title: Coxiella burnetii exploits host cAMP-dependent protein kinase signalling to promote macrophage survival.
abstract: Intracellular bacterial pathogens often subvert apoptosis signalling to regulate survival of their host cell, allowing propagation of the bacterial population. Coxiella burnetii, the intracellular agent of human Q fever, inhibits host cell apoptosis through several mechanisms, including prevention of mitochondrial cytochrome c release, triggering of an anti-apoptotic transcriptional programme, and activation of pro-survival kinases. To control host cell survival, C. burnetii delivers effector proteins to the eukaryotic cytosol using a specialized Dot/Icm type IV secretion system (T4SS). Effectors are predicted to regulate activity of pro-survival host signalling proteins, such as Akt and cAMP-dependent protein kinase (PKA), to control infection. Here, we show that host PKA activity is required for C. burnetii inhibition of macrophage apoptosis. PKA is activated during infection and inhibits activity of the pro-apoptotic protein Bad via phosphorylation. Bad is also phosphorylated at an Akt-specific residue, indicating C. burnetii uses two kinases to fully inactivate Bad. Additionally, Bad and the tethering protein 14-3-3β colocalize at the C. burnetii parasitophorous vacuole (PV) membrane during infection, an event predicted to alter Bad promotion of apoptosis. Inhibiting PKA activity prevents Bad recruitment to the PV, but the protein is retained at the membrane during induction of apoptosis. Finally, PKA regulatory subunit I (RI) traffics to the PV membrane in a T4SS-dependent manner, suggesting a C. burnetii effector(s) regulates PKA-dependent activities. This study is the first to demonstrate subversion of host PKA activity by an intracellular bacterial pathogen to prevent apoptosis and survive within macrophages.
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Macdonald
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Graham
authors.forename: Richard C
authors.initials: RC
authors.lastname: Kurten
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Voth
mesh_terms: D002470:Cell Survival; D002478:Cells, Cultured; D016997:Coxiella burnetii / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D016676:Macrophages, Alveolar / Q000382:microbiology* / Q000502:physiology*
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases
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