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Illuminating Host-Mycobacterial Interactions with Genome-wide CRISPR Knockout and CRISPRi Screens

Author(s)
Lai, Yong; Babunovic, Gregory H; Cui, Liang; Dedon, Peter C; Doench, John G; Fortune, Sarah M; Lu, Timothy K; ... Show more Show less
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Abstract
Existing antibiotics are inadequate to defeat tuberculosis (TB), a leading cause of death worldwide. We sought potential targets for host-directed therapies (HDTs) by investigating the host immune response to mycobacterial infection. We used high-throughput CRISPR knockout and CRISPR interference (CRISPRi) screens to identify perturbations that improve the survival of human phagocytic cells infected with Mycobacterium bovis BCG (Bacillus Calmette-Guérin), as a proxy for Mycobacterium tuberculosis (Mtb). Many of these perturbations constrained the growth of intracellular mycobacteria. We identified over 100 genes associated with diverse biological pathways as potential HDT targets. We validated key components of the type I interferon and aryl hydrocarbon receptor signaling pathways that respond to the small-molecule inhibitors cerdulatinib and CH223191, respectively; these inhibitors enhanced human macrophage survival and limited the intracellular growth of Mtb. Thus, high-throughput functional genomic screens, by elucidating highly complex host-pathogen interactions, can serve to identify HDTs to potentially improve TB treatment.
Date issued
2020-09
URI
https://hdl.handle.net/1721.1/132703
Department
Massachusetts Institute of Technology. Synthetic Biology Center; Massachusetts Institute of Technology. Research Laboratory of Electronics; Ragon Institute of MGH, MIT and Harvard; Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science; Harvard University--MIT Division of Health Sciences and Technology; Massachusetts Institute of Technology. Department of Biological Engineering
Journal
Cell Systems
Publisher
Elsevier BV
Citation
Yong Lai, Gregory H. Babunovic, Liang Cui, Peter C. Dedon, John G. Doench, Sarah M. Fortune, Timothy K. Lu, Illuminating Host-Mycobacterial Interactions with Genome-wide CRISPR Knockout and CRISPRi Screens, Cell Systems, Volume 11, Issue 3, 2020 © 2020 Elsevier Inc.
Version: Original manuscript
ISSN
2405-4712

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