BUBONIC PLAGUE
STEPHANIE SPECK
Bundeswehr Institute of Microbiology, Department of Virology and Rickettsiology, Munich, Germany
Bubonic plague, or sylvatic plague, is an acute, highly virulent zoonotic disease.
Three classic manifestations have been described — bubonic, pneumonic and septicaemia plague, which are primarily seen in susceptible non-rodent species and humans(43).AETIOLOGY
Yersinia pestis, the causative agent of plague, is a small (0.5—0.8 ? 1—3 μm), Gram-negative, non-spore-forming, facultative anaerobic, facultative intracellular, pleomorphic rod. Like other Enterobacteriaceae, Y. pestis is oxidasenegative, capable of fermenting glucose, and usually nitrate reductase-positive. Multilocus sequence typing of housekeeping genes has revealed that Y. pestis resembles a clone derived from the enteric pathogen Y. pseudotuberculosis1'4'1. Among 11 species of Yersinia, four are considered primary pathogens, but Y. pestis is the most important agent in wild mammals(43).
EPIDEMIOLOGY
In Europe, Ypestis occurred for a long period in the past, but is now notably absent from Western and Central Europe (as well as Canada and parts of North and South America). Natural foci of plague exist in the southern and south-eastern regions of the former Soviet Union, i.e. Armenia, Azerbaijan, Georgia, Kazakhstan, Kirghizia, Russia, Tadjikistan, Turkmenistan and Uzbekistan(45). In Mongolia, highly active plague foci have been described from the western parts of the country'46). For more recent information about the occurrence of plague in animals worldwide, see the World Organisation for Animal Health (OIE) World Animal Health Information Database (WAHID) Interface'47).
Plague is fundamentally a disease of rats and other wild rodents. Humans, domestic animals and other wildlife are considered accidental hosts.
Sylvatic plague occurs in wild rodents other than rats. At least 38 species of wild rodents, including marmots and squirrels, have been found to be susceptible; however, the organism has been found in association with more than 200 species of wild rodents throughout the world, except Australia(3). Of these rodent species, only 30—40 serve as permanent reservoirs of plague, with the remainder being temporary or epizootic hosts. Mammalian hosts can be divided into different epi- demiologically important categories based on susceptibility to Y. pestis:1. enzootic or maintenance, reservoir rodent hosts (e.g. Microtus spp., Spermophilus spp., Onychomys spp.)
2. epizootic or amplification rodent hosts (e.g. Cynomys spp.)
3. resistant non-rodent hosts (e.g. ungulates, rodentconsuming carnivores)
4. susceptible non-rodent hosts (e.g. primates including humans, Felis spp., Mustela nigripes')^'’.
Certain features have been identified that are characteristic for the different mammalian host categories: e.g. a high versus a low resistance to plague morbidity and mortality in enzootic versus epizootic hosts, a high reproductive potential and multiple litters in enzootic hosts and, as the death rate is high, a large population density in epizootic hosts. Birds, lagomorphs, carnivores and primates may play an occasional role in disseminating infection1-43’. Siberian marmot (Marmota sibirica), Pallas’s pika (OchotonapallasS), Brandt’s vole (Lasiopodomys brandti) and souslik (Spermophilus spp.) are the main hosts for plague in Mongolia, but Y. pestis has also been detected in Daurian pika ( Ocho- tona daurica), grey marmot (Marmota baibacina), longtailed marmot (M. caudata), vole (Alticola spp., Microtus spp.), gerbil (Meriones spp., Rhombomys spp.), Siberian five-toed jerboa (Allactaga sibirica(, Russian hamster ( Ony- chomys leucogaster), Siberian polecat (Mustela eversmanns'), mountain weasel (M. altaica( and the Northern wheateater (Oenante oenante)(45’46).
A correlation between the feeding behaviour of carnivores and omnivores (i.e. prey species and their susceptibility to Y. pestis) and their exposure to plague has been observed. Predators feeding on enzootic and epizootic hosts probably contract plague.Yersinia pestis requires an animal host for its long-term survival. The bacterium is transmitted by fleas, which become infected during their blood meal on infected rodents. Yersinia ingested by fleas multiplies in the midgut. When the flea bites, aspirated blood containing Y.pestis is regurgitated from the flea into the bite wound. More than 1,500 flea species have been described as potential vectors. Host specificity and host range of fleas, geographic distribution, flea activity throughout the year, and the flea life cycle (nesting versus body flea) account for flea vector competence. Seeking for substitute host species, if the primary host is not available (‘straggling’ ), could contribute to amplification of infection during plague epizootics. The vector efficacy is influenced by the degree of bacter- aemia and the level of antibodies in the host at the time of the blood meal. In addition, transmission of Y. pestis by fleas is affected by host animal behaviour, social structure (group of animals versus the solitary species) and feeding habits. Lagomorphs and insectivores sharing habitats with sylvatic rodents may enhance their exposure to plaguetransmitting fleas. Enzootic plague foci are maintained by certain rodent-flea associations1-43’.
