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Identified Virulence Factors of Francisella : Immune evastion


Related genes: FTT_0790; FTT_0792; FTT_0793; FTT_0794; FTT_0795; FTT_0796; FTT_0797; FTT_0798; FTT_0799; FTT_0800; capA; capB; capC; galE; rpe; waaL/rfaL; waaY;
Keywords: Immune evastion;
Group 4 capsule
High molecular weight (HMW) O-antigen capsule
Structure features:
A polymer of the tetrasaccharide repeat, 4)-a-D-GalNAcAN-(1-.4)-a-D-GalNAcAN-(1-.3)-b-D-QuiNAc-(1-.2)-b-D-Qui4NFm-(1-, which is identical to F. tularensis O-antigen subunit
F. tularensis synthesizes an O-antigen capsule containing approximately 125 to 300 or more O-antigen repeating units
Providing a stealth shield that prevents the host immune system from detecting this potent pathogen
Hood AM, 1977. Virulence factors of Francisella tularensis. J Hyg (Lond) 79(1):47-60.
Sandstrom G, et al., 1988. A capsule-deficient mutant of Francisella tularensis LVS exhibits enhanced sensitivity to killing by serum but diminished sensitivity to killing by polymorphonuclear leukocytes. Infect Immun 56(5):1194-202.
Apicella MA, et al., 2010. Identification, characterization and immunogenicity of an O-antigen capsular polysaccharide of Francisella tularensis. PLoS One 5(7):e11060.
Lindemann SR, et al., 2011. Francisella tularensis Schu S4 O-antigen and capsule biosynthesis gene mutants induce early cell death in human macrophages. Infect Immun 79(2):581-94.
Zarrella TM, et al., 2011. Host-adaptation of Francisella tularensis alters the bacterium's surface-carbohydrates to hinder effectors of innate and adaptive immunity. PLoS One 6(7):e22335.
Rasmussen JA, et al., 2014. Francisella tularensis Schu S4 lipopolysaccharide core sugar and O-antigen mutants are attenuated in a mouse model of tularemia. Infect Immun 82(4):1523-39.
Rasmussen JA, et al., 2015. Characterization of Francisella tularensis Schu S4 mutants identified from a transposon library screened for O-antigen and capsule deficiencies. Front Microbiol 6:338.
Barker JH, et al., 2016. Evidence Suggesting That Francisella tularensis O-Antigen Capsule Contains a Lipid A-Like Molecule That Is Structurally Distinct from the More Abundant Free Lipid A. PLoS One 11(6):e0157842.


Related genes: flmF2; flmK; glmU; kdtA; lpcC; lpxD; lpxD2; lpxE; manB; manC; waaZ; wbtA; wbtB; wbtC; wbtD; wbtE; wbtF; wbtG; wbtH; wbtI; wbtJ; wbtK; wbtL; wbtM; wzx; wzy;
Keywords: Immune evastion;
The structure of Francisella spp. lipid A is unique in that it is modified by various carbohydrates that greatly reduce TLR4 activation and allow for immune evasion
Structure of Francisella LPS (From: Okan NA, et al., 2013. The atypical lipopolysaccharide of Francisella. Carbohydr Res 378:79-83.)

A key virulence factor does not signal through, and is not an agonist of, toll like receptor 4 (TLR-4) and has little endotoxic activity
Francisella lipid A is a very poor stimulant of the hostís innate immunity. The lack of immune recognition of Franciscella lipid A has been attributed to several structural differences compared to E. coli lipid A. These include (1) the absence of phosphate at the 40 position as well as the modification of 1-phosphate with GalN and (2) tetraacylation of lipid A with longer acyl chains (16Ė18 carbons)
An unusual feature of the Francisella LPS core region is the presence of a single Kdo unit. Francisella initially synthesizes its LPS with two Kdo sugars and Kdo hydrolase is involved in removing the second, side-chain Kdo moiety. A probable scenario is the lack of an extra Kdo may alter the bacterial surface and result in decreased access of additional surface molecules to the hostís innate immune system
Vinogradov E, et al., 2002. Structural analysis of Francisella tularensis lipopolysaccharide. Eur J Biochem 269(24):6112-8.
Prior JL, et al., 2003. Characterization of the O antigen gene cluster and structural analysis of the O antigen of Francisella tularensis subsp. tularensis. J Med Microbiol 52(Pt 10):845-51.
Duenas AI, et al., 2006. Francisella tularensis LPS induces the production of cytokines in human monocytes and signals via Toll-like receptor 4 with much lower potency than E. coli LPS. Int Immunol 18(5):785-95.
Thomas RM, 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(1):371-8.
Gunn JS, et al., 2007. The structure and function of Francisella lipopolysaccharide. Ann N Y Acad Sci 1105:202-18.
Kanistanon D, et al., 2008. A Francisella mutant in lipid A carbohydrate modification elicits protective immunity. PLoS Pathog 4(2):e24.
Clay CD, et al., 2008. Evasion of complement-mediated lysis and complement C3 deposition are regulated by Francisella tularensis lipopolysaccharide O antigen. J Immunol 181(8):5568-78.
Zhao J, et al., 2010. A two-component Kdo hydrolase in the inner membrane of Francisella novicida. Mol Microbiol 78(4):820-36.
Soni S, et al., 2010. Francisella tularensis blue-gray phase variation involves structural modifications of lipopolysaccharide o-antigen, core and lipid a and affects intramacrophage survival and vaccine efficacy. Front Microbiol 1:129.
Li Y, et al., 2012. LPS remodeling is an evolved survival strategy for bacteria. Proc Natl Acad Sci U S A 109(22):8716-21.
Okan NA, et al., 2013. Kdo hydrolase is required for Francisella tularensis virulence and evasion of TLR2-mediated innate immunity. MBio 4(1):e00638-12.
Rasmussen JA, et al., 2014. Francisella tularensis Schu S4 lipopolysaccharide core sugar and O-antigen mutants are attenuated in a mouse model of tularemia. Infect Immun 82(4):1523-39.
Twine SM, et al., 2012. Roles for wbtC, wbtI, and kdtA Genes in Lipopolysaccharide Biosynthesis, Protein Glycosylation, Virulence, and Immunogenicity in Francisella tularensis2 Strain SCHU S4. Pathogens 1(1):12-29.
Chance T, et al., 2017. A spontaneous mutation in kdsD, a biosynthesis gene for 3 Deoxy-D-manno-Octulosonic Acid, occurred in a ciprofloxacin resistant strain of Francisella tularensis and caused a high level of attenuation in murine models of tularemia. PLoS One 12(3):e0174106.

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