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* Department of Internal Medicine,
Division of Infectious Disease,
Department of Molecular Virology, Immunology, and Medical Genetics,
Department of Microbiology and
¶ Center for Microbial Interface Biology, Ohio State University, Columbus, OH 43210
The bacterium Francisella tularensis (Ft) is a potential weapon of bioterrorism when aerosolized. Macrophage infection is necessary for disease progression and efficient phagocytosis by human macrophages requires serum opsonization by complement. Microbial complement activation leads to surface deposition of a highly regulated protein complex resulting in opsonization or membrane lysis. The nature of complement component C3 deposition, i.e., C3b (opsonization and lysis) or C3bi (opsonization only) fragment deposition, is central to the outcome of activation. In this study, we examine the mechanisms of Ft resistance to complement-mediated lysis, C3 component deposition on the Ft surface, and complement activation. Upon incubation in fresh nonimmune human serum, Schu S4 (Ft subsp. tularensis), Fn (Ft subsp. novicida), and LVS (Ft subsp. holarctica live vaccine strain) were resistant to complement-mediated lysis, but LVSG and LVSR (LVS strains altered in surface carbohydrate structures) were susceptible. C3 deposition, however, occurred on all strains. Complement-susceptible strains had markedly increased C3 fragment deposition, including the persistent presence of C3b compared with C3bi, which indicates that C3b inactivation results in survival of complement-resistant strains. C1q, an essential component of the classical activation pathway, was necessary for lysis of complement-susceptible strains and optimal C3 deposition on all strains. Finally, use of Francisella LPS mutants confirmed O Ag as a major regulator of complement resistance. These data provide evidence that pathogenic Francisella activate complement, but are resistant to complement-mediated lysis in part due to limited C3 deposition, rapid conversion of surface-bound C3b to C3bi, and the presence of LPS O Ag.
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1 This work was sponsored by the National Institutes of Health/National Institute of Allergy and Infectious Diseases Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research Program. We acknowledge membership within and support from the Region V "Great Lakes" Regional Center of Excellence (National Institutes of Health Award 1-U54-AI-057153). C.D.C. is recipient of a National Institutes of Health Training Grant T32 AI055411.
2 J.S.G. and L.S.S. contributed equally to the work.
3 Address correspondence and reprint requests to Dr. Larry S. Schlesinger, Department of Medicine, Division of Infectious Diseases, Center for Microbial Interface Biology, Ohio State University, Biomedical Research Tower, Room 1004, 460 West 12th Avenue, Columbus, OH, 43210. E-mail address: larry.schlesinger{at}osumc.edu
4 Abbreviations used in this paper: MAC, membrane attack complex; d, depleted; r, replete(d); CR, complement receptor; FB, factor B; Fn, Francisella tularensis subsp. novicida; Ft, Francisella tularensis; HI, heat inactivated; LVS, Francisella tularensis subsp. holarctica live vaccine strain; LVSG, LVS gray phase variant; LVSR, LVS rough mutant; MH, Mueller-Hinton.
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