Yersinia pestis infection pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editors-In-Chief: Esther Lee, M.A.
Overview
Plague can be transmitted from flea bites or the inhalation of aerosol from an individual who has plague pneumonia. Pathogenesis due to the Yersinia pestis infection of mammalian hosts, results from several factors including the bacteria's avoidance of normal immune system responses, such as phagocytosis and antibody production.
Pathophysiology
Adherence and Invasion of Epithelial Cells
Flea bites allow for the bacteria to pass the skin barrier. Yersinia pestis expresses the yadBC gene, which is similar to adhesins in other Yersinia species, allowing for adherence and invasion of epithelial cells.[1]
Evasion of the Immune System
Anti-phagocytic Antigens
Many of the bacteria's virulence factors are anti-phagocytic in nature. Two important anti-phagocytic antigens, named F1 (Fraction 1) and V or LcrV, are both important for virulence. These antigens are produced by the bacterium at normal human body temperature. Furthermore, Yersinia pestis survives and produces F1 and V antigens while it is residing within white blood cells such as monocytes, but not in neutrophils. Natural or induced immunity is achieved by the production of specific opsonic antibodies against F1 and V antigens; antibodies against F1 and V induce phagocytosis by neutrophils.[2]
Type III Secretion System (T3SS)
The Type III secretion system (T3SS) allows Yersinia pestis to inject proteins into macrophages and other immune cells. These T3SS-injected proteins are called Yops (Yersinia Outer Proteins) and include Yop B/D, which form pores in the host cell membrane and have been linked to cytolysis. The YopO, YopH, YopM, YopT, YopJ, and YopE are injected into the cytoplasm of host cells via T3SS into the pore created in part by YopB and YopD.[3] The injected Yop proteins limit phagocytosis and cell signaling pathways important in the innate immune system. In addition, some Yersinia pestis strains are capable of interfering with immune signaling (e.g., by preventing the release of some cytokines).
Yersinia Outer Proteins
- YopH is a protein tyrosine phosphatase that contributes to the ability of Yersinia pestis to evade immune system cells.[4] In macrophages, YopH has been shown to dephosphorylate p130Cas, Fyb (Fyn binding protein) SKAP-HOM and Pyk, a tyrosine kinase homologous to FAK. YopH also binds the p85 subunit of phosphoinositide 3-kinase, the Gab1, the Gab2 adapter proteins, and the Vav guanine nucleotide exchange factor.
- YopE functions as a GTPase activating protein for members of the Rho family of GTPases such as RAC1.
- YopT is a cysteine protease that inhibits RhoA by removing the isoprenyl group, which is important for localizing the protein to the cell membrane. It has been proposed that YopE and YopT may function to limit YopB/D-induced cytolysis.[5] This might limit the function of YopB/D to create the pores used for Yop insertion into host cells and prevent YopB/D-induced rupture of host cells and release of cell contents that would attract and stimulate immune system responses.
- YopJ is an acetyltransferase that binds to a conserved α-helix of MAPK kinases.[6]
- YopJ acetylates MAPK kinases at serines and threonines that are normally phosphorylated during activation of the MAP kinase cascade.[7][8] YopJ is activated in eukaryotic cells by interaction with target cell Phytic acid (IP6).[9] This disruption of host cell protein kinase activity causes apoptosis of macrophages, and it has been proposed that this is important for the establishment of infection and for evasion of the host immune response.
- YopO is a protein kinase also known as Yersinia protein kinase A (YpkA). YopO is a potent inducer of human macrophage apoptosis.[10]
Pathophysiological Findings in the Different Forms of Plague
- In bubonic plague, a local cutaneous proliferation, not usually clinically evident, ensues following inoculation . The infection spreads via the lymphatics to the regional lymph nodes causing inflammation and swelling in one or several nodes (buboes). Buboes may occur in any regional lymph node sites including inguinal, axillary, supraclavicular, cervical, post-auricular, epitrochlear, popliteal or pharyngeal. Deeper nodes (such as intrabdominal or intrathoracic nodes) may also be involved through lymphatic or hematogenous extension.[11] Yersinia pestis proliferates inside lymph nodes where it is able to avoid destruction by cells of the immune system such as macrophages.
- In septicemic plague, the presence of rapidly replicating gram-negative bacilli in the bloodstream initiates a self-perpetuating immunological cascade typically linked to host response to severe injury, in this case the agent inciting injury is bacterial endotoxin. The host response may result in a wide spectrum of pathological events including disseminated intravascular coagulopathy (DIC), multiple organ failure, and adult respiratory distress syndrome (ARDS).
