Yersinia pestis

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Yersinia pestis
A scanning electron micrograph depicting a mass of Yersinia pestis bacteria
Scientific classification
Kingdom:
Eubacteria
Phylum:
Proteobacteria
Class:
Gammaproteobacteria
Order:
Enterobacteriales
Family:
Enterobacteriaceae
Genus:
Yersinia
Species:
Y. pestis
Binomial name
Yersinia pestis
(Lehmann & Neumann, 1896)
van Loghem 1944

Yersinia pestis (formerly Pasteurella pestis) is a Gram-negative rod-shaped bacterium belonging to the family Enterobacteriaceae. It is a facultative anaerobe that can infect humans and other animals.

Human Y. pestis infection takes three main forms: pneumonic, septicemic, and the notorious bubonic plagues.[1] All three forms have been responsible for high mortality rates in epidemics throughout human history, including the Black Death (a bubonic plague) that accounted for the death of at least one-third of the European population in 1347 to 1353.

In September 2009 the death of a molecular genetics professor at the University of Chicago was linked to his work on a weakened strain of Y. pestis.[2].

Y. pestis has gained attention as a possible biological warfare agent and the CDC has classified it as a category A pathogen requiring preparation for a possible terrorist attack.

History

Y. pestis was discovered in 1894 by Alexandre Yersin, a Swiss/French physician and bacteriologist from the Pasteur Institute, during an epidemic of plague in Hong Kong.[3] Yersin was a member of the Pasteur school of thought. Shibasaburo Kitasato, a German-trained Japanese bacteriologist who practiced Koch's methodology was also engaged at the time in finding the causative agent of plague.[4] However, it was Yersin who actually linked plague with Yersinia pestis. Originally named Pasteurella pestis, the organism was renamed in 1967.

Originally three biovars of Y. pestis were thought to correspond to one of the historical pandemics of bubonic plague.[5] Biovar Antiqua is thought to correspond to the Plague of Justinian; it is not known whether this biovar also corresponds to earlier, smaller epidemics of bubonic plague, or whether these were even truly bubonic plague.[6] Biovar Mediaevalis is thought to correspond to the Black Death. Biovar Orientalis is thought to correspond to the Third Pandemic and the majority of modern outbreaks of plague. Y. pestis was transmitted by fleas infesting rats. However, recent MLST data has shown that in fact Yersinia pestis is clonal, so this somewhat overthrows the 'biovar' hypothesis.

Every year thousands of cases of plague are still reported to the World Health Organization, although with proper treatment the prognosis for victims is now much better. A five to sixfold increase in cases occurred in Asia during the time of the Vietnam war, possibly due to the disruption of ecosystems and closer proximity between people and animals. Plague also has a detrimental effect on mammals other than humans. In the United States of America, endangered animals such as the black-tailed prairie dog and the black-footed ferret are both under threat from the disease.[citation needed]

Role in Black Death

DNA from Y. pestis has been found in the teeth of an individual who supposedly died from the Black Death, and medieval corpses who died from other causes have tested positive for Y. pestis.[7][8] This suggests that Y. pestis was, at the very least, a contributing factor in some (though possibly not all) of the European plagues. It is possible that the selective pressures induced by the plague might have changed how the pathogen makes itself manifest in humans, selecting against the individuals or populations which were the most susceptible.

General characteristics

Y. pestis is a rod-shaped facultative anaerobe with bipolar staining (giving it a safety pin appearance).[9] Similar to other Yersinia members, it tests negative for urease, lactose fermentation, and indole.[10] The closest relative is the gastrointestinal pathogen Yersinia pseudotuberculosis, and more distantly Yersinia enterocolitica.

Genome

The complete genomic sequence is available for two of the three sub-species of Y. pestis: strain KIM (of biovar Medievalis),[11] and strain CO92 (of biovar Orientalis, obtained from a clinical isolate in the United States).[12] As of 2006, the genomic sequence of a strain of biovar Antiqua has been recently completed.[13] Similar to the other pathogenic strains, there are signs of loss of function. The chromosome of strain KIM is 4,600,755 base pairs long; the chromosome of strain CO92 is 4,653,728 base pairs long. Like its cousins Y. pseudotuberculosis and Y. enterocolitica, Y. pestis is host to the plasmid pCD1. In addition, it also hosts two other plasmids, pPCP1 (also called pPla or pPst) and pMT1 (also called pFra) which are not carried by the other Yersinia species. pFra codes for a phospholipase D that is important for the ability of Y. pestis to be transmitted by fleas[14]. pPla codes for a protease, Pla, that activates plasminogen in human hosts and is a very important virulence factor for pneumonic plague.[15] Together, these plasmids, and a pathogenicity island called HPI, encode several proteins which cause the pathogenesis for which Y. pestis is famous. Among other things, these virulence factors are required for bacterial adhesion and injection of proteins into the host cell, invasion of bacteria into the host cell, and acquisition and binding of iron harvested from red blood cells. Y. pestis is thought to be descendant from Y. pseudotuberculosis, differing only in the presence of specific virulence plasmids.

