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Postępy Mikrobiologii - Advancements of Microbiology

Polish Society of Microbiologists

Subject: Microbiology


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VOLUME 56 , ISSUE 2 (April 2017) > List of articles


Kamila Formińska * / Aleksandra Anna Zasada

Keywords : F. tularensis, tularemia, czynniki zjadliwości,   F. tularensis, tularemia, virulence factors

Citation Information : Postępy Mikrobiologii - Advancements of Microbiology. Volume 56, Issue 2, Pages 187-195, DOI:

License : (CC BY-NC-ND 4.0)

Published Online: 21-May-2019



Francisella tularensis is an intracellular bacterial pathogen which causes a potentially lethal disease named tularemia. Some studies have been conducted to describe and identify the virulence factors of F. tularensis. This pathogen is able to infect a variety of cells of various hosts, including wild animals, especially rabbits, hares and rodents, and humans. This may suggest that genes of F. tularensis must adapt to many different intraorganismal environments. Still, little is known about the virulence of F. tularensis. This review focuses on the main virulence factors of F. tularensis which are involved in intramacrophage replication and its survival mechanisms during infection.

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1. Anda P., Martínez Nawarro J.F i wsp.: Waterborne outbreak of tularemia associated with crayfish fishing. Emerg. Infect. Dis. 3, 575–582 (2001)

2. Apicella M.A., Gibson B.W. i wsp.: Identification, characterization and immunogenicity of an O-antigen capsular polysaccharide of Francisella tularensis. PLoS ONE, 5, e11060 (2010)

3. Bakshi C.S., Malik M., Regan K., Melendez J.A., Metzger D.W., Pavlov V.M., Sellati J.S.: Super oxide dismutase B gene(sodB)-deficient mutants of Francisella tularensis demonstrate hyper sensitivity to oxidative stress and attenuated virulence. J. Bacteriol. 188, 6443–6448 (2006)

4. Barker J.R, Klose K.E.: Molecular and genetic basis of pathogenesis in Francisella tularensis. Ann. NY Acad. Sci. 1105, 138–159 (2007)

5. Barker J.R., Chong A., Wehrly T.D., Yu J.J., Rodriguez S.A., Liu J., Celli J., Arulanandam B.P., Klose K.E.: The Francisella tularensis pathogenicity island encodes a secretion system that is required for phagosome escape and virulence. Mol. Microbiol. 74, 1459–1470 (2009)

6. Baron G.S, Nano F.E.: MglA and MglB are required for the intramacrophage growth of Francisella novicida. Mol. Microbiol. 29, 247–259 (1998)

7. Baumann-Popczyk A., Sadkowska-Todys M., Zieliński A.: Choroby zakaźne i pasożytnicze-epidemiologia i profilaktyka. Wyd. VII, 2014, Lublin

8. Bernard K., Tessier S., Winstanley J., Chang D., Borczyk A.: Early recognition of atypical Francisella tularensis strains lacking a cysteine requirement. J. Clin. Microbiol. 32, 551–553 (1994)

9. Brevik O.J., Ottem K.F., Kamaishi T., Watanabe K., Nylund A.: Francisella halioticida sp. nov., a pathogen of farmed giant abalone (Haliotis gigantea) in Japan. J. Appl. Microbiol. 5, 1044–1056 (2011)

10. Broms J.E., MeyerL., Sun K., Lavander M., Sjösted A.: Unique substrates secreted by the type VI secretion system of Francisella tularensis during intramacrophage infection. PLoS One, 7, (2012)

11. Bröms J.E., Sjöstedt A., Lavander M.: The role of the Francisella tularensis pathogenicity island in type VI secretion, intracellular survival, and modulation of host cell signaling. Front. Microbiol. 1, 136 (2010)

12. Brotcke A., Weiss A.D., Kim C.C., Chain P., Malfatti S., Garcia E. Monack D.M.: Identification of MglA-regulated genes reveals novel virulence factors in Francisella tularensis. Infect. Immun. 74, 6642–6655 (2006)

