus is deleted from the bacterium, the transition does not. […] While the macrophages help B. anthracis divide, the bacterium is able to escape death by moving from the phagolysosome to the macrophage cytoplasm, where it can safely hide out. The bacteria can leave the infected macrophages in one of two ways. The first involves a gene on the plasmid pXO1 called atxA that allows the bacteria to exit the membrane. Strains of B. anthracis without pXO1 simply divide until, through the sheer volume of bacteria within the macrophage, they disrupt the macrophage membrane and burst the cell.

• #1 Anthrax Pathogenesis and Host Response | SpringerLink

  https://link.springer.com/chapter/10.1007/978-3-642-80451-9_2

  Anthrax has been both a scourge and a fundamental model for infectious disease studies for over a century. […] Death associated with systemic anthrax is mimicked in animals challenged with anthrax lethal toxin, a virulence factor believed to affect only macrophages. […] Animals depleted of macrophages become resistant to the toxin, while reintroduction of cultured macrophages into depleted animals restores sensitivity. […] These studies and others implicate an active role for the innate immune system in the demise of the anthrax victim. […] Many of the molecular factors and events in the cascade of lethal events during anthrax infections have now been identified.

• #1

  https://www.jci.org/articles/view/19581

  The toxins of B. anthracis can be considered classic AB toxins, in which the protective antigen functions as the binding component, providing entry for either of the two toxins into the host cell. […] Recent studies demonstrate that the cleaved protective antigen and its receptor are clustered into lipid rafts and then internalized via the classic clathrin-dependent endocytic pathway, thus providing the toxin molecules access to their targets, including the MAPKs and ATP. […] The most prominent pathology associated with anthrax lethal toxin was extensive tissue necrosis and hypoxic damage in the liver, spleen, and bone marrow. […] This analysis of the pathological effects of the B. anthracis lethal toxin should help focus future studies of optimal therapy for patients exposed to this organism. These results make clear that anthrax patients exhibit a unique pathophysiology and should not be considered to have generic shock analogous to Gram-negative sepsis.

• #1 Anthrax in Animals – Infectious Diseases – Merck Veterinary Manual

  https://www.merckvetmanual.com/infectious-diseases/anthrax/anthrax-in-animals

  The typical incubation period for anthrax is 3-7 days (range, 1-14 days). […] Bacillus anthracis forms highly resistant spores that can persist in the environment for decades and infect grazing animals. […] Anthrax develops without apparent clinical signs, with sudden death due to acute or hyperacute septicemia and leakage of uncoagulated blood from natural openings. […] Treatment with antimicrobials is effective if administered at an early stage of the infection. […] Control measures include the correct disposal of carcasses, disinfection and decontamination of contaminated materials, and decontamination of the environment. […] Vaccination of exposed animals and humans is the best practice to contain and prevent the disease. […] Bacillus anthracis presents concern for animal and human disease from potential use as a bioterrorism agent.

• #1 The Anthrax Capsule: Role in Pathogenesis and Target for Vaccines and Therapeutics | SpringerLink

  https://link.springer.com/chapter/10.1007/978-90-481-9054-6_1

  The polyglutamic acid capsule of Bacillus anthracis is a well-established virulence factor, conferring antiphagocytic properties on the bacillus. […] We have shown that the capsule also confers partial resistance to killing by human defensins. […] Our experiments showed that a capsule vaccine is protective in the mouse model and its efficacy could be enhanced by conjugation to a protein carrier. […] This suggests it may be useful as an addition to a protective antigen-based vaccine. […] We demonstrated that in vitro treatment of the encapsulated anthrax bacillus with CapD enzymatically removed the capsule from the bacterial surface making it susceptible to phagocytic killing. […] Initial experiments in vivo showed that CapD could be used successfully to treat experimental anthrax infections. […] Such a novel approach to target the capsule virulence factor might be of value in the treatment of infections due to antibiotic-resistant strains.

