Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.21.305698v1?rss=1 Authors: Sahoo, D., Katkar, G. D., Khandelwal, S., Behroozikhah, M., Claire, A., Castillo, V., Tindle, C., Fuller, M., Taheri, S., Rogers, T. F., Beutler, N., Ramirez, S., Rawlings, S. A., Pretorius, V., Smith, D., Burton, D. R., Alexander, L. C., Duran, J. M., Crotty, S., Dan, J. M., Das, S., Ghosh, P. Abstract: 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. 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. Surprisingly, this 166-gene signature was conserved in all viral pandemics, including COVID-19, and a subset of 20-genes classified disease severity, inspiring the nomenclatures ViPand severe-ViPsignatures, respectively. The ViPsignatures pinpointed a paradoxical phenomenon wherein lung epithelial and myeloid cells mount an IL15 cytokine storm, and epithelial and NK cell senescence and apoptosis determines severity/fatality. Precise therapeutic goals were formulated and subsequently validated in high-dose SARS-CoV-2-challenged hamsters using neutralizing antibodies that abrogate SARS-CoV-2/ACE2 engagement. IL15/IL15RA were elevated in the lungs of patients with fatal disease, and plasma levels of the cytokine tracked with disease severity. Thus, 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. Copy rights belong to original authors. Visit the link for more info