Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses

AcknowledgmentsOverall. The following reagent was deposited by the Centers for Disease Control and Prevention and obtained through BEI Resources, NIAID, NIH: SARS-Related Coronavirus 2, Isolate USA-WA1/2020, NR-52281. Figure 8A was created using BioRender.com. We thank the members of the SARS-CoV-2 host response team in Chicago for stimulating discussions and support with particular thanks to Julian Solway, Rick Morimoto, Nissim Hay, Anne Sperling, HuanHuan Chen, Raphael Lee, Raymond Roos, Shannon Elf, Alexander Muir, Gokhan Mutlu, Jay Pinto, Steven White, Nickolai Dulin, Ray Moellering, Viswanathan Natarajan, Leonitis Platanias, Karen Ridge and HuanHuan Chen. We thank Dominique Missiakas for facilitating access to the University of Chicago Howard Taylor Ricketts Facility by providing protocols and trained scientists. We also thank Nicole Rosner and Kathleen Cagney for proposing and facilitating analysis of clinical data, Mark Ratain for consideration of pharmacokinetic issues, and Kazuhiko Igarashi for helpful discussions. We thank the University of Chicago Genomics Facility (RRID:SCR_019196) especially Sandhiya Arun and Pieter Faber, for their assistance with RNA sequencing. Finally, we would like to acknowledge the University of Chicago Vice Provost for Research, Karen Kim, and the Dean of the Biological Sciences Division, Kenneth Polonsky, for their steadfast support.National COVID Cohort Collaborative (N3C). The patient data analyses described in this publication were conducted with data or tools accessed through the NCATS N3C Data Enclave covid.cd2h.org/enclave and supported by NCATS U24 TR002306. This research was possible because of the patients whose information is included within the data from participating organizations (covid.cd2h.org/dtas) and the organizations (https://ncats.nih.gov/n3c/resources/data-contribution/data-transfer-agreement-signatories) and scientists who have contributed to the on-going development of this community resource (28). The project described was supported by the National Institute of General Medical Sciences, 5U54GM104942-04. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The analysis used only de-identified data (i.e., N3C Data Access Tier 2, described at https://covid.cd2h.org/N3C_governance). We gratefully acknowledge contributions from the following N3C core teams:

• Principal Investigators: Melissa A. Haendel, Christopher G. Chute, Kenneth R. Gersing, Anita Walden

• Workstream, subgroup and administrative leaders: Melissa A. Haendel, Tellen D. Bennett, Christopher G. Chute, David A. Eichmann, Justin Guinney, Warren A. Kibbe, Hongfang Liu, Philip R.O. Payne, Emily R. Pfaff, Peter N. Robinson, Joel H. Saltz, Heidi Spratt, Justin Starren, Christine Suver, Adam B. Wilcox, Andrew E. Williams, Chunlei Wu

• Key liaisons at data partner sites

• Regulatory staff at data partner sites

• Individuals at the sites who are responsible for creating the datasets and submitting data to N3C

• Data Ingest and Harmonization Team: Christopher G. Chute, Emily R. Pfaff, Davera Gabriel, Stephanie S. Hong, Kristin Kostka, Harold P. Lehmann, Richard A. Moffitt, Michele Morris, Matvey B. Palchuk, Xiaohan Tanner Zhang, Richard L. Zhu

• Phenotype Team (Individuals who create the scripts that the sites use to submit their data, based on the COVID and Long COVID definitions): Emily R. Pfaff, Benjamin Amor, Mark M. Bissell, Marshall Clark, Andrew T. Girvin, Stephanie S. Hong, Kristin Kostka, Adam M. Lee, Robert T. Miller, Michele Morris, Matvey B. Palchuk, Kellie M. Walters

• Project Management and Operations Team: Anita Walden, Yooree Chae, Connor Cook, Alexandra Dest, Racquel R. Dietz, Thomas Dillon, Patricia A. Francis, Rafael Fuentes, Alexis Graves, Julie A. McMurry, Andrew J. Neumann, Shawn T. O’Neil, Usman Sheikh, Andréa M. Volz, Elizabeth Zampino

