Tularemia – zoonosis carrying a potential risk of bioterrorism

Authors: M. Prokšová 1;  J. Bavlovič 1;  J. Klimentová 1;  J. Pejchal 2;  J. Stulík 1
Authors‘ workplace: Katedra molekulární patologie a biologie, Fakulta vojenského zdravotnictví, Univerzita obrany, Hradec Králové 1;  Katedra toxikologie a vojenské farmacie, Fakulta vojenského zdravotnictví, Univerzita obrany, Hradec Králové 2
Published in: Epidemiol. Mikrobiol. Imunol. 68, 2019, č. 2, s. 82-89
Category: Review Article


Tularemia, otherwise known as “rabbit fever”, is a zoonotic disease caused by a gram-negative intracellular bacterium – Francisella tularensis. The species is considered as a potential bioterrorism agent due to its high infectivity, the fact of being relatively easy to culture, the absence of human vaccine, and the potential for spreading through aerosol. In the Czech Republic, infection is usually caused by a tick bite, less frequently by a mosquito bite, direct contact with infected animals, or ingestion of contaminated water. The aim of this review is to provide a comprehensive view of tularemia, its diagnosis, clinical symptoms and treatment, along with the military perspective on a potential risk of F. tularensis to be misused as a biological weapon.


tularemia – epidemiology – diagnostics – treatment – bioterrorism


1. Sjöstedt A. Intracellular survival mechanisms of Francisella tularensis, a stealth pathogen. Microbes and Infection, 2006;8(2):561–567.

2. Steiner DJ, Furuya Y, Metzger DW. Host–pathogen interactions and immune evasion strategies in Francisella tularensis pathogenicity. Infection and Drug Resistance, 2014;7:239–251.

3. Harris S. Japanese Biological Warfare Research on Humans: A Case Study of Microbiology and Ethics. Annals of the New York Academy of Sciences. Nedatováno;666(1):21–52.

4. Welcome to CDC stacks. Tularemia as a biological weapon : medical and public health management – 7168. Guidelines and Recommendations. Dostupné na www: https://stacks.cdc.gov/view/cdc/7168.

5. Kingry LC, Petersen JM. Francisella tularensis. In: Manual of Security Sensitive Microbes and Toxins. B.m.: CRC Press, 2014:359–363.
Dostupné na www: https://books.google.cz/books?id=J37NBQAAQBAJ&pg=PA359&lpg=PA359&dq=francisella+tularensis+misusing&source=bl&ots=

6. Cowley SC, Elkins KL. Immunity to Francisella. Frontiers in Microbiology, 2011;2.

7. WHO. Health aspects of chemical and biological weapons, 1st edition, 1970. WHO. Dostupné na www: http://www.who.int/csr/delibepidemics/biochem1stenglish/en/.

8. McLendon MK, Apicella MA, Allen L.-AH. Francisella tularensis: Taxonomy, Genetics, and Immunopathogenesis of a Potential Agent of Biowarfare. Annual review of microbiology. 2006;60:167–185.

9. Kaufmann AF, Meltzer MI, Schmid GP. The economic impact of a bioterrorist attack: are prevention and postattack intervention programs justifiable? Emerging Infectious Diseases, 1997;3(2):83–94.

10. Sunagar R, Kumar S, Franz BJ, Gosselin EJ. Tularemia vaccine development: paralysis or progress? Vaccine : development and therapy, 2016;6:9–23.

11. Griffin KF, Oyston PCF, Titball RW. Francisella tularensis vaccines. Pathogens and Disease, 2007;49(3):315–323.

12. Sjöstedt A. Tularemia: history, epidemiology, pathogen physiology, and clinical manifestations. Annals of the New York Academy of Sciences. 2007;1105:1–29.

13. Kingry LC, Petersen JM. Comparative review of Francisella tularensis and Francisella novicida. Frontiers in Cellular and Infection Microbiology. 2014;4:35.