- Yersinia pestis expresses a plasminogen activator that is an important virulence factor for pneumonic plague and that might degrade on blood clots in order to facilitate systematic invasion.[12]
- Plague pharyngitis results from contamination of the oropharynx with Y. pestis-infected material from respiratory droplets expelled during coughing by a patient (or animal) with a respiratory plague infection, or ingestion of undercooked or raw tissues of an infected animal.
- Meningeal plague is often associated with delayed, inappropriate or bacteriostatic antibiotic therapy and is more common in patients with axillary (as opposed to inguinal) buboes.
References
- ↑ Forman S, Wulff CR, Myers-Morales T, Cowan C, Perry RD, Straley SC (2008). "yadBC of Yersinia pestis, a New Virulence Determinant for Bubonic Plague". Infect. Immun. 76 (2): 578–87. doi:10.1128/IAI.00219-07. PMC 2223446. PMID 18025093.
- ↑ Salyers AA, Whitt DD (2002). Bacterial Pathogenesis: A Molecular Approach (2nd ed.). ASM Press. pp. 207-12.
- ↑ Viboud GI, Bliska JB (2005). "Yersinia outer proteins: role in modulation of host cell signaling responses and pathogenesis". Annu. Rev. Microbiol. 59: 69–89. doi:10.1146/annurev.micro.59.030804.121320. PMID 15847602.
- ↑ de la Puerta ML, Trinidad AG, del Carmen Rodríguez M, Bogetz J, Sánchez Crespo M, Mustelin T, Alonso A, Bayón Y (2009). Bozza, Patricia, ed. "Characterization of New Substrates Targeted By Yersinia Tyrosine Phosphatase YopH". PLoS ONE. 4 (2): e4431. doi:10.1371/journal.pone.0004431. PMC 2637541. PMID 19221593. Unknown parameter
|month=ignored (help) - ↑ Mejía E, Bliska JB, Viboud GI (2009). "Yersinia Controls Type III Effector Delivery into Host Cells by Modulating Rho Activity". PLoS ONE. 4 (2): e4431. doi:10.1371/journal.ppat.0040003. PMC 2186360. PMID 18193942. Unknown parameter
|month=ignored (help) - ↑ Hao YH, Wang Y, Burdette D, Mukherjee S, Keitany G, Goldsmith E, Orth K (2008). Kobe, Bostjan, ed. "Structural Requirements for Yersinia YopJ Inhibition of MAP Kinase Pathways". PLoS ONE. 2 (3): e1375. doi:10.1371/journal.pone.0001375. PMC 2147050. PMID 18167536. Unknown parameter
|month=ignored (help) - ↑ Mukherjee S, Keitany G, Li Y, Wang Y, Ball HL, Goldsmith EJ, Orth K (2006). "Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation". Science. 312 (5777): 1211–1214. doi:10.1126/science.1126867. PMID 16728640. Unknown parameter
|month=ignored (help) - ↑ Mittal R, Peak-Chew S-Y, McMahon HT (2006). "Acetylation of MEK2 and IκB kinase (IKK) activation loop residues by YopJ inhibits signaling". Proc. Natl. Acad. Sci. USA. 103 (49): 18574–18579. doi:10.1073/pnas.0608995103. PMC 1654131. PMID 17116858. Unknown parameter
|month=ignored (help) - ↑ Mittal R, Peak-Chew SY, Sade RS, Vallis Y, McMahon HT (2010). "The Acetyltransferase Activity of the Bacterial Toxin YopJ of Yersinia Is Activated by Eukaryotic Host Cell Inositol Hexakisphosphate". J Biol Chem. 285 (26): 19927–34. doi:10.1074/jbc.M110.126581. PMC 2888404. PMID 20430892.
- ↑ Park H, Teja K, O'Shea JJ, Siegel RM (2007). "The Yersinia effector protein YpkA induces apoptosis independently of actin depolymerization". J Immunol. 178 (10): 6426–6434. PMID 17475872. Unknown parameter
|month=ignored (help) - ↑ Plague Manual: Epidemiology, Distribution, Surveillance. World Health Organization. Communicable Disease Surveillance and Response and Control. WHO/CDS/CSR/EDC/99.2
- ↑ Lathem WW, Price PA, Miller VL, Goldman WE (2007). "A plasminogen-activating protease specifically controls the development of primary pneumonic plague". Science. 315 (5811): 509–13. doi:10.1126/science.1137195. PMID 17255510.