AI-guided discovery of the invariant host response to viral pandemics.
Debashis Sahoo, Gajanan D Katkar, Soni Khandelwal, Mahdi Behroozikhah, Amanraj Claire, Vanessa Castillo, Courtney Tindle, MacKenzie Fuller, Sahar Taheri, Thomas F Rogers, Nathan Beutler, Sydney I Ramirez, Stephen A Rawlings, Victor Pretorius, Davey M Smith, Dennis R Burton, Laura E Crotty Alexander, Jason Duran, Shane Crotty, Jennifer M Dan, Soumita Das, Pradipta Ghosh
Author Information
Debashis Sahoo: Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, MC 0730, Leichtag Building 132, La Jolla, CA 92093-0831, USA; Department of Computer Science and Engineering, Jacobs School of Engineering, University of California San Diego, USA; Moores Cancer Center, University of California San Diego, USA. Electronic address: dsahoo@ucsd.edu.
Gajanan D Katkar: Department of Cellular and Molecular Medicine, University of California San Diego, USA.
Soni Khandelwal: Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, MC 0730, Leichtag Building 132, La Jolla, CA 92093-0831, USA.
Mahdi Behroozikhah: Department of Computer Science and Engineering, Jacobs School of Engineering, University of California San Diego, USA.
Amanraj Claire: Department of Cellular and Molecular Medicine, University of California San Diego, USA.
Vanessa Castillo: Department of Cellular and Molecular Medicine, University of California San Diego, USA.
Courtney Tindle: Department of Cellular and Molecular Medicine, University of California San Diego, USA.
MacKenzie Fuller: Department of Cellular and Molecular Medicine, University of California San Diego, USA.
Sahar Taheri: Department of Computer Science and Engineering, Jacobs School of Engineering, University of California San Diego, USA.
Thomas F Rogers: Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
Nathan Beutler: Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Sydney I Ramirez: Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA, USA.
Stephen A Rawlings: Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA, USA.
Victor Pretorius: Department of Surgery, University of California San Diego, USA.
Davey M Smith: Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA, USA.
Dennis R Burton: Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA.
Laura E Crotty Alexander: Pulmonary Critical Care Section, Veterans Affairs (VA) San Diego Healthcare System, La Jolla, California; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, USA.
Jason Duran: Division of Cardiology, Department of Internal Medicine, UC San Diego Medical Center, La Jolla 92037.
Shane Crotty: Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA, USA.
Jennifer M Dan: Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA, USA.
Soumita Das: Department of Pathology, University of California San Diego, USA. Electronic address: sodas@ucsd.edu.
Pradipta Ghosh: Moores Cancer Center, University of California San Diego, USA; Department of Cellular and Molecular Medicine, University of California San Diego, USA; Medicine, University of California San Diego, USA. Electronic address: prghosh@ucsd.edu.
BACKGROUND: Coronavirus Disease 2019 (Covid-19) continues to challenge the limits of our knowledge and our healthcare system. Here we sought to define the host immune response, a.k.a, the "cytokine storm" that has been implicated in fatal COVID-19 using an AI-based approach. METHOD: Over 45,000 transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature using ACE2 as a 'seed' gene; ACE2 was rationalized because it encodes the receptor that facilitates the entry of SARS-CoV-2 (the virus that causes COVID-19) into host cells. An AI-based approach was used to explore the utility of the signature in navigating the uncharted territory of Covid-19, setting therapeutic goals, and finding therapeutic solutions. FINDINGS: The 166-gene signature was surprisingly conserved across all viral pandemics, including COVID-19, and a subset of 20-genes classified disease severity, inspiring the nomenclatures ViP and severe-ViP signatures, respectively. The ViP signatures pinpointed a paradoxical phenomenon wherein lung epithelial and myeloid cells mount an IL15 cytokine storm, and epithelial and NK cell senescence and apoptosis determine severity/fatality. Precise therapeutic goals could be formulated; these goals were met in high-dose SARS-CoV-2-challenged hamsters using either neutralizing antibodies that abrogate SARS-CoV-2•ACE2 engagement or a directly acting antiviral agent, EIDD-2801. IL15/IL15RA were elevated in the lungs of patients with fatal disease, and plasma levels of the cytokine prognosticated disease severity. INTERPRETATION: The ViP signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool to rapidly assess disease severity and vet candidate drugs. FUNDING: This work was supported by the National Institutes for Health (NIH) [grants CA151673 and GM138385 (to DS) and AI141630 (to P.G), DK107585-05S1 (SD) and AI155696 (to P.G, D.S and S.D), U19-AI142742 (to S. C, CCHI: Cooperative Centers for Human Immunology)]; Research Grants Program Office (RGPO) from the University of California Office of the President (UCOP) (R00RG2628 & R00RG2642 to P.G, D.S and S.D); the UC San Diego Sanford Stem Cell Clinical Center (to P.G, D.S and S.D); LJI Institutional Funds (to S.C); the VA San Diego Healthcare System Institutional funds (to L.C.A). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists. ONE SENTENCE SUMMARY: The host immune response in COVID-19.