14. Dinc G, Demiraslan H, Doganay M. Unexpected Risks for Campers and Hikers: Tick-Borne Infections. International Journal of Travel Medicine and Global Health, 2017;5(1):5–13.

15. Feldman KA. Tularemia. Journal of the American Veterinary Medical Association. 2003;222(6):725–730.

16. A General Overview of Francisella tularensis and the Epidemiology of Tularemia in Turkey. Dostupné na www: http://www.floradergisi.org/getFileContent.aspx?op=html&ref_id=153&file_name=2010-15-2-037-058.htm&_pk=f8d7f335-fc34-4850-9c6d-d48341f36eef.

17. Hong K-J, Park P-G, Seo S-H, Rhie G, Hwang K-J. Current status of vaccine development for tularemia preparedness. Clinical and Experimental Vaccine Research, 2013;2(1):34–39.

18. Maurin M, Gyuranecz M. Tularaemia: clinical aspects in Europe. The Lancet Infectious Diseases, 2016;16(1):113–124.

19. Gurcan S. Epidemiology of Tularemia. Balkan Medical Journal, 2014;33(1):3–10.

20. MUDr. Fabiánová Kateřina, MUDr. Jitka Částková, CSc. Opatření při výskytu tularémie v ČR. 2011. Dostupné na www: http://www.szu.cz/tema/prevence/opatreni-pri-vyskytu-tularemie-v-cr-1?highlightWords=francisella.

21. Jenzora A, Jansen A, Ranisch H, Lierz M, Wichmann O, Grunow R. Seroprevalence study of Francisella tularensis among hunters in Germany. FEMS immunology and medical mikrobiology, 2008;53(2):183–189.

22. Sewell DL. Laboratory-associated infections and biosafety. Clinical Microbiology Reviews, 1995;8(3):389–405.

23. Pike RM. Laboratory-associated infections: incidence, fatalities, causes, and prevention. Annual Review of Microbiology, 1979;33:41–66.

24. Hightower J, Kracalik IT, Vydayko N, Goodin D, Glass G, Blackburn JK. Historical distribution and host-vector diversity of Francisella tularensis, the causative agent of tularemia, in Ukraine. Parasites & Vectors. 2014;7.

25. Hauri AM, Hofstetter I, Seibold E, Kaysser P, Eckert J, Neubauer H, Splettstoesser WD. Investigating an Airborne Tularemia Outbreak, Germany. Emerging Infectious Diseases. 2010;16(2):238–243.

26. Dennis DT, Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Fine AD, Friedlander AM, Hauer J, Layton M, Lillibridge SR, McDade JE, Osterholm MT, O’Toole T, Parker G, Perl TM, Russell PK, Tonat K, Working Group on Civilian Biodefense. Tularemia as a biological weapon: medical and public health management. JAMA, 2001;285(21):2763–2773.

27. Vybrané infekční nemoci v ČR v letech 2008–2017 – absolutně, SZÚ. Dostupné na www: http://www.szu.cz/publikace/data/vybrane-infekcni-nemoci-v-cr-v-letech-2008-2017-absolutne.

28. Zdroj epidemiologických dat: systémy Epidat (celostátní program hlášení, evidence a analýzy dat o přenosných chorobách v ČR) a ISIN (Informační systém infekčních nemocí) Státního zdravotního ústavu ČR. Dostupné na www: http://szu.cz/.

29. Zprávy o činnosti. Státní veterinární správa. Dostupné na www: https://www.svscr.cz/zdravi-zvirat/zpravy-o-cinnosti/.

30. Celli J, Zahrt TC. Mechanisms of Francisella tularensis intracellular pathogenesis. Cold Spring Harbor Perspectives in Medicine, 2013;3(4):a010314.

31. Jones BD, Faron M, Rasmussen JA, Fletcher JR. Uncovering the components of the Francisella tularensis virulence stealth strategy. Frontiers in Cellular and Infection Microbiology, 2014;4.