• #1 CDC Guidelines for the Prevention and Treatment of Anthrax, 2023 | MMWR

  https://www.cdc.gov/mmwr/volumes/72/rr/rr7206a1.htm

  A wide-area aerosol release of B. anthracis spores would likely result in a mass-casualty incident that could possibly be complicated by use of genetically engineered B. anthracis strains resistant to first-line antimicrobial drugs for postexposure prophylaxis (PEP) and treatment. […] The updated guidelines in this report can be used by health care providers to prevent and treat anthrax and guide emergency preparedness officials and planners as they develop and update plans for a wide-area aerosol release of B. anthracis. […] The intended audiences for the guidelines in this report are primary care providers and public health professionals. The antimicrobial drug, antitoxin, and other recommendations for PEP and treatment are best practices for the clinical management of single patient cases or limited outbreaks of naturally acquired anthrax.

• #2 Biological Databases and Tools

  https://proteinlounge.com/animation_details.php?vId=8

  Anthrax is an acute infectious disease caused by the spore-forming gram positive, aerobic bacterium Bacillus anthracis, whose pathogenesis is primarily the result of a tripartite toxin. This toxin is composed of three proteins: the Protective Antigen (PA), the Edema Factor (EF) and the Lethal Factor (LF). These proteins work together to enter a cell and disrupt the signaling pathways. Secreted from the bacteria as nontoxic monomers, these proteins assemble on the surface of Anthrax Toxin Receptor (ATR)-bearing eukaryotic cells to form toxic noncovalent complexes. The process starts when the 83 kDa PA (PA83) monomers bind to the ATR Receptor. Once bound, a 20 kDa N-terminal fragment (PA20) is cleaved off of PA83, leaving behind the remaining 63 kDa portion (PA63). PA63 rapidly oligomerizes to form a heptamer pre-pore, which then associates with up to three molecules of EF and/or LF.

• #2 Anthrax toxin – Wikipedia

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

  Anthrax toxin is an A-B toxin. Each individual anthrax toxin protein is nontoxic. […] The co-injection of PA and EF causes edema, and the co-injection of PA and LF is lethal. […] The PA requirement observed in animal-model experiments demonstrates a common paradigm for bacterial toxins, called the A/B paradigm. […] Anthrax toxin is of the form A2B, where the two enzymes, EF and LF, are the A components and PA is the B component. […] PA is necessary for the enzymatic components to enter the cell. […] Once in the cytosol, they may then catalyze reactions that disrupt normal cellular physiology. […] Anthrax toxin protein components must assemble into holotoxin complexes to function. […] The low pH encountered in the endosome causes the PA63 pre-channel to convert into a cation-selective channel.

• #2 Anthrax–Innate Immunity

  https://www.bio.davidson.edu/people/sosarafova/Assets/Bio307/javaron/Innate%20Immunity.html

  B. anthracis stimulates a the release of a cocktail of cytokines. Because the molecular factors of anthrax pathogenesis all act in concert, it is difficult to study their individual roles, though recent research suggests that anthrax stands to gain from inhibiting cytokine response. […] To add insult to injury, not only does B. anthracis harness the abilities of the macrophage to help kill the host, but it induces apoptosis as well. LeTx induces apoptosis of activated macrophages by destroying MAPK kinases and inhibiting the activation of p38 MAPK. This leads to apoptosis, but only in activated macrophages. […] Yet another way that anthrax disables innate immunity is by paralyzing the dendritic cells. […] B. anthracis has evolved to easily deal with challenges posed by the innate immune system. While there is still a debate as to whether the pathogenic action is the upregulation of cytokines or the inhibition of the cytokine response, there is no disagreement that B. anthracis is able to proliferate in the host without difficulty. It does this by disabling almost every aspect of innate immunity.