PATHOGENESIS, PATHOLOGY AND IMMUNITY
Temperature and iron acquisition are important for Y. pestis virulence. Depending on the host and cell type infected, other stimuli may also induce the expression of virulence factors. Growing at low temperature inside the flea host results in little or no expression of the F1 capsular antigen, one of several components used by Y. pestis for evading phagocytosis by neutrophils and macrophages. Other virulence factors include the plasminogen activator (Pla), which is required for dissemination from the inoculation site to the surrounding lymph node, and a type III secretion apparatus, which injects virulence proteins into the cytosol of target cells.
The principal route of transmission in mammals is via flea bites. Less commonly seen is ingestion of, or exposure to, another mammal infected with Y. pestis. Inhalation of aerosolized bacteria has also been described. Close contact to recently deceased infected animals such as during skinning or post mortem investigation has been shown to cause infection and death in humans(49). Transmission of the infection by the latter routes differs significantly from flea- borne infection: the bacterial inoculate is much greater and Y. pestis growing in the mammalian host expresses virulence factors that assist in evading the host’s immune response. These Yersinia are more virulent than flea-borne Y. pestis(43).
The lesions seen in Y. pestis-infected mammals vary greatly according to the mode of transmission and susceptibility of the host. Highly susceptible rodents often die so quickly that the lesions may be subtle. Most animals develop a bubonic form of the disease with varying degrees of internal organ involvement and bacteraemia. After an infected flea bite, susceptible animals form an almost immediate red areola around the bite wound, followed by a papule within 2 to 3 days. Yersinia pestis spreads from the wound to the regional lymph nodes, causing the formation of a bubo (swollen lymph node). Oral inoculation can also lead to buboes in the submandibular, cervical, retropharyngeal and mesenteric lymph nodes. The infection can be contained at this level (bubonic plague), or the bacteria multiply greatly and spread, via the bloodstream, to the liver, spleen and other organs, including other lymph nodes, where secondary buboes may develop (sep- ticaemic plague). Septicaemia is frequently followed by death approximately 2 weeks after infection, as a result of disseminated intravascular coagulation, endotoxic shock and widespread haemorrhages and thrombi formation. Pneumonic plague is characterized by severe alveolar oedema and vascular haemorrhage, in addition to fulminant necrotizing pneumonia caused by massive bacterial replication and inflammation.
Histologically, necrosuppurative inflammation associated with very large numbers of Ypestis bacilli is seen — a central area of bacteria, haemorrhage and necrotic debris is surrounded by dense neutrophilic infiltration in affected lymph nodes, liver, spleen and pneumonic lesions. It is unclear what determines resistance or susceptibility to Y. pestis infection in rodents and other animals, and current understanding of immunity to Y. pestis is based largely on studies involving Y. enterolitica and Y. pseudotuberculosis. Both cellular and humoral responses are evoked, but antibodies are not always protective against infection.
CLINICAL SIGNS AND TREATMENT
Clinical signs vary depending on the susceptibility of the host, and in highly susceptible species such as many rodents, rapid death may be the only sign. Carnivores are generally resistant to plague, and ingestion of infected rodents causes inapparent to mild disease and seroconversion. However, orally infected domestic cats become acutely ill with a high fever, depression and anorexia. They develop buboes, septicaemia and pneumonic plague, and approximately one- third of cats die within 10 days of infection — similar susceptibility is suspected in wild felines but has not been proven. Although plague is relatively rare in wild ungulates, mule deer (Odocoileus hemionus) with systemic plague revealed bronchopneumonia and lymphadenitis1-50) and ocular plague has been described in a black- tailed deer (Odocoileus hemionus columbianus) in the USA(51). The black-tailed deer was blind and, histologically, had moderate to severe necrotizing and fibrinopurulent endophthalmitis, with varying degrees of keratoconjunctivitis with abundant intralesional coccobacilli(51). Numerous firm, white foci within the lungs and on pleural surfaces, and necrotic areas within enlarged lymph nodes, were noted in mule deer(50). Microscopically, the lung lesions constituted of necrotic foci containing large, pale basophilic bacterial colonies surrounded by neutrophils.
