Illuminating Host-Mycobacterial Interactions with Genome-wide CRISPR Knockout and CRISPRi Screens
Name
2020.03.30.016139v1.full.pdf
Description
Submitted version
Size
4.37 MB
Format
Adobe PDF
Checksum (MD5)
b88f29537ff1f40855836228b806f218
Author(s)
Lai, Yong
Babunovic, Gregory H
Cui, Liang
Dedon, Peter C
Doench, John G
Fortune, Sarah M
Lu, Timothy K
Date Issued
September 2020
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
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.
MIT 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
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/J.CELS.2020.08.010
