Yersinia Infection
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Yersinia Infection
Yersinia pestis, a gram-negative bacillus, which is responsible for causing bubonic plague, is considered by the Center for Disease Control to be one of the top 5 bioterrorist agents. After infection, the pathogen invades lymphatic tissues and proliferates in the lymph nodes, and symptoms of pneumonic plague are expressed when the organism infects the lungs (Ref.1). The pneumonic plague is highly contagious, with transmission occurring between people via respiratory droplets. The mortality rate of untreated pneumonic plague is almost 100 percent. Altough pneumonic plague is contagious, advances in living conditions, along with public health advances and antibiotics, make natural epidemics of the plague improbable. However, biological terrorist outbreaks of the plague pose a serious threat. A bioterrorism attack by aerosolized Y. pestis would be characterized by pneumonic cases occurring simultaneously in persons within 2 to 6 days following a common exposure, and in a secondary wave in unprotected case contacts. So, utmost care needs to be taken to combat bioterrorism attacks, but till now, there are no effective environmental warning systems to detect an aerosol release of plague bacilli (Ref.2). Apart from Y. pestis, two other pathogenic Yersinia species, Yersinia enterocolitica, Y. pseudotuberculosis, are known to infect human and animal hosts and cause a variety of intestinal and septicemic diseases. While Y. pestis is responsible for the outbreak of plague, infections with Y. enterocolitica and Y. pseudotuberculosis generally cause gastroenteritis and lymphadenitis (Ref.3). Infection is most often acquired by eating contaminated food, especially raw or undercooked pork products. Children are infected more often than adults, and the infection is more common in the winter.

Critical for the development of a systemic infection by pathogenic bacteria is their ability to be internalized by both professional phagocytes and nonphagocytic cells (Ref.4). However, unlike other bacterial pathogens, which must be internalized to induce cell death, Yersiniae are able to induce apoptosis from the outside of the host cells (Ref.1). Yersiniae express several adhesion molecules that allow the bacteria to preferentially attach to different classes of integrin receptors on the surface of epithelial, fibroblast, macrophage, and lymphocyte cells (Ref.3). Yersiniae can trigger several key phagocytic pathways: in the absence of opsonization, Yersinia adherence is mediated by the adhesins YadA and Invasin, which trigger internalization via Beta1-integrins in phagocytic and non-phagocytic cells. Opsonization of Yersinia facilitates cell binding via FcGammaR and complement receptors in professional phagocytes. Regardless of the adherence mechanism, the members of the Yersinia sp. counteracts its own receptor binding and activation by injecting effector proteins that disrupt the Actin cytoskeleton and defuse the triggered phagocytic pathways (Ref.5). To evade phagocytic killing by the hosts immune system, pathogenic Yersiniae employ the TTS (Type III Secretion) machinery, a protein transporter that exports a set of plasmid-encoded virulence factors, named Yops (Yersinia Outermembrane Proteins) into the eucaryotic cells (Ref.4). TTS is a mechanism by which Gram-negative bacteria that are either extracellular or localized in a phagosome communicate with eukaryotic cells by injecting bacterial proteins across cellular membranes into the cytosol of these cells (Ref.6). The Yops interfere with different host cellular processes, including (a) alteration of the cytoskeleton, (b) inhibition of phagocytosis, and (c) induction of apoptosis (Ref.1).

When Yersinia is present in a rich environment and at suitable temperature (37°C), the Ysc secretion apparatus is installed and a stock of Yop proteins is synthesized. The Yop virulon, a weapon common to Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica, endows these three pathogens with the capacity to resist the nonspecific immune response. During their intrabacterial stage, Yops are capped with their specific chaperones, presumably to prevent premature associations (Ref.5). As long as there is no contact with a eukaryotic cell, a stop valve, possibly made of YopN, TyeA, and LcrG, blocks the Ysc secretion channel. Upon contact with the eukaryotic target cell, Yersinia translocates the Yop effectors across the plasma membrane into the cytosol, through the Ysc injectisome while remaining bound to the host cell surface (Ref.7). The Ysc injectisome of Yersinia is an organelle that spans the peptidoglycan layer and the two bacterial membranes, and is topped by a needle-like structure that protrudes outside the bacterium (Ref.6). Delivery of the Yop effectors requires the 25 YscA-Y proteins, YopB, YopD, LcrV and LcrG, which are encoded by four contiguous operons. The Ysc proteins allow the Yops to cross the two bacterial membranes. YopB, YopD, LcrV and LcrG are required to transfer the effector Yops across the eukaryotic cell membrane. Thus, direct cell contact, in combination with the TTS machinery, allows Yersinia to translocate the Yops from the cytoplasm of the bacteria directly into the cytoplasm of a host cell to modify host cell functions (Ref.8).