• #2 What Is Anthrax?

  https://www.mdpi.com/2076-0817/11/6/690

  By disabling these critical innate immune responses at the site of infection, the bacteria can evade the immune response, disseminate throughout the infected host, and produce massive amounts of toxin. Studies in animal models show that both LF and EF induce vascular shock, but through different mechanisms. LF induces a cytokine-independent, nonhemorrhagic vascular collapse resulting in hypoxic necrosis, while EF induces cAMP-mediated vascular dysfunction and hemorrhage. […] The clinical presentation of these metal workers with pulmonary infections has differed from those of patients with inhalation anthrax, who instead usually present with a mediastinitis. The metal workers consistently had necrotizing and suppurative bronchopneumonias. While acute bronchopneumonia occurs in half of inhalation anthrax cases, it is not necrotizing and is felt to be of hematogenous origin. […] These findings imply that patients infected with B. cereus group bacteria containing anthrax toxin genes should receive anthrax antitoxin in addition to antimicrobials with activity against the B. cereus group.

• #2 Anthrax – Wikipedia

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

  Edema factor is a calmodulin-dependent adenylate cyclase. Adenylate cyclase catalyzes the conversion of ATP into cyclic AMP (cAMP) and pyrophosphate. The complexation of adenylate cyclase with calmodulin removes calmodulin from stimulating calcium-triggered signaling, thus inhibiting the immune response. To be specific, LF inactivates neutrophils (a type of phagocytic cell) by the process just described so they cannot phagocytose bacteria. Throughout history, lethal factor was presumed to cause macrophages to make TNF-alpha and interleukin 1 beta (IL1B). TNF-alpha is a cytokine whose primary role is to regulate immune cells, as well as to induce inflammation and apoptosis or programmed cell death. Interleukin 1 beta is another cytokine that also regulates inflammation and apoptosis. The overproduction of TNF-alpha and IL1B ultimately leads to septic shock and death. However, recent evidence indicates anthrax also targets endothelial cells that line serious cavities such as the pericardial cavity, pleural cavity, and peritoneal cavity, lymph vessels, and blood vessels, causing vascular leakage of fluid and cells, and ultimately hypovolemic shock and septic shock.

• #2 ATP depletion in anthrax edema toxin pathogenesis | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1013017

  Anthrax lethal toxin (LT) and edema toxin (ET) are two of the major virulence factors of Bacillus anthracis, the causative pathogen of anthrax disease. […] While the roles of LT in anthrax pathogenesis have been extensively studied, the pathogenic mechanism of ET remains poorly understood. […] Thus, it was postulated that the ET-induced in vivo toxicity is mediated by certain cAMP-dependent events. […] However, mechanisms linking cAMP elevation and ET-induced damage have not been established. […] Surprisingly, in this work, we found that cAMP-mediated PKA/CFTR activation is not essential for ET to exert its in vivo toxicity. Instead, our data suggest that ET-induced ATP depletion may play an important role in the toxins pathogenesis. […] Our results suggest that ATP depletion might also be an important mechanism underlying pathogenesis of other adenylate cyclase toxins.

• #2 Azthena logo with the word Azthena

  https://www.news-medical.net/health/What-is-Anthrax.aspx

  B. anthracis is identified as a possible bioweapon in addition to naturally acquired forms of anthrax, and the risk of obtaining anthrax from laboratory-produced B. anthracis spores highlights the necessity of anthrax surveillance, prevention, and control in anthrax-endemic nations. […] B. anthracis has two key virulence factors: a polyD-glutamic acid capsule and a tripartite toxin. Pathogenic B. anthracis bacteria form a capsule that imitates the host’s immune system by concealing the germs from macrophages. […] Although anthrax infection is rare, the possibility of massive epidemics remains, whether due to bioterrorism or injectional drug usage. More research is required to define the mechanisms driving later-stage anthrax, as well as to design and test effective management measures that may be applied on a large basis. Steps to prevent bioterrorism should be designed and implemented.

