Live Attenuated Vaccine Protects against Pulmonary Challenge in Rats and Non-human Primates

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Francisella tularensis is a bacterium that causes the infectious disease tularemia. F. tularensis has been developed as a biothreat agent, because it causes high morbidity and mortality when spread by aerosol. There is currently no approved vaccine for human use, making mankind vulnerable to the illicit use of this organism. F. tularensis contains a cluster of genes in the Francisella Pathogenicity Island (FPI) that are required for replication inside host macrophages and virulence. In the current study we created a live vaccine strain by inactivating an FPI gene, iglD, in a closely-related species that does not cause disease in humans, F. novicida (Fn iglD). We demonstrate that vaccination with Fn iglD protects against exposure to airborne F. tularensis. Fn iglD vaccination induces antibody and cellular immune responses and protects two different animals, rats and non-human primates, against lethal pulmonary tularemia challenges. These two animal models reflect human sensitivity to F. tularensis. Our results suggest that a vaccine made from the low virulence F. novicida will protect humans against aerosol exposure to this dangerous pathogen.

Vyšlo v časopise: Live Attenuated Vaccine Protects against Pulmonary Challenge in Rats and Non-human Primates. PLoS Pathog 10(10): e32767. doi:10.1371/journal.ppat.1004439
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004439

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Zdroje

1. GolovliovI, BaranovV, KrocovaZ, KovarovaH, SjostedtA (2003) An attenuated strain of the facultative intracellular bacterium Francisella tularensis can escape the phagosome of monocytic cells. Infect Immun 71 : 5940–5950.

2. BarkerJR, ChongA, WehrlyTD, YuJ-J, RodriguezSA, et al. (2009) The Francisella tularensis pathogenicity island encodes a secretion system that is required for phagosome escape and virulence. Mol Microbiol 74 : 1459–1470.

3. BosioCM, Bielefeldt-OhmannH, BelisleJT (2007) Active suppression of the pulmonary immune response by Francisella tularensis Schu4. J Immunol 178 : 4538–4547.

4. TelepnevM, GolovliovI, SjostedtA (2005) Francisella tularensis LVS initially activates but subsequently down-regulates intracellular signaling and cytokine secretion in mouse monocytic and human peripheral blood mononuclear cells. Microb Pathog 38 : 239–247.

5. HajjarAM, HarveyMD, ShafferSA, GoodlettDR, SjostedtA, et al. (2006) Lack of in vitro and in vivo recognition of Francisella tularensis subspecies lipopolysaccharide by Toll-like receptors. Infect Immun 74 : 6730–6738.

6. WuTH, ZsemlyeJL, StatomGL, HuttJA, SchraderRM, et al. (2009) Vaccination of Fischer 344 rats against pulmonary infections by Francisella tularensis type A strains. Vaccine 27 : 4684–4693.

7. HornickRB, EigelsbachHT (1966) Aerogenic Immunization of Man with Live Tularemia Vaccine. Bacteriol Rev 30 : 532–538.

8. SalomonssonE, KuoppaK, ForslundAL, ZingmarkC, GolovliovI, et al. (2009) Reintroduction of two deleted virulence loci restores full virulence to the live vaccine strain of Francisella tularensis. Infect Immun 77 : 3424–3431.

9. CowleySC, ElkinsKL (2011) Immunity to Francisella. Front Microbiol 2 : 26.

10. LyonsCR, WuTH (2007) Animal models of Francisella tularensis infection. Ann N Y Acad Sci 1105 : 238–265.

11. RayHJ, ChuP, WuTH, LyonsCR, MurthyAK, et al. (2010) The Fischer 344 rat reflects human susceptibility to Francisella pulmonary challenge and provides a new platform for virulence and protection studies. PLoS One 5: e9952.

12. TwenhafelNA, AlvesDA, PurcellBK (2009) Pathology of Inhalational Francisella tularensis spp. tularensis SCHU S4 in African Green Monkeys (Chlorocebus aethiops). Vet Pathol 46 : 698–706.

13. NelsonM, LeverMS, DeanRE, SavageVL, SalgueroFJ, et al. (2010) Characterization of lethal inhalational infection with Francisella tularensis in the common marmoset (Callithrix jacchus). J Med Microbiol 59 : 1107–1113.

14. SchrickerRL, EigelsbachHT, MittenJQ, HallWC (1972) Pathogenesis of tularemia in monkeys aerogenically exposed to Francisella tularensis 425. Infect Immun 5 : 734–744.

15. Valderas MW, Zinter E, Brasel T, Barr E, Hutt J, et al. (2009) Characterization of aerosol infection with F. tularensis Schu S4 in cynomolgus macaques and LD50 determination. 6th International Conference on Tularemia, Berlin Germany Abstract P2-29.

16. NanoFE, ZhangN, CowleySC, KloseKE, CheungKK, et al. (2004) A Francisella tularensis Pathogenicity Island Required for Intramacrophage Growth. J Bacteriol 186 : 6430–6436.

