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Immune Response to Primary Aerosol Infection with Francisella novicida

Roth, Kimberly M.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1213116078

Abstract Details

2008, Doctor of Philosophy, Ohio State University, Microbiology.
Francisella tularensis causes tularemia and death in humans without treatment. It has been classified as a group A bioterror agent due to its infectivity, extreme virulence and rapid dissemination. Aerosolized F. tularensis infection poses the greatest threat because pneumonic tularemia results in high mortality and would likely be the route used in a bioterrorist attack. Despite this, little is known about the host immune response to this pathogen, particularly after primary aerosol infection. Therefore, we have developed a novel aerosol model in mice using Francisella novicida, a subspecies of F. tularensis, to elucidate host immune responses to primary, pulmonary tularemia. Here we show that a F. novicida aerosol model in mice provides a useful tool for investigating immune responses that can be applied to human tularemia. We also report for the first time that primary F. novicida infection causes dystrophic cardiac calcinosis (DCC) in BALB/c mice and demonstrate that F. novicida interferes with antigen-specific CD4+ T cell responses by disrupting IFN-γ signaling in macrophages. In addition, we have shown that STAT1-/- mice are more susceptible to tularemia. Characterization of this murine aerosol model has shown that F. novicida causes severe lung pathology and disseminates to the liver and the heart, where it causes pericardial calcification. We have also confirmed that macrophages are the prominent cell population in the lung following aerosol infection. Using this model, we show development of DCC in BALB/c mice is associated with significant induction of RANKL but not osteopontin (OPN) mRNA in their organs. Depletion of lung macrophages prior to infection markedly reduces pericarditis and calcification in BALB/c mice but does not affect their survival. We have also demonstrated the effect of F. novicida infection on antigen-specific CD4+ T cell responses. We have shown that F. novicida disrupts STAT1-dependent IFN-γ signaling in macrophages by down-regulation of IFN-γRα expression. This disruption decreases MHC class II surface expression on macrophages and ultimately decreases antigen-specific CD4+ T cell responses. This is the first report of F. novicida interference in antigen-specific CD4+ T cell responses following primary infection.
Abhay Satoskar, MD/PhD (Advisor)
John Gunn, PhD (Committee Member)
Neil Baker, PhD (Committee Member)
Chad Rappleye, PhD (Committee Member)
192 p.
Immunology
Francisella; dystrophic cardiac calcinosis; interferon gamma; STAT1

Recommended Citations

Citations

  • Roth, K. M. (2008). Immune Response to Primary Aerosol Infection with Francisella novicida [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1213116078

    APA Style (7th edition)

  • Roth, Kimberly. Immune Response to Primary Aerosol Infection with Francisella novicida. 2008. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1213116078.

    MLA Style (8th edition)

  • Roth, Kimberly. "Immune Response to Primary Aerosol Infection with Francisella novicida." Doctoral dissertation, Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1213116078

    Chicago Manual of Style (17th edition)

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© 2008, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.