32. Barker JR, Chong A, Wehrly TD, Yu J-J, Rodriguez SA, Liu J, Celli J, Arulanandam BP, Klose KE. The Francisella tularensis pathogenicity island encodes a secretion system that is required for phagosome escape and virulence. Molecular Microbiology, 2009;74(6):1459–1470.

33. Nano FE, Zhang N, Cowley SC, Klose KE, Cheung KKM, Roberts MJ, Ludu JS, Letendre GW, Meierovics AI, Stephens G, Elkins KL. A Francisella tularensis pathogenicity island required for intramacrophage growth. Journal of Bacteriology, 2004;186(19):6430–6436.

34. Ellis J, Oyston PCF, Green M, Titball RW. Tularemia. Clinical Microbiology Reviews. 2002;15(4):631–646.

35. Hansen B-A, Tilseth R, Finjord T, Bruserud Ø. Francisella tularensis bacteraemia causing multi-organ failure. Oxford Medical Case Reports, 2018;2018(9).

36. Rothfeldt LKL, Jacobs RF, Wheeler JG, Weinstein S, Haselow DT. Variation in Tularemia Clinical Manifestations – Arkansas, 2009–2013. Open Forum Infectious Diseases, 2017;4(1).

37. Foley JE, Nieto NC. Tularemia. Veterinary Microbiology. 2010;140(3):Zoonoses: Advances and Perspectives:332–338.

38. Thomas LD, Schaffner W. Tularemia Pneumonia. The Atypical Pneumonias. Infectious Disease Clinics of North America, 2010;24(1):43–55.

39. Carvalho CL, Lopes de Carvalho I, Zé-Zé L, Núncio MS, Duarte EL. Tularaemia: A challenging zoonosis. Comparative Immunology, Microbiology and Infectious Diseases. 2014;37(2):85–96.

40. Borde JP, Zange S, Antwerpen MH, Georgi E, von Buttlar H, Kern WV, Rieg S. Five cases of vector-borne Francisella tularensis holarctica infections in south-western Germany and genetic diversity. Ticks and Tick-Borne Diseases, 2017;8(5):808–812.

41. Wherry WB, Lamb BH. Infection of Man with Bacterium Tularense. Journal of Infectious Diseases, 1914;15(2):331–340.

42. Kaiser AB, Rieves D, Price AH, Gelfand MR, Parrish RE, Decker MD, Evans ME. Tularemia and Rhabdomyolysis. JAMA, 1985;253(2):241–243.

43. Feldman KA, Enscore RE, Lathrop SL, Matyas BT, McGuill M, Schriefer ME, Stiles-Enos D, Dennis DT, Petersen LR, Hayes EB. An outbreak of primary pneumonic tularemia on Martha’s Vineyard. The New England Journal of Medicine, 2001;345(22):1601–1606.

44. Shapiro DS, Schwartz DR. Exposure of Laboratory Workers to Francisella tularensis despite a Bioterrorism Procedure. Journal of Clinical Microbiology, 2002;40(6):2278–2281.

45. Yaglom H. Notes from the Field: Fatal Pneumonic Tularemia Associated with Dog Exposure – Arizona, June 2016. MMWR. Morbidity and Mortality Weekly Report. 2017;66.

46. Karakas A, Coskun O, Artuk C, Savasci U, Gul HC, Mert G, Avci IY, Besirbellioglu BA a Eyigun CP. Oropharyngeal tularemia cases admit-
ted to a military hospital in Ankara, Turkey. Journal of Infection in Developing Countries, 2014;8(8):994–999.

47. Al AD, et. Epidemiology and Ecology of Tularemia in Sweden, 1984–2012 - Volume 21, Number 1 – January 2015 – Emerging Infectious Disease journal – CDC. nedatováno.

