Yersinia pestis infection pathophysiology: Difference between revisions

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===Septicemic plague===
===Septicemic plague===
* May be classified in primary or secondary plague:<ref name="Koirala2006">{{cite journal|last1=Koirala|first1=Janak|title=Plague: Disease, Management, and Recognition of Act of Terrorism|journal=Infectious Disease Clinics of North America|volume=20|issue=2|year=2006|pages=273–287|issn=08915520|doi=10.1016/j.idc.2006.02.004}}</ref>
* May be classified in primary or secondary septicemic plague:<ref name="Koirala2006">{{cite journal|last1=Koirala|first1=Janak|title=Plague: Disease, Management, and Recognition of Act of Terrorism|journal=Infectious Disease Clinics of North America|volume=20|issue=2|year=2006|pages=273–287|issn=08915520|doi=10.1016/j.idc.2006.02.004}}</ref>
:* '''''Primary Septicemic Plague''''':
:* '''''Primary Septicemic Plague''''':
:: [[Cutaneous]] exposure to the [[bacteria]], without [[lymphadenopathy]], followed by systemic [[bacteremia]].
:: [[Cutaneous]] exposure to the [[bacteria]], without [[lymphadenopathy]], followed by systemic [[bacteremia]].

Revision as of 13:59, 27 July 2014

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editors-In-Chief: Esther Lee, M.A.; Rim Halaby, M.D. [2]; João André Alves Silva, M.D. [3]

Overview

The route of infection (fleabite or aerosolized particles) classifies plague into: bubonic, pulmonic or septicemic. Yersinia pestis produces several virulence factors which are responsible for: evasion of the immune system, survival of the bacteria inside host cells, and infectious mechanisms, such as: degradation of extracellular proteins, production of endotoxins and inhibition of platelet aggregation. Y. pestis aggregates in different tissues, causing inflammation and necrosis, that are responsible for some of the clinical findings of plague: lymphadenopathy and abscesses (bubonic); bacteremia and sepsis (septicemic) and pneumonia and ARDS (pulmonic).

Pathogenesis

According to the route of infection, the plague may be divided into:[1]

Bubonic plague

Pulmonic Plague

Septicemic plague

  • May be classified in primary or secondary septicemic plague:[1]
  • Primary Septicemic Plague:
Cutaneous exposure to the bacteria, without lymphadenopathy, followed by systemic bacteremia.
Althought it affects all age groups, elderly are more commonly affected.
  • Secondary Septicemic Plague:
Bacterial spread, from an initial focus of infection, such as the skin (bubonic plague) or the lungs (pulmonic plague).
Simillar clinical presentation to other gram-negative septicemias.

Meningeal plague

Virulence Factors

Yersinia pestis produces several risk factors that allow it to evade the host's immune system and cause infection. These virulence factors include:[1]

Phospholipase D

  • Survival inside the flea

V antigen and W antigen

Low-calcium-response plasmid

Hemin storage system

Plasminogen activator

Lipopolysaccharide endotoxin

Yersinia outer proteins (Yops)

  • Inhibitor of:

F1 antigen

Evasion of the Immune System

Anti-phagocytic Antigens

Many of the bacteria's virulence factors are anti-phagocytic in nature. Two important antiphagocytic 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.[7]

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.[8]

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 also binds the p85 subunit of phosphoinositide 3-kinase, the Gab1, the Gab2 adapter proteins, and the Vav guanine nucleotide exchange factor.
  • YopT - Cysteine protease that inhibits RhoA by removing the isoprenyl group. It has been proposed that YopE and YopT may function to limit YopB/D-induced cytolysis.[10] This might limit the function of YopB/D to create the pores used for Yop insertion into host cells. It may also prevent YopB/D-induced rupture of host cells, and the release of cell contents that would attract and stimulate immune system responses.
Responsible for acetylation of MAPK at serines and threonine groups, which are normally phosphorylated during activation of the MAP kinase cascade.[12][13] YopJ is activated in eukaryotic cells by interaction with target cell Phytic acid (IP6).[14] This disruption of host cell protein kinase activity causes apoptosis of macrophages.
This mechanism has been proposed to play a role in the establishment of infection, and evasion of the host immune response, by the bacteria.

Genetics

Yersinia pestis expresses the yadBC gene, which is similar to adhesins in other Yersinia species, allowing for adherence and invasion of epithelial cells.[16]

Transmission

Transmission of Y. pestis may occur through:[17]

  • Droplet contact – coughing or sneezing on another person
  • Direct physical contact – touching an infected person, including sexual contact
  • Indirect contact – usually by touching soil contamination or a contaminated surface
  • Airborne transmission – if the microorganism can remain in the air for long periods
  • Fecal-oral transmission – usually from contaminated food or water sources
  • Vector borne transmission – carried by insects or other animals

Unlike other types of plague, the pneumonic type can be transmitted from person to person. Pneumonic plague affects the lungs and is transmitted when a person breathes in Y. pestis particles in the air.