Extensive necrosis was also found in the medulla of mandibular and pharyngeal lymph nodes. In addition, a severe degenerative myopathy was described(50).Treatment of wild animals with plague is generally not possible or practical. However, supportive care and antibiotic therapy with doxycycline, tetracycline or potentiated sulphonamides can be effective in uncomplicated cases.
DIAGNOSIS
Diagnosis of plague is restricted to reference laboratories, because Y. pestis is a highly virulent and zoonotic agent that must be processed under biosafety level 3 conditions. Attending staff should use standard barrier precautions, including gloves, FFP3 masks and gowns while examining and treating suspect animals. Surgical masks may not provide protection from respiratory droplet exposure via inhalation, and a well-fitted FFP3 mask is recommended. Gross and microscopic lesions may be suggestive of plague but culture of Y. pestis is necessary for definitive diagnosis. Fluorescence antibody tests and detection of Y. pestis DNA by PCR are also frequently used.
PUBLIC HEALTH CONCERN
Plague is a zoonotic disease. People working with wildlife and in veterinary practice as well as hunters in plagueendemic areas should be aware of the signs and symptoms suggestive of plague and the risks associated with handling possibly plague- infected animals. Appropriate hygiene is recommended in order to minimize the risk of disease transmission to humans. Treating suspect animals and post mortem investigations should be carried out using appropriate personal protective equipment (gloves, FFP3 masks, gowns) and in biosecure cabinets.
SIGNIFICANCE AND IMPLICATIONS FOR ANIMAL HEALTH
The effect of plague on wild animal populations depends on the susceptibility of the host species. In reintroduced Canada lynx (Lynx canadensis), six of 52 fatal casualties died from pneumonic plague. The disease appeared as a significant mortality factor that warrants further investigation to determine its potential for impact on the recovery of lynx in their habitat range(52). Epizootic plague affects prairie dogs (Cynomys spp.) and black-footed ferrets (Mustela nigripes) and is a major factor limiting recovery of the highly endangered black-footed ferret in the USA. Flea control as well as vaccination studies have been initiated in ferrets(53).
REFERENCES
1. Bottone, E.J. Yersinia enterocolitica: overview and epidemiologic correlates. Microbes and Infection. 1999;1:323-33.
2. Heesemann, J., Gross, U., Schmidt, N. et al. Immunochemical analysis of plasmid-encoded proteins released by enter opatho genic Yersinia grown in calcium deficient medium. Infection and Immunity. 1986;2:561-7.
3. Mair, N.S. Yersiniosis in wildlife and its public health implications. Journal of Wildlife Diseases. 1973;3:64-71.
4. Zhang, S., Zhang, Z., Liu, S. et al. Fatal yersiniosis in farmed deer
caused by Y. pseudotuberculosis serotype O:3 encoding a
mannosyltransferase-like protein WbyK. Journal of Veterinary Diagnostic Investigation. 2008;20:356-9.
5. Mollaret, H.H. L'infection a bacille de Malassez etVignal. World Health Organization/Zoonoses. 1967;67:99.
6. Bercovier, H., Brault, J., Treignier, M. et al. Biochemical, serological, and phage typing characteristics of 459 Yersinia strains isolated from a terrestrial ecosystem. Current Microbiology. 1978;1:353-7.
7. Alonso, J.M., Bercovier, H., Servan, J. et al. Contribution to the study of the ecology of Yersinia enterocolitica in France. In: Carter, P.B., Lafleur, L. &Toma, S. (eds). Contributions to Microbiology and Immunology. Basel: S. Karger AG; 1979; pp. 132 43.
8. Kapperud, G. Yersinia enterocolitica in small rodents from Norway, Sweden and Finland. Acta Pathologica et Microbiologica Scandinavica, B. 1975;83:335-42.
9. Niskanen, T., Waldenstrom, J., Fredriksson-Ahomaa, M. et al. virF- positive Yersinia pseudotuberculosis and Yersinia enterocolitica found in migratory birds in Sweden. Applied and Environmental Microbiology. 2003;69:4670-5.
10. Griffin, J.F.T., Thomson, A.J., Cross, J.P. et al. The impact of domestication on red deer immunity and disease resistance. The Biology of Deer. 1992;14:120-5.
11. Aldova, E., Cerni, J. & Chmella, J. Findings of Yersinia in rats and sewer rats. Zentralblatt fuer Bakteriologie, Mikrobiologie und Hygiene A. 1977;239:208-12.