48. Statistics. Tularemia. CDC. 11. leden 2018. Dostupné na www:

49. Tularaemia – Annual Epidemiological Report 2016 [2014 data]. European Centre for Disease Prevention and Control. 31. srpen 2016. Dostupné na www: http://ecdc.europa.eu/en/publications-data/tularaemia-annual-epidemiological-report-2016-2014-data.

50. Caspar Y, Hennebique A, Maurin M. Antibiotic susceptibility of Francisella tularensis subsp. holarctica strains isolated from tularaemia patients in France between 2006 and 2016. The Journal of Antimicrobial Chemotherapy. 2017.

51. Enderlin G, Morales L, Jacobs RF, Cross JT. Streptomycin and alternative agents for the treatment of tularemia: review of the literature. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 1994;19(1):42–47.

52. Tärnvik A, Weltgesundheitsorganisation, ed. WHO guidelines on tularaemia: epidemic and pandemic alert and response. Geneva: World Health Organization, 2007.

53. Johansson A, Berglund L, Sjöstedt A, Tärnvik A. Ciprofloxacin for Treatment of Tularemia. Clinical Infectious Diseases, 2001;33(2):267–268.

54. Tomaso H, Hotzel H, Otto P, Myrtennäs K, Forsman M. Antibiotic susceptibility in vitro of Francisella tularensis subsp. holarctica isolates from Germany. The Journal of Antimicrobial Chemotherapy, 2017;72(9):2539–2543.

55. Maurin M, Mersali NF, Raoult D. Bactericidal Activities of Antibiotics against Intracellular Francisella tularensis. Antimicrobial Agents and Chemotherapy, 2000;44(12):3428–3431.

56. Sutera V, Hoarau G, Renesto P, Caspar Y, Maurin M. In vitro and in vivo evaluation of fluoroquinolone resistance associated with DNA gyrase mutations in Francisella tularensis, including in tularaemia patients with treatment failure. International Journal of Antimicrobial Agents, 2017;50(3):377–383.

57. Sawyer WD, Dangerfield HG, Hogge AL, Crozier D. Antibiotic prophylaxis and therapy of airborne tularemia. Bacteriological Reviews, 1966;30(3):542–550.

58. Limaye AP, Hooper CJ. Treatment of tularemia with fluoroquinolones: two cases and review. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 1999;29(4):922–924.

59. Johansson A, Petersen JM, Sjöstedt A. Laboratory diagnostics and discrimination of subspecies and strains. In: WHO Guidelines on Tularaemia. France: WHO, 2007, s. 27–33. Dostupné na www: http://www.who.int/csr/resources/publications/WHO_CDS_EPR_2007_7.pdf?ua=1.

60. Payne MP, Morton RJ. Effect of culture media and incubation temperature on growth of selected strains of Francisella tularensis. Journal of Veterinary Diagnostic Investigation: Official Publication of the American Association of Veterinary Laboratory Diagnosticians, Inc. 1992;4(3):264–269.

61. Baker CN, Hollis DG, Thornsberry C. Antimicrobial susceptibility testing of Francisella tularensis with a modified Mueller-Hinton broth. Journal of Clinical Microbiology, 1985;22(2):212–215.

62. Bernard K, Tessier S, Winstanley J, Chang D, Borczyk A. Early recognition of atypical Francisella tularensis strains lacking a cysteine requirement. Journal of Clinical Microbiology, 1994;32(2):551–553.

63. Provenza JM, Klotz SA, Penn RL. Isolation of Francisella tularensis from blood. Journal of Clinical Microbiology, 1986;24(3):453–455.

64. Pohanka M. Biologické zbraně. Hradec Králové: Univerzita obrany, 2010.

65. Johansson A, Forsman M, Sjöstedt A. The development of tools for diagnosis of tularemia and typing of Francisella tularensis. APMIS: acta pathologica, microbiologica, et immunologica Scandinavica, 2004;112(11–12):898–907.

