Illuminating Host-Mycobacterial Interactions with Genome-wide CRISPR Knockout and CRISPRi Screens
Existing antibiotics are insufficient to defeat t . b (TB), a number one reason for dying worldwide. We searched for potential targets for host-directed therapies (HDTs) by investigating the host immune reaction to mycobacterial infection. We used high-throughput CRISPR knockout and CRISPR interference (CRISPRi) screens to recognize perturbations that enhance the survival of human phagocytic cells have contracted Mycobacterium bovis BCG (Bacillus Calmette-Guérin), like a proxy for Mycobacterium t . b (Mtb). A number of these perturbations restricted the development of intracellular mycobacteria. We identified over 100 genes connected with diverse biological pathways as potential HDT targets. We validated critical factors from the type I interferon and aryl hydrocarbon receptor signaling pathways that react to the little-molecule inhibitors cerdulatinib and CH223191, correspondingly these inhibitors enhanced human macrophage survival and limited the intracellular development of Mtb. Thus, high-throughput functional genomic screens, by elucidating highly complex host-virus interactions, can actually identify HDTs to potentially improve TB treatment.