Coxiella Cell Variant Gene Regulation and Membrane Proteins

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Abstract Coxiella burnetii is the etiologic agent of an acute, disabling influenza-like illness in humans termed Q fever. This pathogen can cause chronic disease that usually manifests as hepatitis or endocarditis. Acute disease with its nonspecific symptoms is difficult to diagnose and chronic disease requires long-term antibiotic treatment during which patient compliance is problematic. C. burnetii infects a wide range of vertebrate and invertebrate hosts and is found worldwide. The Centers for Disease Control and Prevention have recognized C. burnetii as a potential agent of bioterrorism. Characteristics of C. burnetii that warrant this classification include aerosolic infection, low infectious dose (as low as one organism), and the ability to survive for prolonged periods in the environment. C. burnetii undergoes a biphasic developmental cycle with the environmentally stable and chemically resistant small cell variant (SCV) thought to be the cell form responsible for environmental persistence, and the more fragile large cell variant (LCV) as the metabolically and replicatively active cell variant. Little is known about the regulation of development in this organism, so we propose to: 1) examine the kinetics of global regulatory genes that have been shown to regulate morphological differentiation in L pneumophila. Regulatory genes controlling C. burnetii development would be promising targets for mutagenesis. Environmentally stable SCV are likely the cell form responsible for infection of new hosts. We therefore propose to: 2) identify immunodominant SCV membrane proteins that could then be used in a subunit vaccine. As has been found for other obligate intracellular bacteria, C. burnetii likely expresses genes in an immunocompetent host that are not expressed when the bacteria are grown in cell culture. We propose to: 3) compare bacterial gene expression for virulent bacteria grown in vitro to bacteria isolated from infected alveolar macrophages from infected mice. We will be collaborating with Dr. Allen Harmsen at MSU on the last research goal.