66. Sjöstedt A, Eriksson U, Berglund L, Tärnvik A. Detection of Francisella tularensis in ulcers of patients with tularemia by PCR. Journal of Clinical Microbiology, 1997;35(5):1045–1048.

67. Versage JL, Severin DDM, Chu MC, Petersen JM. Development of a Multitarget Real-Time TaqMan PCR Assay for Enhanced Detection of Francisella tularensis in Complex Specimens. Journal of Clinical Microbiology, 2003;41(12):5492–5499.

68. Molins CR, Carlson JK, Coombs J, Petersen JM. Identification of Francisella tularensis subsp. tularensis A1 and A2 infections by real-time polymerase chain reaction. Diagnostic Microbiology and Infectious Disease, 2009;64(1):6–12.

69. Koskela P, Salminen A. Humoral immunity against Francisella tularensis after natural infection. Journal of Clinical Microbiology, 1985;22(6):973–979.

70. Tarnvik A, Chu MC. New Approaches to Diagnosis and Therapy of Tularemia. Annals of the New York Academy of Sciences, 2007;1105(1):378–404.

71. Nakajima R, Escudero R, Molina DM, Rodríguez-Vargas M, Randall A, Jasinskas A, Pablo J, Felgner PL, AuCoin DP, Anda P, Davies DH. Towards Development of Improved Serodiagnostics for Tularemia by Use of Francisella tularensis Proteome Microarrays. Journal of Clinical Microbiology, 2016;54(7):1755–1765.

72. Cunningham SA, Patel R. Importance of Using Bruker’s Security-Relevant Library for Biotyper Identification of Burkholderia pseudomallei, Brucella Species, and Francisella tularensis. Journal of Clinical Microbiology, 2013;51(5):1639–1640.

73. Seibold E, Maier T, Kostrzewa M, Zeman E, Splettstoesser W. Identification of Francisella tularensis by whole-cell matrix-assisted laser desorption ionization-time of flight mass spectrometry: fast, reliable, robust, and cost-effective differentiation on species and subspecies levels. Journal of Clinical Microbiology, 2010;48(4):1061–1069.

74. Švabenska E. Systems for Detection and Identification of Biological Aerosols (Review Paper). Defence Science Journal, 2012;62(6):404–411.

75. O’Malley KJ, Bowling JL, Stinson E, Cole KS, Mann BJ, Namjoshi P, Hazlett KRO, Barry EM, Reed DS. Aerosol prime-boost vaccination provides strong protection in outbred rabbits against virulent type A Francisella tularensis. PLOS ONE, 2018;13(10):e0205928.

76. Whelan AO, Flick-Smith HC, Homan J, Shen ZT, Carpenter Z, Khoshkenar P, Abraham A, Walker NJ, Levitz SM, Ostroff GR, Oyston PCF. Protection induced by a Francisella tularensis subunit vaccine delivered by glucan particles. PLOS ONE, 2018;13(10):e0200213.

77. Jia Q, Horwitz MA. Live Attenuated Tularemia Vaccines for Protection Against Respiratory Challenge With Virulent F. tularensis subsp. tularensis. Frontiers in Cellular and Infection Microbiology, 2018;8.

78. Place DE, Williamson DR, Yuzefpolskiy Y, Katkere B, Sarkar S, Kalia V, Kirimanjeswara GS. Development of a novel Francisella tularensis Live Vaccine Strain expressing ovalbumin provides insight into antigen-specific CD8+ T cell responses. PLOS ONE, 2017;12(12):e0190384.

79. Wayne Conlan J a Oyston PCF. Vaccines against Francisella tularensis. Annals of the New York Academy of Sciences. 2007;1105:325–350.

Práce byla podpořena projektem bezpečnostního výzkumu Ministerstva vnitra ČR – VI20172020095.

Hygiene and epidemiology Medical virology Clinical microbiology
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