12. Chernyanskii, VF. The simultaneous isolates of Y. pseudotuberculosis and Y. enterocolitica in the arctic regions. Zhurnal Mikrobiologii, Epi- demiologii, i Immunobiologii. 1981;6:104-5.
13. Nikolova, S., Tzvetkov, Y., Najdenski, H. et al. Isolation of pathogenic yersiniae from wild animals in Bulgaria. Journal of Veterinary Medicine B. 2001;48:203-9.
14. Macdonald, J.W Mortality in wild birds with some observations on bird weights. Bird Study. 1962;9:147-67.
15. Macdonald, J.W Mortality in wild birds. Bird Study. 1965;12: 181-95.
16. Frolich, K., Wisser, J., Schmuser, H. et al. Epizootologic and ecologic investigations of European brown hares (L epus europaeus) in selected populations from Schleswig-Holstein, Germany. Journal of Wildlife Diseaset. 2003;39:751-61.
17. Wuthe, H.H. Aleksic, S. & Kwapil, S. Yersinia in the European brown hare of Northern Germany. In: Chiesa, G.R.C. (ed.) Yersiniosis: Presence and Future Contributions to Microbiology and Immunology. Basel: S. Karger AG; 1995; pp. 51-4.
18. Dubois, P, Fievez, L. & Granville, A. Le lievre, porteur asymptomatic de Yersinia enterocolitica. Medicine and Maladies Infectieuxi. 1971;1:227-8.
19. Dahouk, S.A., Nockler, K., Tomaso, H. et al. Seroprevalence of brucellosis, tularemia, and yersiniosis in wild boars (Sus scrofa) from NorthEastern Germany. Journal of Veterinary Medicine B. 2005;52:444-55.
20. Blanc, G. & Baltazard, M. Contribution a l'etude de comportement des microbes pathogenes chez les insects hematophages: la memoire. Archives de lTnstitut Pasteur de Maroc. 1944;3:21^9.
21. Blackmore, D.K. A survey of diseases in British wild foxes (Vulpes vulpes). Veterinary Record. 1964;76:527-33.
22. Becht, H. Untersuchungen uber die pseudotuberkulose beim chinchilla. Deutsche Tieraeztliche Wochenschrift. 1962;69:626-7.
23. Najdenski, H. Vesselinova, A., Golkocheva, E., garbom, S, & Wolf- Watz, H. Experimental infections with wild and mutant Yersinia pseudotuberculosis strains in rabbits. Journal of Veterinary Medicine B. 2003;50:280-8.
24. Bengis, R.G., Kock, R.A. & Fischer, J. Infectious animal diseases: the
wildlife/lifestock interface. Revue Scientifique et Technique.
2002;21:53-63.
25. Hubbert, WT Yersiniosis in mammals and birds in the United States. American Journal of Tropical Medicine and Hygiene. 1972;21:458-63.
26. Veljanov, D., Nikolova, S., Najdenski, H. et al. Studies on aerosol Yersinia pseudotuberculosis infection of guinea pigs. Acta Microbiologica Bulgarica. 1993;30:3-10.
27. Fisher, M.L., Castillo, C. & Mecsas J. Intranasal inoculation of mice with Yersinia pseudotuberculosis causes a lethal lung infection that is dependent on yersinia outer protein and PhoP. Infection and Immunity. 2007;75:429-42.
28. Ulyanova, N.I. The natural focal occurrence of pseudotuberculosis.
Journal of Microbiology, Epidemiology and Immunobiology.
1961;32:2268-73
29. Autenrieth, I.B. & Firsching, R. Penetration of M cells and destruction of Peyer's patches by Yersinia enterocolitica'. an ultrastructural and histological study. Journal of Medical Microbiology. 1996;44:285-94.
30. Grutzkau, A., Hanski, C., Hahn, H. et al. Involvement of M-cells in the bacterial invasion of Peyer ,s patches: a common mechanism shared by Yersinia enterocolitica and other entero invasive bacteria. Gut. 1990;31:1011-5.
31. Autenrieth, I.B., Beer, M., Bohn, E. et al. Immune responses to Yersinia enterocolitica in susceptible BALB/c and resistant C57BL/6 mice: an essential role for gamma interferon. Infection and Immunity. 1994;62:2590-9.
32. Carter, PB. Pathogenicity of Yersinia enterocolitica for mice. Infection and Immunity. 1975;11:164-70.
33. Aili, M., Isaksson, E.L., Carlsson, S.E. et al. Regulation of Yersinia Yop-effector delivery by translocated YopE. International Journal of Medical Microbiology. 2007;298:183-92.