Binding of Yersinia to host-cell phagocytic receptors, triggers phagocytic pathways that would normally promote Actin polymerization and result in bacterial uptake (Ref.9). The rapid translocation of several Yops by Yersinia disarms these pathways, facilitating bacterial avoidance of phagocytosis. Once inside the host cell, each of the effectors targets signalling pathways to ensure survival of the bacterium within its host. At least six characterized Yop effectors are thought to be active in the host cell: YopH, YopE, YopJ/YopP, YopO/YpkA, YopM, and YopT that are injected into the eukaryotic cytosol (type III targeting) (Ref.5) to disrupt vital signalling cascades, required for innate immunity (Ref.4). YopH (Yersinia Outer Protein-H), a protein tyrosine phosphatase, dephosphorylates a number of tyrosine-phosphorylated signalling proteins including P130CAS (Crk-Associated Substrate-P130), FAK (Focal Adhesion Kinase) and Paxillin, causing disruption of FA (Focal Adhesion) complexes, which impairs the phagocytosis of the bacterium into the eukaryotic cells. It also dephosphorylates the Fyn-binding protein Fyb and the scaffolding protein SKAP-HOM/ SCAP2 (Src family Associated Phosphoprotein-2) (Ref.9). YopE, a GAP (Rho GTPase-Activating Protein), inactivates the Rho family of GTPases, Rac1, Rho and CDC42 (Cell Division Cycle-42) resulting in altered Actin cytoskeleton, thus preventing ingestion of the bacteria (Ref.3), while YopT proteolytically cleaves this family of proteins, presumably to alter the Actin cytoskeleton. YopO/YpkA (Yersinia Protein Kinase-A), a protein serine/threonine kinase, disrupts the Actin cytoskeleton by blocking the activation of Rho. Both YopO and YopT can perturb the cytoskeleton of epithelial cells in the absence of YopE (Ref.8). Unlike the other Yops, YopM is targeted to the nucleus of the cell, but its exact function is unknown. It contains leucine-rich repeats, which are presumably used to bind to host proteins and, probably plays a role in plasma clotting (Ref.4).

Yop effectors promote the intracellular survival of Yersinia by counteracting the normal proinflammatory response of cells to infection. YopJ (YopP in Y. enterocolitica) reduces the release of TNF-Alpha (Tumor Necrosis Factor-Alpha) by macrophages and of IL-8 (Interleukin-8) by epithelial and endothelial cells. It also reduces the presentation of adhesion molecules ICAM1 (Intercellular Adhesion Molecule-1) and E-selectin at the surface of endothelial cells and presumably reduces neutrophil recruitment to the site of infection. All of these events result from the inhibition of activation of NF-KappaB (Nuclear Factor-KappaB), a transcription factor known to be of central importance in the onset of inflammation, by YopP/YopJ (Ref.9). YopP/YopJ, putative cysteine proteases, disrupt multiple signalling pathways, resulting in inactivation of MAPKs (Mitogen-Activated Protein Kinases) and NF-KappaB that ultimately lead to apoptosis and inhibition of Cytokine production. As a result of these inhibitory actions, transcription activators such as the CREB (cAMP-Response Element Binding protein), a transcription factor involved in the immune response, and ATF1 (Activating Transcription Factor-1), as well as NF-KappaB, cannot stimulate the transcription of genes that are involved in the synthesis of pro-inflammatory cytokines and adhesion molecules. Translocated YopP/YopJ also induces apoptosis by a mechanism involving Caspase activation. Caspase8 is activated by YopP/YopJ, which in turn, cleaves Bid — a pro-apoptotic member of the Bcl-2 family of proteins —to its pro-apoptotic truncated form: tBid. The protein tBid then triggers the release of CytoC (Cytochrome-C) from mitochondria. CytoC binds the APAF1 (Apoptotic Protease Activating Factor-1) resulting in the recruitment of Caspase9. Caspase3, Caspase6 and Caspase7 are then activated in turn, which promotes apoptosis (Ref.10). On contact of LPS (Lipopolysaccharide) or other bacterial signals with an unidentified RTK (Receptor Tyrosine Kinase), PI3K (Phosphatidylinositol-3-Kinase) is recruited to the membrane. Activated PI3K recruits proteins such as PDK-1 (Phosphoinositide-Dependent Kinase-1), which activates the Akt/PKB (Protein Kinase-B) pathway, that leads, among many other events, to the synthesis of MCP1 (Monocyte Chemotactic Protein-1). YopH inhibits the production of MCP1 by dephosphorylating key players in the PI3K-Akt pathway (Ref.9).

The infective dose of Y. pestis in aerosol form is 100 to 500 organisms. The incubation period of the disease is 2 to 3 days. The initial symptoms of pneumonic plague include: a sudden high fever, headache, malaise, respiratory difficulty, and a productive cough with frothy secretions, often accompanied by gastrointestinal symptoms (nausea, vomiting, abdominal pain and diarrhea). Within 2 to 4 days, the disease progresses and often results in septic shock and death. The diagnosis is made with a blood, sputum, or lymph node aspirate testing positive for the plague. Early treatment of pneumonic plague is essential to prevent death. Prophylactic treatment includes tetracycline or doxycycline given for 7 days. Several antibiotics are effective post-exposure, including tetracyclines, doxycycline, streptomycin, and chloramphenicol. There is no vaccine currently available to prevent plague. Face-to-face contact with infected persons must be avoided unless medically necessary. When in contact with infected persons, utilization of protective isolation equipment, especially highly specialized air-filtration masks is usually recommended (Ref.2).