Defining the impact of host-directed drugs on Coxiella burnetii growth in macrophages

Coxiella burnetii is an intracellular bacterial pathogen that causes human Q fever. Q fever presents most often as an acute flu-like illness but can present as fatal chronic endocarditis. Unfortunately, treatment options for Q fever endocarditis are highly ineffective and require many months of antibiotic administration. We recently discovered numerous host-directed drugs that suppress C. burnetii replication within the pathogen’s target cell, the human macrophage. These drugs, which are typically used to treat psychosis- or mood-related disorders by inhibiting neurotransmitter (NTM) system signaling, potentially represent novel anti-Q fever therapies. The current proposal will define the impact of NTM-acting drugs on the ability of C. burnetii to replicate within alveolar macrophages and regulate the macrophage innate immune response to infection. Aim 1 will define the specific NTM machinery involved in C. burnetii replication in macrophages. Aim 2 will define the impact of host-directed drugs on the pathogen’s ability to dampen the cytokine response and shift alveolar macrophages to a pro-replication, anti-inflammatory phenotype. Throughout the proposal, we will use primary human alveolar macrophages and human precision-cut lung slices to provide disease relevance. Collectively, the current proposal will lay the groundwork to characterize novel anti-C. burnetii treatments.