Bubonic plague is transmitted through the bite of an infected flea or exposure to infected material through a break in the skin.

Flea Bites

Plague bacteria are most often transmitted by the bite of an infected flea. During plague epizootics, many rodents die, causing hungry fleas to seek other sources of blood. People and animals that visit places where rodents have recently died from plague, are at risk of being infected from flea bites. Dogs and cats may also bring plague-infected fleas into the home. Flea bite exposure may result in primary bubonic plague or septicemic plague.

This way of transmission distinguishes Yersinia pestis from other enterobacteriaceae such as Yersinia pseudotuberculosis.[1]

Contact with Contaminated Fluid or Tissue

Humans can become infected when handling tissue or body fluids of a plague-infected animal. For example, a hunter skinning a rabbit or other infected animal without using proper precautions could become infected with plague bacteria. This form of exposure most commonly results in bubonic plague or septicemic plague.

Infectious Droplets

When a person has plague pneumonia, they may cough droplets containing the plague bacteria into air. If these bacteria-containing droplets are breathed in by another person, they can cause pneumonic plague.

Typically this requires direct and close contact with the person with pneumonic plague. Transmission of these droplets is the only way that plague can spread between people. This type of spread has not been documented in the United States since 1924, but still occurs with some frequency in developing countries.

Cats are particularly susceptible to plague, and can be infected by eating infected rodents. Sick cats pose a risk of transmitting infectious plague droplets to their owners or to veterinarians. Several cases of human plague have occurred in the United States in recent decades as a result of contact with infected cats.

Gross Pathology

Bubonic Plague

Common presentation includes a skin lesion, that may be a papule, vesicle, ulcer or eschar on the site of the bite, and enlarged regional lymph nodes. The "buboes" may measure from 1 to 10 cm. There may also be deeper enlarged lymph nodes.[1]

Pulmonic Plague

Commonly occurs with pulmonary lobe involvement, progressing into bilateral pneumonia, pleurisy, cavitations, potentially culminating in ARDS.[1]

Septicemic Plague

This type of plague commonly leads to small vessel thrombosis, which is responsible for the necrosis of extremities, such as fingers, toes and tip of the nose. These manifestations may occur in advanced disease.[1]

Microscopic Pathology

Studies in Y. pestis-infected cats revealed similar histological changes to those verified in humans. Common microscopic findings include:[18]

Gallery

Gross Pathology

Microscopic Pathology

References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 Koirala, Janak (2006). "Plague: Disease, Management, and Recognition of Act of Terrorism". Infectious Disease Clinics of North America. 20 (2): 273–287. doi:10.1016/j.idc.2006.02.004. ISSN 0891-5520.
  2. 2.0 2.1 Plague Manual: Epidemiology, Distribution, Surveillance. World Health Organization. Communicable Disease Surveillance and Response and Control. WHO/CDS/CSR/EDC/99.2
  3. 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.
  4. "Plague manual--epidemiology, distribution, surveillance and control". Wkly Epidemiol Rec. 74 (51–52): 447. 1999. PMID 10635759.
  5. Bossi P, Tegnell A, Baka A, Van Loock F, Hendriks J, Werner A; et al. (2004). "Bichat guidelines for the clinical management of plague and bioterrorism-related plague". Euro Surveill. 9 (12): E5–6. PMID 15677847.
  6. Cleri DJ, Vernaleo JR, Lombardi LJ, Rabbat MS, Mathew A, Marton R; et al. (1997). "Plague pneumonia disease caused by Yersinia pestis". Semin Respir Infect. 12 (1): 12–23. PMID 9097371.
  7. Salyers AA, Whitt DD (2002). Bacterial Pathogenesis: A Molecular Approach (2nd ed.). ASM Press. pp. 207-12.
  8. 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.
  9. 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)
  10. 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)
  11. 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)
  12. 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)
  13. 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)
  14. 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.
  15. 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)
  16. 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.
  17. Plague Manual: Epidemiology, Distribution, Surveillance and Control, pp. 9 and 11. WHO/CDS/CSR/EDC/99.2
  18. Watson RP, Blanchard TW, Mense MG, Gasper PW (2001). "Histopathology of experimental plague in cats". Vet Pathol. 38 (2): 165–72. PMID 11280372.
  19. 19.00 19.01 19.02 19.03 19.04 19.05 19.06 19.07 19.08 19.09 19.10 19.11 19.12 19.13 19.14 19.15 19.16 19.17 19.18 19.19 19.20 19.21 19.22 19.23 19.24 19.25 19.26 19.27 "Public Health Image Library (PHIL), Centers for Disease Control and Prevention".


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