• #2 Anthrax–Innate Immunity

  https://www.bio.davidson.edu/people/sosarafova/Assets/Bio307/javaron/Innate%20Immunity.html

  To use a historical metaphor, if the macrophages are the brave and noble cavalry of the innate immune system, then bacillus anthracis are the tanks and planes that blind them with superior technology. The complicated interactions between B. anthracis and the innate immune system are some of the most complicated and well researched aspects of the disease. […] The first step of anthrax pathogenesis is the bacterial spores entry into a macrophage via phagocytosis. Once inside the macrophage, the cells become vegetative, rapidly dividing cells. Macrophage-conditioned media has been found to promote transition of B. anthracis from spores to the vegetative state. This process is mediated by the gerH operon, as when this locus is deleted from the bacterium, the transition does not. […] While the macrophages help B. anthracis divide, the bacterium is able to escape death by moving from the phagolysosome to the macrophage cytoplasm, where it can safely hide out. The bacteria can leave the infected macrophages in one of two ways. The first involves a gene on the plasmid pXO1 called atxA that allows the bacteria to exit the membrane. Strains of B. anthracis without pXO1 simply divide until, through the sheer volume of bacteria within the macrophage, they disrupt the macrophage membrane and burst the cell.

• #2 The Relationship Between Cutaneous Anthrax and Melanogenesis: A Toxic Affair

  https://escholarship.org/uc/item/074423h9

  We propose that a similar mechanism is at play in human cells, and that EF and LF may act similarly in melanocytes, potentially leading to uncontrolled melanogenesis in anthrax-infected skin tissues. […] Ultimately, this leads to the question as to whether these black cutaneous lesions are a product of host defense aimed at controlling the spread of the pathogen, or whether they are a part of Bacillus anthracis virulence strategy.

• #2 Convergent evolution of diverse Bacillus anthracis outbreak strains toward altered surface oligosaccharides that modulate anthrax pathogenesis – Geography

  https://geog.ufl.edu/2020/12/28/convergent-evolution-of-diverse-bacillus-anthracis-outbreak-strains-toward-altered-surface-oligosaccharides-that-modulate-anthrax-pathogenesis/

  Convergent evolution of diverse Bacillus anthracis outbreak strains toward altered surface oligosaccharides that modulate anthrax pathogenesis. […] The sugar additions are capped with the unique monosaccharide anthrose. […] The role of anthrose in physiology and pathogenesis was investigated in B. anthracis Sterne. […] Loss of anthrose delayed spore germination and enhanced sporulation. […] Spores without anthrose were phagocytized at higher rates than spores with anthrose, indicating that anthrose may serve an antiphagocytic function on the spore surface. […] The anthrose mutant had half the LD50 and decreased time to death (TTD) of wild type and complement B. anthracis Sterne in the A/J mouse model. […] Following infection, anthrose mutant bacteria were more abundant in the spleen, indicating enhanced dissemination of Sterne anthrose mutant.

• #2 What Is Anthrax?

  https://www.mdpi.com/2076-0817/11/6/690

  Anthrax is, however, a toxin-mediated disease. The toxins edema toxin and lethal toxin are formed from protein components encoded for by the pXO1 virulence plasmid present in pathogenic B. anthracis strains. […] This suggested that the pathophysiology associated with anthrax was likely toxin-mediated. This hypothesis was confirmed with the discovery that B. anthracis harbors two large virulence plasmids, pXO1 and pXO2. The pXO1 plasmid encodes for the protein components edema factor (EF), lethal factor (LF), and protective antigen (PA), which form the anthrax toxins. The pXO2 plasmid encodes for the capsule, which helps the bacterium evade the innate host immune response. […] During infection, vegetative cells produce EF and PA that combine to form edema toxin and LF and PA that combine to form lethal toxin. The PA component binds to cell receptors, which allow the enzymatic components EF and LF to be transported into the cell. Within the cell cytoplasm, LF cleaves and inactivates members of the mitogen-activated protein kinase family and NLRP1; EF rapidly increases cyclic AMP resulting in activation of signaling pathways through protein kinase A. Early in the infection, the toxins target cellular pathways, inhibiting the host’s innate immune responses, such as neutrophil priming, chemotaxis, and chemokine production.

