Francisella tularensis is a class A bacterial select agent due to its extreme pathogenicity and potential use as a bioweapon. Early studies by Carlisle and Hood have indicated that F. tularensis produces a capsule-like material. Many bacteria produce capsules and the genes required to produce them encode proteins for transport, biosynthesis and regulation. Homologs of genes implicated in capsular biosynthesis are present in the Francisella genome database. Preliminary studies, using electron microscopy, indicate and confirm that a capsule-like material (CLM) surrounds F. tularensis. We can now isolate this material, free from Francisella LPS, based on chemical, chromatographic and immunochemical analysis. This material is loosely associated with the bacterial cell, is easily removed from the bacterial surface and is composed of a repeating tetrasaccharide repeat. Using transposon mutagenesis in F. tularensis Schu S4, we have identified a number of mutants with no or limited reactivity to our CLM specific antibody XE8. We have currently identified the site of insertion of 7 of these transposon mutants that have altered CLM expression that will serve as acapsular strains for the studies in this proposal. Based on these observations, we would pose the following hypotheses 1) Francisella tularensis expresses a capsular-like material that is important in pathogenesis and that we believe is a group 1 capsule;2) Alteration of this capsule-like structure by mutations of the genes involved in biosynthesis and expression of CLM will alter pathogenicity of Francisella tularensis in cell culture models and in an animal model of respiratory infection;3) Induction of an immune response targeted to the CLM will provide host immunity. The following specific aims will be used to resolve these hypotheses: 1) Characterization of the F. tularensis Schu S4 mutants that are defective in production of capsule-like material and 2) Characterization of the biological role of the P. tularensis Schu S4 capsule like material and 3) Study the immunogenicity and protective efficacy of passive and active immunization in murine models of Francisella infection

Public Health Relevance

The proposed work will focus on characterizing the Francisella capsule-like material which remains poorly understood. There is a significant possibility that efforts to understand this potentially critical virulence factor will not only increase our understanding of Francisella pathogenesis but open up new avenues for therapeutic development, using acapsular strains or antibodies to the capsule-like material.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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University of Iowa
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Nauseef, William M; Kubes, Paul (2016) Pondering neutrophil extracellular traps with healthy skepticism. Cell Microbiol 18:1349-57
McCracken, Jenna M; Kinkead, Lauren C; McCaffrey, Ramona L et al. (2016) Francisella tularensis Modulates a Distinct Subset of Regulatory Factors and Sustains Mitochondrial Integrity to Impair Human Neutrophil Apoptosis. J Innate Immun 8:299-313
Nauseef, William M (2016) Neutrophils, from cradle to grave and beyond. Immunol Rev 273:5-10
Chen, Linxiao; Valentine, Jenny L; Huang, Chung-Jr et al. (2016) Outer membrane vesicles displaying engineered glycotopes elicit protective antibodies. Proc Natl Acad Sci U S A 113:E3609-18
Ulland, Tyler K; Jain, Nidhi; Hornick, Emma E et al. (2016) Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment. Nat Commun 7:13180
Kinkead, Lauren C; Allen, Lee-Ann H (2016) Multifaceted effects of Francisella tularensis on human neutrophil function and lifespan. Immunol Rev 273:266-81
Greenlee-Wacker, Mallary C (2016) Clearance of apoptotic neutrophils and resolution of inflammation. Immunol Rev 273:357-70
Greenlee-Wacker, Mallary; DeLeo, Frank R; Nauseef, William M (2015) How methicillin-resistant Staphylococcus aureus evade neutrophil killing. Curr Opin Hematol 22:30-5
Wang, Guoshun; Nauseef, William M (2015) Salt, chloride, bleach, and innate host defense. J Leukoc Biol 98:163-72
Mashruwala, Ameya A; Pang, Yun Y; Rosario-Cruz, Zuelay et al. (2015) Nfu facilitates the maturation of iron-sulfur proteins and participates in virulence in Staphylococcus aureus. Mol Microbiol 95:383-409

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