13. Bruin O.M., Duplantis B.N., Ludu J.S., Hare R.F., Nix E.B., Schmerk C.L., Robb C.S., Boraston A.B., Hueffer K., Francis E.: The biochemical properties of the Francisella pathogenicity island (FPI)-encoded proteins IglA, IglB, IglC, PdpB and DotU suggest roles in type VI secretion. Microbiology, 157, 3483–3491 (2011)

14. Bruin O.M., Ludu J.S., Nano F.E.: The Francisella pathogenicity island protein IglA localizes to the bacterial cytoplasm and is needed for intracellular growth. BMC Microbiology, 7, doi:10.1186/1471-2180-7 (2007)

15. Carvalho C.L., Lopes de Carvalho L., Zé-Zé L., Núncio M.S., Duarte E.L.: Tularaemia: A challenging zoonosis. Microbiol. Infect. Dis. 37, 85–96 (2014)

16. Centers for Disease Control and Prevention: Emergency Preparedness and Response, (20.02.2017)

17. Champion M.D., Galagan J i wsp.: Comparative genomic characterization of Francisella tularensis strains belonging to low and high virulence subspecies. PloS Pathog. 5, e1000459 (2009)

18. Chong A., ChildR., Wehrly T.D., Rockx-Brouwer D., Qin A., Mann B.J., Jean C. Structure-function analysis of DipA a virulence factor required for intracellular replication. PLoS One, 8, e67965 (2013)

19. Clemens D. L., Lee B.Y., Horwitz M.A.: Virulent and avirulent strains of Francisella tularensis prevent acidification and maturation of their phagosomes and escape into the cytoplasm in human macrophages. Infect. Immun. 72, 3204–3217 (2004)

20. Clemens D.L, Lee B.Y, Horwitz M.A.: Francisella tularensis enters macrophages via a novel process involving pseudopod loops. Infect. Immun. 73, 5892–5902 (2005)

21. Clemens D.L., Ge P., Lee B.Y., Horwitz M.A., Zhou Z.H.: Atomics structure of T6SS reveals interlaced array essential to function. Cell, 160, 940–951 (2015)

22. Corey A. Dillaha T. and J.A.: Francisella tularensis endocarditis. Clin. Infect. Dis. 30, 399–400 (2000)

23. Dai S., Mohapatra N.P., Schlesinger L.S., Gunn J.S.: The acid phosphatase AcpA issecreted in vitro and in macrophages by Francisella spp. Infect. Immun. 80, 1088–1097 (2012)

24. Dennis D.T., Tonat K.: Tularemia as a biological weapon: medical and public management. JAMA, 285, 2763–2773 (2001)

25. Formińska K., Zasada A.A, Rastawicki W., Śmietańska K., Bander D., Wawrzynowicz-Syczewska M., Yanushevych M., Niścigórska-Olsen J., Wawszczak M.: Increasing role of arthropod bites in tularemia transmission in Poland – case reports and diagnostic methods. Ann. Agric. Environ. Med. 22, 443–6 (2015)

26. Forslund A.L., Salomonsson E.N., Golovliov I., Kuoppa K., Michell S., Titball R., Oyston P., Noppa L., Sjöstedt A., Forsber A.: The type IV pilin, PilA, is required for full virulence of Francisella tularensis subspecies tularensis. BMC Microbiol. 10, 227 (2010)

27. Francis E.,M.D., Moore D. M.D.: Identity of Ohara’s disease and tularemia. JAMA, 86, 1329–1332 (1926)

28. Franke J., Fritzsch J., Tomaso H., Straube E., Dorn W., Hildebrandt A.: Coexistence of pathogens In host-seeking and feeding ticks within a single natural habitat In Central Germany. Appl. Environ. Microbiol. 76, 6929–6836 (2010)

