Identification and targeting of regulators of SARS-CoV-2-host interactions in the airway epithelium
Brooke Dirvin, Heeju Noh, Lorenzo Tomassoni, Danting Cao, Yizhuo Zhou, Xiangyi Ke, Jun Qian, Sonia Jangra, Michael Schotsaert, Adolfo García-Sastre, Charles Karan, Andrea Califano, Wellington V Cardoso
The impact of SARS-CoV-2 in the lung has been extensively studied, yet the molecular regulators of host-cell programs hijacked by the virus in distinct human airway epithelial cell populations remain poorly understood. Some of the reasons include overreliance on transcriptomic profiling and use of nonprimary cell systems. Here we report a network-based analysis of single-cell transcriptomic profiles able to identify master regulator (MR) proteins controlling SARS-CoV-2-mediated reprogramming in pathophysiologically relevant human ciliated, secretory, and basal cells. This underscored chromatin remodeling, endosomal sorting, ubiquitin pathways, as well as proviral factors identified by CRISPR assays as components of the viral-host response in these cells. Large-scale drug perturbation screens revealed 11 candidate drugs able to invert the entire MR signature activated by SARS-CoV-2. Leveraging MR analysis and perturbational profiles of human primary cells represents an innovative approach to investigate pathogen-host interactions in multiple airway conditions for drug prioritization.
Acknowledgments: M.S. and A.G.-S.want to thank R. Albrecht for management and organization of the BSl-3 facility. Funding: this work was supported by the grants nih-nhlBi R35-hl135834 to W.v.c.; nih-nci R35 cA197745, S10 OD012351, S10 OD021764, S10 OD032433, and U01 cA 272610 to A.c.; nih/niAiD R01Ai160706, nih/niDDK R01DK130425 and U19Ai135972 to A.G.-S. Author contributions: W.v.c.: Writing-original draft, conceptualization, investigation, writing-review and editing, methodology, resources, validation, supervision, project administration, and supervision. A.c.: Writing-original draft, conceptualization, writing-review and editing, methodology, resources, funding acquisition, validation, supervision, and project administration. A.G.-S.: conceptualization, writing-review and editing, methodology, resources, funding acquisition, and supervision. B.D.: Writingoriginal draft, conceptualization, investigation, writing-review and editing, methodology, resources, validation, supervision, project administration, and visualization. h.n.: Writingoriginal draft, conceptualization, investigation, writing-review and editing, methodology, data curation, validation, formal analysis, software, and visualization. l.t.: Writing-original draft, conceptualization, investigation, writing-review and editing, methodology, data curation, validation, formal analysis, software, and visualization. D.c.: conceptualization, investigation, writing-review and editing, methodology, data curation,..
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