34. Lemaitre, N., Sebanne, F., Long, D. & Hinnebusch, J.B. Yersiniapestis YopJ suppresses tumor necrosis factor alpha induction and contributes to apoptosis of immune cells in the lymph node but is not required for virulence in a rat model of bubonic plague. Infection and Immunity. 2006;74:5126-31.
35. Heesemann, J., Sing, A. & Trulzsch, K. Yersinias stratagem: targeting innate and adaptive immune defence. Current Opinion in Microbiology. 2006;9:55-61.
36. Skurnik, M. Molecular genetics, biochemistry and biological role of Yersinia lipopolysaccharide. Advances in Experimental Medicine and Biology. 2003;529:187-97.
37. Veljanov, D.K., Vesselinova, A.M., Nikolova, S.F. et al. Experimental infection with Yersinia pseudotuberculosis of ground squirrels (Cytellus cytellus). Journal of Veterinary Medicine B. 1993;40:589-96.
38. Najdenski, H., Nikolova, S., Vesselinova, A. et al. Studies of Yersinia enterocolitica O:3 experimental infection in pigs. Journal of Veterinary Medicine B. 1998;45:59-64.
39. Wuthe, H.H. & Aleksic, S. Yersinia enterocolitica serovar 2a, wb, 3:b,c biovar 5 in hares and sheep. Berliner und Muenchener Tierarztlische Wochenschrift. 1997;110:176-7.
40. Sanford, S.E. Outbreaks of yersiniosis caused by Yersinia pseudotuberculosis in farmed cervids. Journal of Veterinary Diagnostic Investigation. 1995;7:78-81.
41. Jerrett, I.V & Slee, K.J. Bovine abortion associated with Yersiniapseudotuberculosis infection. Veterinary Pathology. 1989;26:181-3.
42. Niskanen, T., Fredriksson-Ahomaa, M. & Korkeala, H. Yersinia pseudotuberculosis with limited genetic diversity is a common finding in tonsils of fattening pigs. Journal of Food Protection. 2002;65:540-5.
43. Gasper, P.W. & Watson, R.P. Plague and Yersiniosis. In: Williams, E.S. & Barker, I.K., (eds). Infectious Diseases of Wild Mammals, 3rd edn. 2001; pp. 313-29.
44. Achtman, M., Zurth, K., Morelli, G., Torrea, G., Guiyoule, A. & Carniel, E. Yersinia pestis, the cause of plague, is a recently emerged clone of Yersinia pseudotuberculosis. Proceedings of the National Academy of Science USA. 1999;96:14043-8.
45. Anisimov, A.P, Lindler, L.E. & Pier, G.B. Intraspecific diversity of Yersinia pestis. Clinical Microbiology Reviews. 2004;17:434-64.
46. Galdan, B., Undraa, B., Baigalmaa, M. & Otgonbaatar, D. Plague in Mongolia. Vector-borne and Zoonotic Diseases. 2010;10:69-75.
47. OIE. World Animal Health Information Database (WAHID) Interface. Available online at: http://www.oie.int/wahis/public.php?page= home [accessed 20 March 2012].
48. Poland, J.D., Quan, TJ. & Barnes, A.M. Plague. In: Steele, J.H. (ed.) CRC Handbook series in Zoonoses, Section A: Bacterial, Rickettsial, and Mycotic Diseases. Boca Raton, Fl: CRC Press; 1994; pp. 93-112.
49. Wong, D., Wild, M.A., Walburger, M.A. et al. Primary pneumonic plague contracted from a mountain lion carcass. Clinical Infectious Diseases. 2009;49:e33-8.
50. Thorne, E.T., Quan, TJ., Williams, E.S., Walthall, TJ. & Daniels, D. Plague in a free-ranging mule deer from Wyoming. Journal of Wildlife Diseases. 1978;23:155-9.
51. Jessup, D.A., Murphy, CJ., Kock, N., Jang, S. & Hoefler, L. Ocular lesions of plague (Yersinia pestis) in a black- tailed deer (Odocoileus hemionus columbianus). Journal of Zoo and Wildlife Medicine. 1989;20:360-3.
52. Wild, M.A., Shenk, T.M. & Spraker, T.R. Plague as mortality factor in Canada lynx (Lynx canadensis) reintroduced to Colorado. Journal of Wildlife Diseases. 2006;42:646-50.
53. Matchett, M.R., Biggins, D.E., Carlson, V., Powell, B. & Rocke, T. Enzootic plague reduces black-footed ferret (Mustela nigripes) survival in Montana. Vector-borne and Zoonotic Diseases. 2010;10:27-35.