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AI-guided discovery of the invariant host response to viral pandemics
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 tran...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193764/ https://www.ncbi.nlm.nih.gov/pubmed/34127431 http://dx.doi.org/10.1016/j.ebiom.2021.103390 |
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author | Sahoo, Debashis Katkar, Gajanan D. Khandelwal, Soni Behroozikhah, Mahdi Claire, Amanraj Castillo, Vanessa Tindle, Courtney Fuller, MacKenzie Taheri, Sahar Rogers, Thomas F. Beutler, Nathan Ramirez, Sydney I. Rawlings, Stephen A. Pretorius, Victor Smith, Davey M. Burton, Dennis R. Alexander, Laura E. Crotty Duran, Jason Crotty, Shane Dan, Jennifer M. Das, Soumita Ghosh, Pradipta |
author_facet | Sahoo, Debashis Katkar, Gajanan D. Khandelwal, Soni Behroozikhah, Mahdi Claire, Amanraj Castillo, Vanessa Tindle, Courtney Fuller, MacKenzie Taheri, Sahar Rogers, Thomas F. Beutler, Nathan Ramirez, Sydney I. Rawlings, Stephen A. Pretorius, Victor Smith, Davey M. Burton, Dennis R. Alexander, Laura E. Crotty Duran, Jason Crotty, Shane Dan, Jennifer M. Das, Soumita Ghosh, Pradipta |
author_sort | Sahoo, Debashis |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8193764 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-81937642021-06-11 AI-guided discovery of the invariant host response to viral pandemics Sahoo, Debashis Katkar, Gajanan D. Khandelwal, Soni Behroozikhah, Mahdi Claire, Amanraj Castillo, Vanessa Tindle, Courtney Fuller, MacKenzie Taheri, Sahar Rogers, Thomas F. Beutler, Nathan Ramirez, Sydney I. Rawlings, Stephen A. Pretorius, Victor Smith, Davey M. Burton, Dennis R. Alexander, Laura E. Crotty Duran, Jason Crotty, Shane Dan, Jennifer M. Das, Soumita Ghosh, Pradipta EBioMedicine Research Paper 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. Elsevier 2021-06-11 /pmc/articles/PMC8193764/ /pubmed/34127431 http://dx.doi.org/10.1016/j.ebiom.2021.103390 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Paper Sahoo, Debashis Katkar, Gajanan D. Khandelwal, Soni Behroozikhah, Mahdi Claire, Amanraj Castillo, Vanessa Tindle, Courtney Fuller, MacKenzie Taheri, Sahar Rogers, Thomas F. Beutler, Nathan Ramirez, Sydney I. Rawlings, Stephen A. Pretorius, Victor Smith, Davey M. Burton, Dennis R. Alexander, Laura E. Crotty Duran, Jason Crotty, Shane Dan, Jennifer M. Das, Soumita Ghosh, Pradipta AI-guided discovery of the invariant host response to viral pandemics |
title | AI-guided discovery of the invariant host response to viral pandemics |
title_full | AI-guided discovery of the invariant host response to viral pandemics |
title_fullStr | AI-guided discovery of the invariant host response to viral pandemics |
title_full_unstemmed | AI-guided discovery of the invariant host response to viral pandemics |
title_short | AI-guided discovery of the invariant host response to viral pandemics |
title_sort | ai-guided discovery of the invariant host response to viral pandemics |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193764/ https://www.ncbi.nlm.nih.gov/pubmed/34127431 http://dx.doi.org/10.1016/j.ebiom.2021.103390 |
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