17. BonquistL, LindgrenH, GolovliovI, GuinaT, SjostedtA (2008) MglA and Igl proteins contribute to the modulation of Francisella tularensis live vaccine strain-containing phagosomes in murine macrophages. Infect Immun 76 : 3502–3510.

18. AhlundMK, RydenP, SjostedtA, StovenS (2010) Directed screen of Francisella novicida virulence determinants using Drosophila melanogaster. Infect Immun 78 : 3118–3128.

19. SanticM, MolmeretM, BarkerJR, KloseKE, DekanicA, et al. (2007) A Francisella tularensis pathogenicity island protein essential for bacterial proliferation within the host cell cytosol. Cell Microbiol 9 : 2391–2403.

20. KraemerPS, MitchellA, PelletierMR, GallagherLA, WasnickM, et al. (2009) Genome-wide Screen in Francisella novicida for Genes required for pulmonary and systemic infection in mice. Infect Immun 77 : 232–244.

21. WeissDS, BrotckeA, HenryT, MargolisJJ, ChanK, et al. (2007) In vivo negative selection screen identifies genes required for Francisella virulence. Proc Natl Acad Sci U S A 104 : 6037–6042.

22. GolovliovI, TwineSM, ShenH, SjostedtA, ConlanW (2013) A clpB Mutant of Francisella tularensis subpsecies holarctica strain FSC200 is a more effective Live Vaccine than F. tularensis LVS in a mouse respiratory challenge model of tularemia. PLoS One 8: e78671.

23. SignarovitzAL, RayHJ, YuJJ, GuentzelMN, ChambersJP, et al. (2012) Mucosal immunization with live attenuated Francisella novicida U112DiglB protects against pulmonary F. tularensis SCHU S$ in the Fischer 344 rat model. PLoS One 7: e47639.

24. ThomasRM, TitballR, OystonPC, GriffinK, WatersE, et al. (2007) The Immunologically Distinct O Antigens from Francisella tularensis subspecies tularensis and Francisella novicida are both Virulence Determinants and Protective Antigens. Infect Immun 75 : 371–378.

25. WangQ, ShiX, LeymarieN, MadicoG, SharonJ, et al. (2011) A typical preparation of Francisella tularensis O-antigen yields a mixture of three types of saccharides. Biochemistry 50 : 10941–10950.

26. ApicellaMA, PostDM, FowlerAC, JonesBD, RasmussenJA, et al. (2010) Identification, characterization and immunogenicity of an O = antigen capsular polysaccharide of Francisella tularensis. PLoS One 5: e11060.

27. EylesJE, UnalB, HartleyMG, NewsteadSL, Flick-SmithH, et al. (2007) Immunodominant Francisella tularensis antigens identified using proteome microarray. Proteomics 7 : 2172–2183.

28. NutiDE, CrumpRB, HandayaniFD, ChantratitaN, PeacockSJ, et al. (2011) Identification of Circulating Bacterial Antigens by In Vivo Microbial Antigen Discovery. MBio 2: e00136–00111.

29. Mara-KooshamG, HuttJA, LyonsCR, WuTH (2011) Antibodies contribute to effective vaccination against respiratory infection by type A Francisella tularensis strains. Infect Immun 79 : 1770–1778.

30. RayHJ, CongY, MurthyAK, SelbyDM, KloseKE, et al. (2009) Oral live vaccine strain-induced protective immunity against pulmonary Francisella tularensis challenge is mediated by CD4+ T cells and antibodies, including immunoglobulin A. Clin Vaccine Immunol 16 : 444–452.

31. RohmerL, FongC, AbmayrS, WasnickM, Larson FreemanTJ, et al. (2007) Comparison of Francisella tularensis genomes reveals evolutionary events associated with the emergence of human pathogenic strains. Genome Biol 8: R102.

32. SundareshS, RandallA, UnalB, PetersenJM, BelisleJT, et al. (2007) From protein microarrays to diagnostic antigen discovery: a study of the pathogen Francisella tularensis. Bioinformatics 23: i508–518.

33. HavlasovaJ, HernychovaL, HaladaP, PellantovaV, KrejsekJ, et al. (2002) Mapping of immunoreactive antigens of Francisella tularensis live vaccine strain. Proteomics 2 : 857–867.

34. ZogajX, KloseKE (2010) Genetic manipulation of Francisella tularensis. Front Microbiol 1 : 142.

35. RodriguezSA, YuJ-J, DavisG, ArulanandamBP, KloseKE (2008) Targeted inactivation of Francisella tularensis genes by group II introns. Appl Environ Microbiol 74 : 2619–2626.

36. ChamberlainRE (1965) Evaluation of Live Tularemia Vaccine Prepared in a Chemically Defined Medium. Appl Microbiol 13 : 232–235.

37. ZogajX, WyattGC, KloseKE (2012) Cyclic di-GMP Stimulates Biofilm Formation and Inhibits Virulence of Francisella novicida. Infect Immun 80 : 4239–4247.