29. Garrity G.M, Bell J.A., Lilburn T.G.: Taxonomic outline of the prokaryotes Bergey’s manual of systemic bacteriology, wyd. 2, Springer, New York, 2004

30. Gil H., Benach J.L., ThanassiD.G.: Presence of pili on the surface of Francisella tularensis. Infect. Immun. 72, 3042–3047 (2004)

31. Golovilov I., Baranov Z., Krocova., Kovarova H., Sjöstedt A.: An attenuated strain of the facultative intracellular bacterium Francisella tularensis can escape the phagosome of monocytic cells. Infect. Immun. 71, 5940–5950 (2003)

32. Golovliov I., Ericsson M., Sandstrom G., Tarnvik A., Sjostedt A.: Identification of proteins of Francisella tularensis induced during growth in macrophages and cloning of the gene encoding a prominently induced 23-kilodalton protein. Infect. Immun. 65, 2183–2189 (1997)

33. Gray C. G., Cowley S.C., Cheung K.K, Nano F.E.: The identification of five genetic loci of Francisella novicida associated with intracellular growth. FEMS Microbiol. Lett. 215, 53–56 (2002)

34. Gun J.S., Ernst R.K.: The ctructure and function of Francisella Lipopolysaccharide. Ann. Ny. Acad. Sci. 1105, 202–218 (2007)

35. Gunnell M.K., Robison R.A., Adams B.J.: Natural selection in virulence genes of Francisella tularensis. J Mol. Evol. 82, 264–278 (2016)

36. Gürcan S.: Epidemiology of tularemia. Balkan Med. J. 31, 3–10 (2014)

37. Hodges L., Penn R.L.: Tularemia and bioterrorism. JAMA, 21, 285 (2001)

38. Hager A.J., Bolton D.L., Pelletier M.R., Brittnacher M.J., Gallagher L.A., Kaul R., Skerrett S.J., Miller S.I., Guina T.: Type IV pili-mediated secretion modulates Francisella virulence. Mol. Microbiol. 62, 227–237 (2006)

39. Hanke C.A., Otten J.E., Berner R., Serr A., Splettstoesser W., Schnakenburg C.: Ulceroglandular tularemia in a toddler in Germany after a mosquito bite. Eur. J. Pediatr. 168, 937–940 (2009)

40. Hare R.F., Hueffer K.: Francisella novicida pathogenicity island encoded proteins were secreted during infection of macrophage-like cells. Plos One, 9, (2014) e105773

41. Hauri A.M., Hofstetter I., Seibold E., Kaysser P., Eckert J., Neubauer H., Splettstoesser W.D.: Investigating an airborne tularemia outbreak, Germany. Emerg. Infect. Dis. 2, 238–224 (2010)

42. Huber B., Escudero R., Busse H.J., Seibold E., Scholz H.C. Anda P., Ka¨mpfer P., Huntley J.F., Conley P.G., Hagman K.E., Norgard M.V.: Characterization of Francisella tularensis outer membrane proteins. J. Bacteriol. 189, 561–574 (2007)

43. Huber B., Escudero R., Busse H.J., Seibold E., Scholz H.C., Anda P., Kamper P., SplettstoessermW.D.: Description of Francisella hispaniensis sp. nov., isolates from human blood, reclassification of Francisella novicida (Larson et al. 1955) olsufiev et al. 1959 as Francisella tularensis subsp. Novicida comb. nov. and emended description of the genus Francisella. Int. J. Syst. Bacteriol. 60, 1887–1896 (2010)

44. Huntley J.F., Conley P.G., Hagman K.E., Norgard M.V.: Characterization of Francisella tularensis outer membrane eproteins.
J. Bacteriol. 189, 561–574(2007)

45. Jaohansson A., Keim P.: Worldwide genetic relationships among Francisella tularensis isolates determined by multiple – locus variable – number tandem repeat analysis. J. Bacteriol. 17, 5808–5818 (2004)