A comprehensive and comparative proteomics analysis of Y. pestis: strain KIM was performed in 2006;[16] this analysis focused on the transition to a growth condition mimicking growth in host cells.

Pathogenics and immunity

In the urban and sylvatic cycles of Y. pestis most of the spreading occurs between rodents and fleas. In the sylvatic cycle the rodent is wild, unlike in the urban cycle, where the rodent is domestic. Additionally Y. pestis can spread from the urban environment and back again. Every infected animal can transmit the infection to humans through contact with skin tissue. Humans can also spread the bacteria to other humans through sneezing, coughing or direct contact with infected tissue.

In reservoir hosts

The reservoir commonly associated with Y. pestis are several species of rodents. In the steppes, the reservoir species is principally believed to be the marmot. In the United States, several species of rodents are thought to maintain Y. pestis. However, the case is not very clear because the expected disease dynamics have not been found in any rodent species. It is known that some individuals in a rodent population will have a different resistance, which could lead to a carrier status.[17] There is some evidence that fleas from other mammals have a role in human plague outbreaks.[18]

This lack of knowledge of the dynamics of plague in mammal species is also true among susceptible rodents such as the black-tailed prairie dog (Cynomys ludovicianus), in which plague can cause colony collapse resulting in a massive effect on prairie food webs.[19] However, the transmission dynamics within prairie dogs does not follow the dynamics of blocked fleas; carcasses, unblocked fleas, or another vector could possibly be important instead.[20]

In other regions of the world the reservoir of the infection is not clearly identified, which complicates prevention and early warning programs. One such example was seen in a 2003 outbreak in Algeria.[21]

Infector

The transmission of Y. pestis by fleas is well characterized.[22] Initial acquisition of Y. pestis by the vector occurs during feeding on an infected animal. Several proteins then contribute to the maintenance of the bacteria in the flea digestive tract, among them the hemin storage (Hms) system and Yersinia murine toxin (Ymt).

Although Ymt is highly toxic to rodents and was once thought to be produced to insure reinfection of new hosts, it has been demonstrated that murine toxin is important for the survival of Y. pestis in fleas.[14]

The Hms system plays an important role in the transmission of Y. pestis back to a mammalian host.[23] The proteins encoded by Hms genetic loci aggregate in the esophagus and proventriculus of the flea, which is a structure that ruptures blood cells. Aggregation of Hms proteins inhibits feeding and causes the flea to feel hungry. Transmission of Y. pestis occurs during the futile attempts of the flea to feed. Ingested blood is pumped into the esophagus, where it dislodges bacteria growing there and is regurgitated back into the host circulatory system.

In humans and other susceptible hosts

Pathogenesis due to Y. pestis infection of mammalian hosts is due to several factors including an ability of these bacteria to suppress and avoid normal immune system responses such as phagocytosis and antibody production. Flea bites allow for the bacteria to enter through the skin. Y. pestis expresses the yadBC gene, which is similar to adhesins in other Yersinia species, allowing for adherence and invasion of epithelial cells.[24] Y. pestis expresses a plasminogen activator that is an important virulence factor for pneumonic plague and which might act on blood clots in order to facilitate systematic invasion.[15] 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.[9] These antigens are produced by the bacterium at normal human body temperature. Furthermore, Y. pestis survives and produces F1 and V antigens while it is residing within 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.[25]

Additionally, the Type III secretion system allows Y. 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. YopO, YopH, YopM, YopT, YopJ and YopE are injected into the cytoplasm of host cells via T3SS into a pore created in part by YopB and YopD.[26] These injected Yop proteins limit phagocytosis and cell signaling pathways important in the innate immune system, as discussed below.