• #2 Bacillus anthracis- An Overview

  https://microbenotes.com/bacillus-anthracis/

  The toxins are also released in the form of three different protein components that undergo cleavage and binding to form the toxins eventually. […] The edema toxin interacts with the host protein calmodulin and becomes an active adenylyl cyclase. The enzyme causes increased levels of cAMP and leads to hypovolemic shock. […] The lethal toxin then cleaves the members of the mitogen-activated protein kinase family interfering with certain signaling pathways and increasing the levels of shock-inducing cytokines like TNF and IL-1. […] During the early stages of infection as a result of the synergistic effect of both toxins, a reduction in the release of pro-inflammatory cytokines occurs, which significantly permits bacterial proliferation in the host. […] Lethal and edema toxins together can also induce vascular shock, but the nature of the shock might differ. […] As the infection continues, the bacteria make their way into the blood with the terminal levels of bacteria reaching, 107 to 109 cells/ml in susceptible hosts.

• #2 Anthrax: Transmission, Pathogenesis, Prevention and Treatment

  https://www.mdpi.com/2072-6651/17/2/56

  In B. anthracis, the role of protein phosphorylation is especially significant orchestrating essential stages of its life cycle, including toxin production and virulence. […] AtxA contains two phosphotransferase system regulation domains (PRDs) and an EIIB-like domain, which can be phosphorylated at specific histidine residues. […] This regulation is mediated by the phosphoenolpyruvate phosphotransferase system (PEP-PTS), a multicomponent system that serves as a key link between carbon source availability and the regulation of virulence factors. […] By influencing the expression of genes involved in toxin production, this system helps B. anthracis adjust their pathogenic potential according to environmental nutrient conditions. […] In conclusion, protein phosphorylation serves as a central regulatory mechanism that allows B. anthracis to fine-tune its response to environmental signals, optimize energy usage and coordinate virulence factor expression.

• #2 Anthrax – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/gram-positive-bacilli/anthrax

  Bacteremia may occur in any form of anthrax and occurs in nearly all fatal cases; meningeal involvement is common. […] Limited data suggest that cutaneous anthrax does not result in acquired immunity, particularly if early effective antimicrobial therapy was used. Inhalation anthrax may provide some immunity in patients who survive, but data are very limited.

• #2 Treating and Preventing Anthrax | Respiratory Therapy

  https://respiratory-therapy.com/disorders-diseases/critical-care/ards/treating-and-preventing-anthrax/

  Anthrax toxin also results in necrosis of lymphatic tissue, thereby allowing large numbers of organisms into the body. After the organisms and their toxins enter the circulation, a clinical syndrome reminiscent of septic shock ensues. […] Death from anthrax in humans or animals usually occurs suddenly and unexpectedly. The level of lethal anthrax toxin in the circulation increases rapidly quite late in the course of the disease, and it closely parallels the concentration of organisms in the blood. […] Both the capsule and the anthrax toxin are involved in the early stages of infection, through direct effects on phagocytic cells. […] B. anthracis coordinates the expression of its virulence factors in response to a specific environmental signal. Anthrax toxin proteins and the antiphagocytic capsule are produced in response to growth in the presence of increased atmospheric carbon dioxide. This carbon dioxide signal is thought to be of physiological significance for pathogens that invade mammalian host tissue.

• #2 Anthrax – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/gram-positive-bacilli/anthrax

  Anthrax is caused by the gram-positive Bacillus anthracis, which are toxin-producing, encapsulated, facultative anaerobic organisms. […] Spores germinate and begin multiplying rapidly when they enter an environment rich in amino acids and glucose (eg, tissue, blood). […] After entering the body, spores germinate inside macrophages, which migrate to regional lymph nodes where the bacteria multiply. In inhalation anthrax, spores are deposited in alveolar spaces, where they are ingested by macrophages, which migrate to mediastinal lymph nodes, usually causing a hemorrhagic mediastinitis. […] The virulence of B. anthracis is due to its antiphagocytic capsule, toxins (factors), and rapid replication capability. […] The predominant toxins are edema toxin and lethal toxin. A cell-binding protein, called protective antigen (PA), binds to target cells and facilitates cellular entry of edema toxin and lethal toxin. Edema toxin causes massive local edema. Lethal toxin triggers a massive release of cytokines from macrophages, which is responsible for the sudden death common among people with anthrax infection.