46. Johansson A., Petersen J.M.: Genotyping of Francisella tularensis, the causative agent of tularemia. J. AOAC Int. 93(6), 1930–1943 (2010)

47. Jones B.D., Faron M., Rasmussen J.A., Fletcher J.R.: Uncovering the components of the Francisella tularensis virulence stealth strategy. Front. Cell. Infect. Microbiol. 7(4), 2014

48. Kłapeć T., Cholewa A.: Tularemia – wciąż groźna zoonoza. MONZ, 3, 155–160 (2011)

49. Larson M.A., Nalbantoglu U., Sayood K., Zentz E.B., Cer R.Z., Iwen P.C., Francesconi S.C., Bishop-Lilly K.A., Mokashi V.P., Sjöstedt A., Hinrichs S.H.: Reclassification of Wolbachia persica as Francisella persica comb. nov. and emended description of the family Francisellaceae. Int. J. Syst. Evol. Microbiol. 66, 1200–1205 (2016)

50. Larson M.A., Fey P.D., Hinrichs S.H., Iwen P.C.: Francisella tularensis bacteria associated with feline tularemia in the United States. Emerg. Infect. Dis. 20(12), 2068–2071 (2014)

51. Leelaporn A., Yongyod S., Limsrivanichakorn S., Yungyuen T., Kiratisin P. Emergence of Francisella novicida bacteremia, Thailand. Emerg. Infect. Dis. 14(12), 1935–1937 (2008)

52. Lindemann S.R., Peng K., Long M.E., Hunt J.R., Apicella M.A., Monack D.M., Allen L.A, Jones B.D.: Francisella tularensis SchuS4O-antigen and capsule biosynthesis gene mutants induce early cell death in human macrophages. Infect. Immun. 79,
581–594 (2011) doi:10.1128/IAI.00863-10

53. Lindgren H., Shen H., Zingmark C., Golovliov I., Conlan W., Sjöstedt A.: Resistance of Francisella tularensis strains against reactive nitrogen and oxygen species with special reference to the role of KatG. Infect. Immun. 75, 1303–1309 (2007)

54. Mahawar M., Atianand M.K., Dotson R.J., MoraV., Rabadi S.M., MetzgerD. W., Huntley J.F., Harton J.A., Malik M., Bakshi C.S.: Identification of a novel Francisella tularensis factor required for intramacrophage survival and subversion of innate immuneresponse. J. Biol. Chem. 287, 25216–25229 (2012)

55. Marrs C.F, Weir S.: Pili (fimbriae) of Branhamella species. Am. J. Med. 14, 36–40 (1990)
56. May C. Chu., Carey R.B., Welch D.F.: Basic protocols for level a laboratories. For the presumptive identification of Francisella tularensis. Centers for Disease Control and Prevention.

57. Meldunki epidemiologiczne NIZP-PZH, (07.02.2017)

58. Melillo A., Sledjeski D.D., Lipski S., Wooten R.M., Basrur V., Lafontaine E.R.: Identificationofa Francisella tularensis LVS outer membrane protein that confers adherence to A549 human lungcells. FEMS Microbiol Lett. 263, 102–108 (2006)

59. Mierzyńska D., Hermanowska-Szpakowicz T.: Tularemia jako potencjalna broń bioterrorystów. Med. Pr. 53, 279–281 (2002)

60. Mohapatra N.P., Balagopal A., Soni S., Schlesinger L.S., Gunn J.S.: AcpA is a Francisella acid phosphatase that affects intra macrophage survival and virulence. Infect. Immun. 75, 390–396 (2007)

61. Monike L van Hoek.: Biofilms an advancement in our understanding of Francisella species. Virulence, 4: 8, 833–846 (2015)

62. Moniuszko A., Zajkowska J., Pancewicz S. i wsp.: Arthropod-Borne Tularemia In Poland: A Case Report. Vector Borne Zoonotic Dis. 10, 1399–1401 (2011)