• Partners from NIH and other federal agencies: Christopher P. Austin, Kenneth R. Gersing, Samuel Bozzette, Mariam Deacy, Nicole Garbarini, Michael G. Kurilla, Sam G. Michael, Joni L. Rutter, Meredith Temple-O’Connor

• Analytics Team (Individuals who build the Enclave infrastructure, help create codesets, variables, and help Domain Teams and project teams with their datasets): Benjamin Amor, Mark M. Bissell, Katie Rebecca Bradwell, Andrew T. Girvin, Amin Manna, Nabeel Qureshi

• Publication Committee Management Team: Mary Morrison Saltz, Christine Suver, Christopher G. Chute, Melissa A. Haendel, Julie A. McMurry, Andréa M. Volz, Anita Walden

• Publication Committee Review Team: Carolyn Bramante, Jeremy Richard Harper, Wenndy Hernandez, Farrukh M Koraishy, Federico Mariona, Saidulu Mattapally, Amit Saha, Satyanarayana Vedula

• Data partners with released data (50). Stony Brook University — U24TR002306 • University of Oklahoma Health Sciences Center — U54GM104938: Oklahoma Clinical and Translational Science Institute (OCTSI) • West Virginia University — U54GM104942: West Virginia Clinical and Translational Science Institute (WVCTSI) • University of Mississippi Medical Center — U54GM115428: Mississippi Center for Clinical and Translational Research (CCTR) • University of Nebraska Medical Center — U54GM115458: Great Plains IDeA-Clinical & Translational Research • Maine Medical Center — U54GM115516: Northern New England Clinical & Translational Research (NNE-CTR) Network • Wake Forest University Health Sciences — UL1TR001420: Wake Forest Clinical and Translational Science Institute • Northwestern University at Chicago — UL1TR001422: Northwestern University Clinical and Translational Science Institute (NUCATS) • University of Cincinnati — UL1TR001425: Center for Clinical and Translational Science and Training • The University of Texas Medical Branch at Galveston — UL1TR001439: The Institute for Translational Sciences • Medical University of South Carolina — UL1TR001450: South Carolina Clinical & Translational Research Institute (SCTR) • University of Massachusetts Medical School Worcester — UL1TR001453: The UMass Center for Clinical and Translational Science (UMCCTS) • University of Southern California — UL1TR001855: The Southern California Clinical and Translational Science Institute (SC CTSI) • Columbia University Irving Medical Center — UL1TR001873: Irving Institute for Clinical and Translational Research • George Washington Children’s Research Institute — UL1TR001876: Clinical and Translational Science Institute at Children’s National (CTSA-CN) • University of Kentucky — UL1TR001998: UK Center for Clinical and Translational Science • University of Rochester — UL1TR002001: UR Clinical & Translational Science Institute • University of Illinois at Chicago — UL1TR002003: UIC Center for Clinical and Translational Science • Penn State Health Milton S. Hershey Medical Center — UL1TR002014: Penn State Clinical and Translational Science Institute • The University of Michigan at Ann Arbor — UL1TR002240: Michigan Institute for Clinical and Health Research • Vanderbilt University Medical Center — UL1TR002243: Vanderbilt Institute for Clinical and Translational Research • University of Washington — UL1TR002319: Institute of Translational Health Sciences • Washington University in St. Louis — UL1TR002345: Institute of Clinical and Translational Sciences • Oregon Health & Science University — UL1TR002369: Oregon Clinical and Translational Research Institute • University of Wisconsin-Madison — UL1TR002373: UW Institute for Clinical and Translational Research • Rush University Medical Center — UL1TR002389: The Institute for Translational Medicine (ITM) • The University of Chicago — UL1TR002389: The Institute for Translational Medicine (ITM) • University of North Carolina at Chapel Hill — UL1TR002489: North Carolina Translational and Clinical Science Institute • University of Minnesota — UL1TR002494: Clinical and Translational Science Institute • Children’s Hospital Colorado — UL1TR002535: Colorado Clinical and Translational Sciences Institute • The University of Iowa — UL1TR002537: Institute for Clinical and Translational Science • The University of Utah — UL1TR002538: Uhealth Center for Clinical and Translational Science • Tufts Medical Center — UL1TR002544: Tufts Clinical and Translational Science Institute • Duke University — UL1TR002553: Duke Clinical and Translational Science Institute • Virginia Commonwealth University — UL1TR002649: C. Kenneth and Dianne Wright Center for Clinical and Translational Research • The Ohio State University — UL1TR002733: Center for Clinical and Translational Science • The University of Miami Leonard M. Miller School of Medicine — UL1TR002736: University of Miami Clinical and Translational Science Institute • University of Virginia — UL1TR003015: iTHRIVL Integrated