Coxiella burnetii is the intracellular bacterial agent of human Q fever, a debilitating flu-like illness that can also present as severe chronic endocarditis. C. burnetii is spread by contaminated aerosols and targets alveolar macrophages in vivo, where the pathogen regulates vesicular trafficking to establish a phagolysosome-like parasitophorous vacuole (PV) in which to replicate. Eukaryotic kinase signaling is heavily involved in phagosome maturation and host responses to bacterial pathogens;however, their involvement in C. burnetii infection has not been fully defined. The current proposal is designed to test the hypothesis that C. burnetii manipulates host cAMP/PKA signaling to generate the PV and prevent host cell death.
Aim 1 will elucidate the role of PKA in PV formation. The experiments in this aim will explore the requirement for PKA and actin-related protein trafficking to the PV.
Aim 2 will determine the role of PKA in C. burnetii anti-apoptotic activity. These experiments will assess PKA-dependent inactivation of pro-apoptotic Bad and the requirement of this event for prevention of apoptosis.
Aim 3 will probe the overall role of cAMP production in PV formation, bacterial replication, apoptosis inhibition, and transcriptional regulation. Collectively, the aims in the current proposal will explore a multi-functional role for cAMP/PKA signaling in C. burnetii parasitism of macrophages.
Coxiella burnetii is the intracellular bacterial agent of human Q fever, a debilitating acute disease that can present as chronic endocarditis. C. burnetii virulence determinants are poorly understood and the pathogen's use of kinase signaling in alveolar macrophages has not been addressed. Characterization of cAMP/PKA manipulation by C. burnetii will provide candidate therapeutic targets to combat Q fever and provide needed insight into the interaction between the pathogen and its host cell. The goals of the proposed research are to 1) define C. burnetii regulation of PV formation and apoptosis in a PKA-dependent manner and 2) explore the global role of cAMP in infection.
|Macdonald, Laura J; Graham, Joseph G; Kurten, Richard C et al. (2014) Coxiella burnetii exploits host cAMP-dependent protein kinase signalling to promote macrophage survival. Cell Microbiol 16:146-59|