Cellular Microbiology

Host based systems are disease relevant platforms for screening anti Mtb compounds. New target and chemical spaces open up for drug discovery in these platforms while recent advances enable sensitive detection and identification of subtle phenotypes. This review provides an overview of these advances and the recent host based chemical screens for identification of anti-Mtb compounds.

The intracellular bacterial pathogen Coxiella burnetii uses a Dot/Icm type IVB secretion system to deliver effector proteins into host cells during intracellular growth. The Cbu1754 protein was found to be important for the biogenesis of the Coxiella-containing vacuole (CCV) and intracellular replication. Our data demonstrate that the Cbu1754 protein through interactions with IcmSW is a component of the Dot/Icm coupling protein complex, which is a type IVB subassembly essential for recruitment and delivery of effectors to the secretion machinery.

Infection of macrophages by Salmonella Typhimurium (red) promotes accumulation of cholesterol (green) in both endo-lysosomal compartments and the Salmonella-containing vacuole (SCV). Here we show that this process is driven by the secreted effector protein SseJ, through a signaling pathway involving the host kinases FAK and Akt, that transcriptionally suppresses expression of the host cholesterol exporter ABCA1. Loss of SseJ acyltransferase activity (SseJ^H384N), FAK/Akt inhibition or pharmacological induction of ABCA1 expression (T090) prevent cholesterol accumulation and significantly attenuate bacterial survival.