Cellular and soluble requirements for survival of pulmonary infection with virulent Francisella tularensis (99.29)

Abstract

Abstract Francisella tularensis is a facultative intracellular bacterium and the causative agent of tularemia. Inhalation of as few as 15 bacteria can cause lethal disease in humans. Development of novel vaccines and therapeutics for tularemia has been hampered by the lack of understanding of what immune components are required to survive infection. Defining requirements of immunity against virulent F. tularensis, such as strain SchuS4, has been difficult since animals typically die within 5 days after exposure to as few as 10 bacteria. To enable reliable identification of the components of the immune system that are important for defense against infection with F. tularensis we developed a convalescent model of tularemia in C57Bl/6 mice. We show that administration of a low dose of antibiotic over the course of 14 days resulted in clearance of SchuS4 from all organs within 21 days, regardless of the route of infection. However, only 60% of mice infected intranasally survived more than 30 days of infection, whereas 100% of mice infected intradermally survived past this time point. Using mice deficient of specific immune components in this model revealed that both T cells and B cells, are necessary to control SchuS4. Similarly, IL-12p40 and IFN-gamma are also critical for host defense against SchuS4 infection. Together this data provides a novel mechanism by which to identify host factors involved in both resolution and exacerbation of tularemia.