Yersinia pestis proliferates inside lymph nodes where it is able to avoid destruction by cells of the immune system such as macrophages. The ability of Yersinia pestis to inhibit phagocytosis allows it to grow in lymph nodes and cause lymphadenopathy. YopH is a protein tyrosine phosphatase that contributes to the ability of Yersinia pestis to evade immune system cells.[27] 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 and 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.[28] This might limit the function of YopB/D to creating 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.[29] YopJ acetylates MAPK kinases at serines and threonines that are normally phosphorylated during activation of the MAP kinase cascade.[30] 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.[31]

Immunity

A formalin-inactivated vaccine once was available for adults at high risk of contracting the plague until removal from the market by the U.S. Food and Drug Administration. It was of limited effectiveness and may cause severe inflammation. Experiments with genetic engineering of a vaccine based on F1 and V antigens are underway and show promise; however, bacteria lacking antigen F1 are still virulent, and the V antigens are sufficiently variable, that vaccines composed of these antigens may not be fully protective.[32] United States Army Medical Research Institute of Infectious Diseases (USAMRIID) have found that an experimental F1/V antigen based vaccine protect cynomolgus macaques, but fails to protect African green monkeys.[33] A report found that Europeans were less likely to catch the plague, because they are the descendants of the survivors of the plagues that affected Europe in the medieval times.[citation needed]

Clinical aspects

Symptoms and disease progression

  • Bubonic plague
    • Incubation period of 2–6 days, when the bacteria is actively replicating.
    • Universally a general lack of energy
    • Fever
    • Headache and chills occur suddenly at the end of the incubation period. From this point the infection is resolved or lethal.
    • Swelling of lymph nodes resulting in buboes, the classic sign of bubonic plague
  • Pneumonic plague
    • Fever
    • Chills
    • Cough
    • Chest pain
    • Dyspnea
    • Hemoptysis
    • Lethargy
    • Hypotension
    • Shock
    • Symptoms of bubonic or septicemic plague, not always present [34]

If this occurs with the classic buboes, this is considered primary, while secondary occurs after symptoms of bubonic or pneumonic infection. Since the bacteria are blood-bourne, several organs can be affected including the spleen and brain. The diffuse infection can cause an immunologic cascade to occur, leading to DIC, which in turn results in bleeding and necrotic skin and tissue. Such a disseminated infection increases mortality to 22%.

Pneumonic plague can be spread from one human to another directly by aerosol. Rarely bubonic and even more rarely septicemic plague can gain pneumonic characteristics. As with the other forms of plague, after the incubation period there is a sudden onset of coughing, high temperature, and lack of energy. From this point the infection increases in severity. Due to its high replication rates, plague proves fatal in roughly 50% of cases even with medical treatment, and is almost universally fatal without treatment.[35]

With the exception of the buboes, the initial symptoms of plague are very similar to many other disease, making diagnosis difficult.[36]

ICD-9 codes for the diseases caused by Y. pestis:

  • 020.0 Bubonic plague
  • 020.2 Septicemic plague
  • 020.5 Unspecified pneumonic plague
  • 020.3 Primary pneumonic plague
  • 020.4 Secondary pneumonic plague

Clinical determination

Grams stains can confirm the presence of gram negative rods, and in some cases the identification of the double curved shape. More definitive test is a Anti-F1 serology test, which can differentiate between different species of Yersinia.

Treatment

The traditional first line treatment for Y. pestis has been streptomycin,[37][38] chloramphenicol, tetracycline,[39] and fluoroquinolones. There is also good evidence to support the use of doxycycline or gentamicin.[40] Resistant strains have been isolated; treatment should be guided by antibiotic sensitivities where available. Antibiotic treatment alone is insufficient for some patients, who may also require circulatory, ventilator, or renal support.

In an emergency department setting, Harrison's Principles of Internal Medicine outlines the following treatment course.[41] Antibiotics within the first 24 hours is very beneficial, with intravenous being preferred in pulmonary or advanced cases. Streptomycin or gentamicin are the first-line drugs, with chloramphenicol for critically ill patients, or rarely for suspected neuro-involvement.