Translational health Research Institute of Virginia • Carilion Clinic — UL1TR003015: iTHRIVL Integrated Translational health Research Institute of Virginia • University of Alabama at Birmingham — UL1TR003096: Center for Clinical and Translational Science • Johns Hopkins University — UL1TR003098: Johns Hopkins Institute for Clinical and Translational Research • University of Arkansas for Medical Sciences — UL1TR003107: UAMS Translational Research Institute • Nemours — U54GM104941: Delaware CTR ACCEL Program • University Medical Center New Orleans — U54GM104940: Louisiana Clinical and Translational Science (LA CaTS) Center • University of Colorado Denver, Anschutz Medical Campus — UL1TR002535: Colorado Clinical and Translational Sciences Institute • Mayo Clinic Rochester — UL1TR002377: Mayo Clinic Center for Clinical and Translational Science (CCaTS) • Tulane University — UL1TR003096: Center for Clinical and Translational Science • Loyola University Medical Center — UL1TR002389: The Institute for Translational Medicine (ITM) • Advocate Health Care Network — UL1TR002389: The Institute for Translational Medicine (ITM) • OCHIN — INV-018455: Bill and Melinda Gates Foundation grant to Sage Bionetworks• Additional data partners who have signed DTA and data release pending (35). The Rockefeller University — UL1TR001866: Center for Clinical and Translational Science • The Scripps Research Institute — UL1TR002550: Scripps Research Translational Institute • University of Texas Health Science Center at San Antonio — UL1TR002645: Institute for Integration of Medicine and Science • The University of Texas Health Science Center at Houston — UL1TR003167: Center for Clinical and Translational Sciences (CCTS) • NorthShore University HealthSystem — UL1TR002389: The Institute for Translational Medicine (ITM) • Yale New Haven Hospital — UL1TR001863: Yale Center for Clinical Investigation • Emory University — UL1TR002378: Georgia Clinical and Translational Science Alliance • Weill Medical College of Cornell University — UL1TR002384: Weill Cornell Medicine Clinical and Translational Science Center • Montefiore Medical Center — UL1TR002556: Institute for Clinical and Translational Research at Einstein and Montefiore • Medical College of Wisconsin — UL1TR001436: Clinical and Translational Science Institute of Southeast Wisconsin • University of New Mexico Health Sciences Center — UL1TR001449: University of New Mexico Clinical and Translational Science Center • George Washington University — UL1TR001876: Clinical and Translational Science Institute at Children’s National (CTSA-CN) • Stanford University — UL1TR003142: Spectrum: The Stanford Center for Clinical and Translational Research and Education • Regenstrief Institute — UL1TR002529: Indiana Clinical and Translational Science Institute • Cincinnati Children’s Hospital Medical Center — UL1TR001425: Center for Clinical and Translational Science and Training • Boston University Medical Campus — UL1TR001430: Boston University Clinical and Translational Science Institute • The State University of New York at Buffalo — UL1TR001412: Clinical and Translational Science Institute • Aurora Health Care — UL1TR002373: Wisconsin Network For Health Research • Brown University — U54GM115677: Advance Clinical Translational Research (Advance-CTR) • Rutgers, The State University of New Jersey — UL1TR003017: New Jersey Alliance for Clinical and Translational Science • Loyola University Chicago — UL1TR002389: The Institute for Translational Medicine (ITM) • #N/A — UL1TR001445: Langone Health’s Clinical and Translational Science Institute • Children’s Hospital of Philadelphia — UL1TR001878: Institute for Translational Medicine and Therapeutics • University of Kansas Medical Center — UL1TR002366: Frontiers: University of Kansas Clinical and Translational Science Institute • Massachusetts General Brigham — UL1TR002541: Harvard Catalyst • Icahn School of Medicine at Mount Sinai — UL1TR001433: ConduITS Institute for Translational Sciences • Ochsner Medical Center — U54GM104940: Louisiana Clinical and Translational Science (LA CaTS) Center • HonorHealth — None (Voluntary) • University of California, Irvine — UL1TR001414: The UC Irvine Institute for Clinical and Translational Science (ICTS) • University of California, San Diego — UL1TR001442: Altman Clinical and Translational Research Institute • University of California, Davis — UL1TR001860: UCDavis Health Clinical and Translational Science Center • University of California, San Francisco — UL1TR001872: UCSF Clinical and Translational Science Institute • University of California, Los Angeles — UL1TR001881: UCLA Clinical Translational Science Institute • University of Vermont — U54GM115516: Northern New England Clinical & Translational Research (NNE-CTR) Network • Arkansas Children’s Hospital — UL1TR003107: UAMS Translational Research Institute

