Mechanisms of B-1 cell-mediated immunity against Coxiella burnetii infection

Coxiella burnetii is an obligate intracellular gram-negative bacterium that causes acute Q fever and chronic infections in humans. Since there is no licensed vaccine for prevention of human Q fever in the US. the development of safe and effective prophylactic and therapeutic strategies for controlling C. burnetii infection remains an important goal for public health. However. there is a fundamental gap in the knowledge regarding the mechanisms of host immune response to C. burnetii natural infection. The long-term goal of this program is to develop novel approaches for safe immunoprophylaxis and immunotherapy of acute and chronic Q fever.The objective of this application is to understand the mechanisms of B1 cell-mediated protective immunity against C. burnetii aerosol infection. To achieve this objective. we will test the central hypothesis that B1 cell-mediated protective immunity against C. burnetii infection depends on its abilities to control bacterial replication and regulate inflammatory response by pursuing two specific aims. Aim 1 is to determine whether B1 cells can mediate killing of C. burnetii. We will determine whether i) B1 cells play a critical role in host defense against C. burnetii aerosol infection; ii) B1a or B1b cells are responsible for B1 cell-mediated protective immunity against C. burnetii aerosol infection; and iii) B1a or B1b cells function as phagocytes to mediate clearance of C. burnetii. Aim 2 is to determine whether B1 cells can regulate C. burnetii infection-induced inflammatory response. We will determine whether i) B1 cells are critical for regulating aerosolized C. burnetii-induced inflammatory response; and ii) B1a and/or B1b cells are responsible for regulating inflammatory response against C. burnetii infection. As an outcome of the proposed research. we expect to enhance our understanding of the mechanisms of B1 cell-mediated protective immunity against C. burnetii natural infection. This will have significant positive effects on human health. because it will provide critical information for developing novel immunotherapeutic strategies against Q fever.