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
Affiliations
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; Corresponding authors at: Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, MC 0730, Leichtag Building 132; La Jolla, CA 92093-0831, USA.
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; Corresponding authors at: Department of Pathology, University of California San Diego, USA
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; Corresponding authors at: Department of Cellular and Molecular Medicine, University of California San Diego, USA.
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.