• Additional N3C acknowledgments. We would also like to thank others not listed above: Joy Alamgir (ARIScience), Seth Russell, MS (University of Colorado), and Hui Zhang, PhD MBA (University of Chicago), who created N3C concept sets that we used to define some of the medical condition indicator covariates for our statistical analysis. We would also like to thank Steve Johnson, PhD (University of Minnesota) for writing a BMI calculation Knowledge Object that we modified for calculating BMI values from weight and height data.

Funding: This work was supported directly by: BIG Vision grant from the University of Chicago (M.R.R.). National Institutes of Health grant R01 GM121735 (M.R.R.). National Institutes of Health grant R01 CA184494 (M.R.R.). National Institutes of Health grant R01 AI137514 (G.R.). National Institutes of Health grant R01 AI127518 (G.R.). National Institutes of Health grant R01 AI134980 (G.R.). National Institutes of Health grant R01 CA219815 (S.A.O.). National Institutes of Health grant R35 GM119840 (B.C.D). National Institutes of Health grant P30 CA014599 (University of Chicago Comprehensive Cancer Center Support grant). Harry B. and Leona M. Helmsley Charitable Trust (K. E. P). The patient analysis component of this work was supported indirectly by the funding listed in the N3C section of the Acknowledgements section.

Author contributions: Conceptualization: MRR, LCN, DY, GR, SAO, GFP, DOM, ND, TJB. Methodology: MRR, LCN, DY, GR, SAO, DOM, GFP, ND, BCD, TJB. Software: DY, TJB. Formal analysis: DY, TJB. Investigation: LCN, DY, VN, TJB, TO, SN-C, JBF, ND, AM, CD, Diane Silva, HG, LS, LR-M, AV, ES, KAJ, S-AA. Resources: GR, MRR, GFP, ST, BCD. Data Curation: DOM, TJB, DY, National COVID Cohort Collaborative Consortium. Writing – original draft: MRR. Writing – review & editing: LCN, DY, VN, TJB, SN-C, JBF, ND, AM, KAJ, Diane Silva, JMM, BCD, ST, SAO, GFP, DOM, GR, MRR. Visualization: LCN, DY, ND, AM, SN-C, BCD, JBF. Supervision: MRR. GR, DOM, GFP, SAO, ST, BCD. Project Administration: MRR. Funding acquisition: MRR. For the animal experiment: Investigation: Divyasha Saxena, CDA. Formal analysis: Divyasha Saxena, JDG. Methodology: JDG, JKD, Divyasha Saxena, WES, KEP. Obtaining approvals: WES, JDG. Funding acquisition: KEP.

Competing interests: S.A.O. is a cofounder and consultant at OptiKira., L.L.C. (Cleveland, OH). The authors declare no other competing interests.

Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper, the Supplementary Materials, and/or the Supplementary Data S1. Raw and processed RNA-seq data were deposited into the GEO database (GSE168797).

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