Distinct gene programs underpinning disease tolerance and resistance in influenza virus infection

Ofir Cohn, Gal Yankovitz, Naama Peshes-Yaloz, Yael Steuerman, Amit Frishberg, Rachel Brandes, Michal Mandelboim, Jennifer R. Hamilton, Tzachi Hagai, Ido Amit, Mihai G. Netea, Nir Hacohen, Fuad A. Iraqi, Eran Bacharach, Irit Gat-Viks

Research output: Contribution to journalArticlepeer-review

Abstract

When challenged with an invading pathogen, the host-defense response is engaged to eliminate the pathogen (resistance) and to maintain health in the presence of the pathogen (disease tolerance). However, the identification of distinct molecular programs underpinning disease tolerance and resistance remained obscure. We exploited transcriptional and physiological monitoring across 33 mouse strains, during in vivo influenza virus infection, to identify two host-defense gene programs—one is associated with hallmarks of disease tolerance and the other with hallmarks of resistance. Both programs constitute generic responses in multiple mouse and human cell types. Our study describes the organizational principles of these programs and validates Arhgdia as a regulator of disease-tolerance states in epithelial cells. We further reveal that the baseline disease-tolerance state in peritoneal macrophages is associated with the pathophysiological response to injury and infection. Our framework provides a paradigm for the understanding of disease tolerance and resistance at the molecular level.

Original languageEnglish
Pages (from-to)1002-1015.e9
JournalCell Systems
Volume13
Issue number12
DOIs
StatePublished - 21 Dec 2022

Keywords

  • disease tolerance
  • immune defense strategies
  • influenza A virus
  • molecular signatures
  • resistance

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

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