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Identified Virulence Factors of Francisella : Immune evastion


Capsule  

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;
Characteristics:
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
Functions:
Providing a stealth shield that prevents the host immune system from detecting this potent pathogen
References:
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.


LPS  

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;
Characteristics:
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
Figures:
Structure of Francisella LPS (From: Okan NA, et al., 2013. The atypical lipopolysaccharide of Francisella. Carbohydr Res 378:79-83.)

Functions:
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
Mechanism:
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
References:
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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