Notes

  1. ^ Ryan KJ; Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. pp. 484–8. ISBN 0-8385852-9-9. {{cite book}}: |author= has generic name (help)CS1 maint: multiple names: authors list (link)
  2. ^ Sadovi, Carlos (September 19, 2009). "U. of C. researcher dies after exposure to plague bacteria". Chicago Breaking News Center. Retrieved October 29, 2009.
  3. ^ Bockemühl J (1994). "[100 years after the discovery of the plague-causing agent--importance and veneration of Alexandre Yersin in Vietnam today]". Immun Infekt. 22 (2): 72–5. PMID 7959865.
  4. ^ Howard-Jones N (1973). "Was Shibasaburo Kitasato the discoverer of the plague bacillus?". Perspect Biol Med. 16 (2): 292–307. PMID 4570035.
  5. ^ Zhou D, Tong Z, Song Y, Han Y, Pei D, Pang X, Zhai J, Li M, Cui B, Qi Z, Jin L, Dai R, Du Z, Wang J, Guo Z, Wang J, Huang P, Yang R (2004). "Genetics of metabolic variations between Yersinia pestis biovars and the proposal of a new biovar, microtus". J Bacteriol. 186 (15): 5147–52. doi:10.1128/JB.186.15.5147-5152.2004. PMID 15262951.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Guiyoule A, Grimont F, Iteman I, Grimont P, Lefèvre M, Carniel E (1994). "Plague pandemics investigated by ribotyping of Yersinia pestis strains". J Clin Microbiol. 32 (3): 634–41. PMID 8195371.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Drancourt M, Aboudharam G, Signolidagger M, Dutourdagger O, Raoult D. (1998). "Detection of 400-year-old Yersinia pestis DNA in human dental pulp: An approach to the diagnosis of ancient septicemia". PNAS. 95 (21): 12637–12640. PMID 9770538.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Drancourt M; Raoult D. (2002). "Molecular insights into the history of plague". Microbes Infect. 4: 105–9. doi:10.1016/S1286-4579(01)01515-5. PMID 11825781.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ a b Collins FM (1996). Pasteurella, Yersinia, and Francisella. In: Baron's Medical Microbiology (Baron S et al, eds.) (4th ed.). Univ of Texas Medical Branch. ISBN 0-9631172-1-1.
  10. ^ Stackebrandt, Erko; Dworkin, Martin; Falkow, Stanley; Rosenberg, Eugene; Karl-Heinz Schleifer (2005). The Prokaryotes: A Handbook on the Biology of Bacteria:Volume 6: Proteobacteria: Gamma Subclass. Berlin: Springer. ISBN 0-387-25499-4.{{cite book}}: CS1 maint: multiple names: authors list (link)
  11. ^ Deng W; et al. (2002). "Genome Sequence of Yersinia pestis KIM". Journal of Bacteriology. 184 (16): 4601–4611. doi:10.1128/JB.184.16.4601-4611.2002. PMID 12142430. {{cite journal}}: Explicit use of et al. in: |author= (help)
  12. ^ Parkhill J; et al. (2001). "Genome sequence of Yersinia pestis, the causative agent of plague". Nature. 413: 523–527. doi:10.1038/35097083. PMID 11586360. {{cite journal}}: Explicit use of et al. in: |author= (help)
  13. ^ Chain PS, Hu P, Malfatti SA; et al. (2006). "Complete genome sequence of Yersinia pestis strains Antiqua and Nepal516: evidence of gene reduction in an emerging pathogen". J. Bacteriol. 188 (12): 4453–63. doi:10.1128/JB.00124-06. PMID 16740952. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  14. ^ a b Hinnebusch BJ, Rudolph AE, Cherepanov P, Dixon JE, Schwan TG, Forsberg A (2002). "Role of Yersinia murine toxin in survival of Yersinia pestis in the midgut of the flea vector". Science. 296 (5568): 733–5. doi:10.1126/science.1069972. PMID 11976454.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ a b 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ Hixson K; et al. (2006). "Biomarker candidate identification in Yersinia pestis using organism-wide semiquantitative proteomics". Journal of Proteome Research. 5 (11): 3008–3017. doi:10.1021/pr060179y. PMID 16684765. {{cite journal}}: Explicit use of et al. in: |author= (help)
  17. ^ MEYER KF (1957). "The natural history of plague and psittacosis". Public Health Rep. 72 (8): 705–19. PMID 13453634.
  18. ^ von Reyn CF, Weber NS, Tempest B; et al. (1977). "Epidemiologic and clinical features of an outbreak of bubonic plague in New Mexico". J. Infect. Dis. 136 (4): 489–94. PMID 90884. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  19. ^ Pauli JN, Buskirk SW, Williams ES, Edwards WH (2006). "A plague epizootic in the black-tailed prairie dog (Cynomys ludovicianus)". J. Wildl. Dis. 42 (1): 74–80. PMID 16699150.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Webb CT, Brooks CP, Gage KL, Antolin MF (2006). "Classic flea-borne transmission does not drive plague epizootics in prairie dogs". Proc. Natl. Acad. Sci. U.S.A. 103 (16): 6236–41. doi:10.1073/pnas.0510090103. PMID 16603630.