AI-guided discovery of the invariant host response to viral pandemics

EBioMedicine. 2021 Jun;68:103390. doi: 10.1016/j.ebiom.2021.103390. Epub 2021 Jun 11.


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.

Keywords: Angiotensin converting enzyme (ACE)-2; Artificial intelligence/machine learning; Boolean equivalent clusters; Coronavirus COVID-19; Immune response; Interleukin 15 (IL15); Lung alveoli; Natural Killer (NK) cells.

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics*
  • Animals
  • Antibodies, Neutralizing / administration & dosage
  • Antibodies, Neutralizing / pharmacology
  • Antiviral Agents / administration & dosage*
  • Antiviral Agents / pharmacology
  • Artificial Intelligence
  • Autopsy
  • COVID-19 / genetics*
  • COVID-19 / immunology
  • COVID-19 Drug Treatment
  • Cricetinae
  • Cytidine / administration & dosage
  • Cytidine / analogs & derivatives
  • Cytidine / pharmacology
  • Databases, Genetic
  • Disease Models, Animal
  • Gene Expression Profiling / methods*
  • Gene Regulatory Networks / drug effects
  • Genetic Markers / drug effects
  • Humans
  • Hydroxylamines / administration & dosage
  • Hydroxylamines / pharmacology
  • Interleukin-15 / blood
  • Interleukin-15 / genetics*
  • Lung / immunology
  • Mesocricetus
  • Pandemics
  • Receptors, Interleukin-15 / blood
  • Receptors, Interleukin-15 / genetics*
  • Virus Diseases / genetics*
  • Virus Diseases / immunology


  • Antibodies, Neutralizing
  • Antiviral Agents
  • Genetic Markers
  • Hydroxylamines
  • IL15 protein, human
  • IL15RA protein, human
  • Interleukin-15
  • Receptors, Interleukin-15
  • Cytidine
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • molnupiravir