• #3 Anthrax Toxin

  https://www2.gvsu.edu/chm463/toxins/anthrax.htm

  The translocation of LF into the cell leads to the cleavage of MAPKKs (Mitogen Activated Protein Kinase Kinases) near their amino termini. Although the action of LF in cleaving MAPKKs has been documented by several independent researchers, the cellular effects are still not fully understood. The cell type most affected by LF is the macrophage, which is a leukocyte responsible for engulfing and destroying bacteria and other foreign organisms or debris. The result of high levels of B. anthracis in the bloodstream is macrophage lysis and the release of large amounts of NO and TNF-a (Tumor Necrosis Factor-alpha). Yet, the same investigators have found that the eventual lysis of macrophages is preceded by inhibition of the release of NO and TNF-a at low concentration of B. anthracis in the bloodstream.

• #3 ATP depletion in anthrax edema toxin pathogenesis | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1013017

  One characteristic cytotoxic effect of ET to cultured cells is its ability to rapidly induce morphological change including cell rounding. […] Therefore, the ET-induced cell rounding, compromised cell junctions, and tissue edema are more likely due to the cellular ATP depletion rather than the cAMP over-production and the cAMP-mediated events. […] In summary, our results support the notion that the ET-induced cellular ATP depletion rather than the cAMP overproduction contributes to ET lethality. Our results further suggest that ATP depletion might be an important mechanism underlying pathogenesis of other related adenylate cyclase toxins.

• #3 The Anthrax Capsule: Role in Pathogenesis and Target for Vaccines and Therapeutics | SpringerLink

  https://link.springer.com/chapter/10.1007/978-90-481-9054-6_1

  The polyglutamic acid capsule of Bacillus anthracis is a well-established virulence factor, conferring antiphagocytic properties on the bacillus. […] We have shown that the capsule also confers partial resistance to killing by human defensins. […] Our experiments showed that a capsule vaccine is protective in the mouse model and its efficacy could be enhanced by conjugation to a protein carrier. […] This suggests it may be useful as an addition to a protective antigen-based vaccine. […] We demonstrated that in vitro treatment of the encapsulated anthrax bacillus with CapD enzymatically removed the capsule from the bacterial surface making it susceptible to phagocytic killing. […] Initial experiments in vivo showed that CapD could be used successfully to treat experimental anthrax infections. […] Such a novel approach to target the capsule virulence factor might be of value in the treatment of infections due to antibiotic-resistant strains.

• #3 Convergent evolution of diverse Bacillus anthracis outbreak strains toward altered surface oligosaccharides that modulate anthrax pathogenesis | PLOS Biology

  https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001052

  Bacillus anthracis, a spore-forming gram-positive bacterium, causes anthrax. The external surface of the exosporium is coated with glycosylated proteins. The sugar additions are capped with the unique monosaccharide anthrose. […] Loss of anthrose delayed spore germination and enhanced sporulation. Spores without anthrose were phagocytized at higher rates than spores with anthrose, indicating that anthrose may serve an antiphagocytic function on the spore surface. […] The absence of the BclA glycoprotein results in enhanced attachment to epithelial cells. […] Mutational removal of anthrose increased binding of host cell phagocytic receptor CD14 with exosporium rhamnose residues, directly implicating anthrose as an antiphagocytic exosporium residue. […] The importance of glycosylated BclA in targeting spores to integrin CD11b-expressing cells (macrophages and classical dendritic cells) was demonstrated by BclA knockout.

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