63. Nano F.E, Zhang N., Cowley S.C., Klose K.E, Cheung K.M., Roberts M.J., Ludu J.S, Letendre G.W, Meierovics A.I, Stephens G,. Elkings K.L.: A Francisella tularensis pathogenicity island required for intramacrophage growth. J. Bacteriol. 186, 6430–6436 (2004)

64. Nano F.E., Schmerk C.: The Francisella pathogenicity island. Ann. NY Acad. Sci. 1105, 122–137 (2007)

65. Nano F.E.: Identification of a heat-modifiable protein of Francisella tularensis and molecular cloning of the encoding gene. Microb. Pathogenesis. 5, 109–119 (1988)

66. Nordstoga A., Handeland K., Johansen T.B., Iversen L., Gavier-Wide’n D., Mattsson R., Wik-Larssen K., Afset J.G., Næverdal R., Lund A.: Tularaemia in Norwegian dogs. Vet. Microbiol. 10, 318–322 (2014)

67. Olsufjew N., Meshcheryakova I.S.: Subspecific taxonomy of Francisella tularensis. Int. J. Syst. Bacteriol. 33, 872–874 (1983)

68. Ottem K.F., Nylund A., Karlsbakk E., Friis-Møller A., Krossøy B., Knappskog B.: New species in the genus Francisella (Gammaproteobacteria; Francisellaceae); Francisella piscicida sp. nov. isolated from cod (Gadus morhua). Arch. Microbiol. 188, 547–550 (2007)

69. Pechous R.D, McCarthy T.R, Zahrt T.C. Working toward the future: insights into Francisella tularensis pathogenesis and vaccine development. Microbiol. Mol. Biol. Rev. 73, 684–711 (2009)

70. Pierini L.M.: Uptake of serum-opsonized Francisella tularensis by macrophages can be mediated by class A scavenger receptors. Cell. Microbiol. 8, 1361–1370 (2006)

71. Pilo P., Johansson A., Frey J.: Identification of Francisella tularensis Cluster in Central and Western Europe. Emerg. Infect. Dis. 12, 2049–2051 (2009)

72. Qin A., Scott D.W., Thompson J.A., Mann B.J.: Identification of an essential Francisella tularensis subsp. tularensis virulence factor. Infect. Immun. 77, 152–161 (2009)

73. Qu P.H., Chen S.Y., Scholz H.C., Busse H.J., Gu Q., Kämpfer P., Foster J.T., Glaeser S.P., Chen C., Yang Z.C.: Francisella guangzhouensis sp. nov., isolated from air-conditioning systems. Int. J. Syst. Evol. Microbiol. 63, 3628–3635 (2013)

74. Ramakrishnan G., Sen B., Johnson R.: Paralogous outer membrane proteins mediate uptake of different forms of iron and synergistically govern virulence in Francisella tularensis tularensis. J. Biol. Chem. 287, 25191–25202 (2012)

75. Reye A.L., Hübschen J.M., Sausy A. i wsp.: Prevalence and seasonality of Tick-Borne pathogens in Questing Ixodes ricinus Ticks from Luxembourg. Appl. Environ. Microbiol. 9, 2923–2931 (2010)

76. Robertson G.T., Case E.D., Dobbs N., Ingle C., Balaban M., Celli J., Norgard M.V.: FTT0831c/FTL_0325 contributes to Francisella tularensis cell division maintenance of cell shape, and structural integrity. Infect. Immun. 82, 2935–2948 (2014)

77. Rohmer L. Brittnacher M.J. i wsp.: Comparison of Francisella tularensis genomes reveals evolutionary events associated with the emergence of human pathogenic strains. Genome Biol. 8, (2007)

78. Rowe H.M, Huntley J.F.: From the outside-in: the Francisella tularensis envelope and virulence. Front. Cell. Infect. Microbiol. 5, 1–20 (2015)