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Bertherat E, Bekhoucha S, Chougrani S; et al. (2007). "Plague Reappearance in Algeria after 50 Years, 2003". Emerging Infect. Dis. 13 (10): 1459–1462. PMID 18257987. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  22. ^ Zhou D, Han Y, Yang R (2006). "Molecular and physiological insights into plague transmission, virulence and etiology". Microbes Infect. 8 (1): 273–84. doi:10.1016/j.micinf.2005.06.006. PMID 16182593.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ B.J. Hinnebusch, R.D. Perry and T.G. Schwan (1996). "Role of the Yersinia pestis hemin storage (hms) locus in the transmission of plague by fleas". Science. 8 (1): 367–70. doi:10.1126/science.273.5273.367. PMID 8662526.
  24. ^ 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. PMID 18025093.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ Salyers AA, Whitt DD (2002). Bacterial Pathogenesis: A Molecular Approach (2nd ed.). ASM Press. pp. 207-12.
  26. ^ 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.
  27. ^ de la Puerta ML, Trinidad AG, del Carmen Rodríguez M, Bogetz J, Sánchez Crespo M, Mustelin T, Alonso A, Bayón Y (2009). "Characterization of new substrates targeted by Yersinia tyrosine phosphatase YopH". PLoS ONE. 4 (2): e4431. doi:doi:10.1371/journal.pone.0004431. PMID 19221593. {{cite journal}}: Check |doi= value (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  28. ^ 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:doi:10.1371/journal.ppat.0040003. PMID 18193942. {{cite journal}}: Check |doi= value (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  29. ^ Hao YH, Wang Y, Burdette D, Mukherjee S, Keitany G, Goldsmith E, Orth K (2008). "Structural requirements for Yersinia YopJ inhibition of MAP kinase pathways". PLoS ONE. 2 (3): e1375. doi:doi:10.1371/journal.pone.0001375. PMID 18167536. {{cite journal}}: Check |doi= value (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  30. ^ Monack DM, Mecsas J, Ghori N, Falkow S (1997). "Yersinia signals macrophages to undergo apoptosis and YopJ is necessary for this cell death". Proc Natl Acad Sci U S A. 94 (19): 10385–10390. PMID 9294220. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  31. ^ 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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  32. ^ Welkos S; et al. (2002). "Determination of the virulence of the pigmentation-deficient and pigmentation-/plasminogen activator-deficient strains of Yersinia pestis in non-human primate and mouse models of pneumonic plague". Vaccine. 20: 2206–2214. doi:10.1016/S0264-410X(02)00119-6. PMID 12009274. {{cite journal}}: Explicit use of et al. in: |author= (help)
  33. ^ Pitt ML (October 13-14). "Non-human primates as a model for pneumonic plague. In: Animals Models and Correlates of Protection for Plague Vaccines Workshop". {{cite journal}}: Check date values in: |date= and |year= / |date= mismatch (help); Cite has empty unknown parameter: |unused_data= (help); Cite journal requires |journal= (help); Text "[1]" ignored (help)
  34. ^ Info taken from "Harrison's Principles of Internal Medicine 16th Edition"
  35. ^ Riedel S (2005). "Plague: from natural disease to bio-terrorism". Proc (Bayl Univ Med Cent). 18 (2): 116–24. PMID 16200159.
  36. ^ Prentice MB, Rahalison L (2007). "Plague". Lancet. 369 (9568): 1196–207. doi:10.1016/S0140-6736(07)60566-2. PMID 17416264.
  37. ^ Wagle PM. (1948). "Recent advances in the treatment of bubonic plague". Indian J Med Sci. 2: 489–94.
  38. ^ Meyer KF. (1950). "Modern therapy of plague". JAMA. 144: 982–5. PMID 14774219.
  39. ^ Kilonzo BS, Makundi RH, Mbise TJ. (1992). "A decade of plague epidemiology and control in the Western Usambara mountains, north-east Tanzania". Acta Tropica. 50: 323–9. doi:10.1016/0001-706X(92)90067-8. PMID 1356303.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  40. ^ Mwengee W, Butler T, Mgema S; et al. (2006). "Treatment of plague with gentamicin or doxycycline in a randomized clinical trial in Tanzania". Clin Infect Dis. 42: 614–21. doi:10.1086/500137. PMID 16447105. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  41. ^ Jameson, J. N. St C.; Dennis L. Kasper; Harrison, Tinsley Randolph; Braunwald, Eugene; Fauci, Anthony S.; Hauser, Stephen L; Longo, Dan L. (2005). Harrison's principles of internal medicine. New York: McGraw-Hill Medical Publishing Division. ISBN 0-07-140235-7.{{cite book}}: CS1 maint: multiple names: authors list (link)

External links

Wikispecies has information related to Yersinia pestis.
Wikimedia Commons has media related to Yersinia pestis.
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