79. Salomonsson Näslund E., Forslund A.L., Forsberg Å.: Type IV pili in Francisella – a virulence trait in an intracellular pathogen. Front. Microbiol. 2, 29 (2011)

80. Sandström G., Sjöstedt A., Johansson T., Kuoppa K., Williams J.C.: Immunogenicity and toxicity of lipopolysaccharide from Francisella tularensis LVS. FEMS Microbiol. Immunol. 105, 201–210 (1992)

81. Schulert G.S., Allen L.A.: Differential infection of mononuclear phagocytes by Francisella tularensis: role of the macrophage mannose receptor. J. Leukoc. Biol. 80, 563–571 (2006)

82. Sjöstedt A., Sandström G., Tärnvik A., Jaurin B.: Nucleotide sequence and T cell epitopes of a membrane protein of Francisella tularensis. J. Immunol. 145, 311–317 (1990)

83. Splettstoesser W.D, Piechotowski I., Buckendahl A., Fran-
goulidis D., Kaysser P., Kratzer W., Kimmig P., Seibold E., Brockmann S.O.: Tularemia in Germany: the tip of the iceberg? Epidemiol. Infect. 137, 736–743 (2009)

84. Schmidt H, Hensel M.: Pathogenicity islands in bacterial pathogenesis. Clin. Microbial. Rev. 17, 14–56 (2004)

85. Strom M.S, Lory S.: Structure-function and biogenesis of the type IV pili. Ann. Rev. Microbiol. 47, 565–596 (1993)

86. Su J., Yang J., Zhao D., Kawula T.H., Banas J.A. and Zhang J.R.: Genome-wide identification of Francisella tularensis virulence determinants. Infect. Immun. 75, 3089–3101 (2007)

87. Surveillance Report Annual epidemiological report. Reporting on 2009 surveillance data and 2010 epidemic intelligence data. ECDC, 2011

88. Svensson K., Johansson A. i wsp.: Genome sequence of Francisella tularensis subspecies holarctica strain FSC200, isolated from a child with tularemia. J. Bacteriol. 194, 6965–6966.

89. Svensson K., Larsson P., Johansson D., Bystrom M., Forsman M., Johansson A.: Evolution of subspecies of Francisella tularensis. J. Bacteriol. 187(11), 3903–3908 (2005)

90. Tomaso H., Scholz H.C., Naubauer H., Al Dahouk S., Seibold E., Landt O., Forsman M., Splettstoesser W.D.: Real-time PCR using hybridization probes for rapid and specific identification of Francisella tularensis subspecies tularensis. Mol. Cell. Probes. 21, 12–16 (2007)

91. Versage J.L, Severin D.D.M., Chu M.C., Petersen J.M.: Development of multitarget real-time TaqMan PCR assay for enhanced detection of Francisella tularensis in complex speciments. J. Clin. Micorbiol. 41, 5492–5499 (2003)

92. Vogler A.J., Keim P.: Phylogeography of Francisella tularensis: global expansion of a highly fit clone. J. Bacteriol. 191, 2474–2484 (2009)

93. Vogler AJ, Keim P. i wsp.: Phylogeography of Francisella tularensis: global expansion of a highly fit clone. J. Bacteriol. 191, 2474–2484 (2009)

94. Wang X., Ribeiro A.A., Guan Z., Abraham S.M., Raetz C.R.H.: Attenuated virulence of a Francisella mutant lacking the lipid A 4’-phosphatase. Proc. Natl. Acad. Sci. USA, 104, 4136–4141 (2006)

95. Whipp M.J., Davis J.M., Lum G., De Boer J., Zhou J.Y., Bearden S.W., Petersen J.M., Chu M.C., Hogg G.: Characterization of a novicida-like subspecies of Francisella tularensis isolated in Australia. J. Med. Microbiol. 52, 839–842 (2003)