Endogenous retroviruses promote homeostatic and inflammatory responses to the microbiota

Djalma S. Lima-Junior, Siddharth R. Krishnamurthy, Nicolas Bouladoux, Nicholas Collins, Seong Ji Han, Erin Y. Chen, Michael G. Constantinides, Verena M. Link, Ai Ing Lim, Michel Enamorado, Christophe Cataisson, Louis Gil, Indira Rao, Taylor K. Farley, Galina Koroleva, Jan Attig, Stuart H. Yuspa, Michael A. Fischbach, George Kassiotis, Yasmine Belkaid

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

The microbiota plays a fundamental role in regulating host immunity. However, the processes involved in the initiation and regulation of immunity to the microbiota remain largely unknown. Here, we show that the skin microbiota promotes the discrete expression of defined endogenous retroviruses (ERVs). Keratinocyte-intrinsic responses to ERVs depended on cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes protein (STING) signaling and promoted the induction of commensal-specific T cells. Inhibition of ERV reverse transcription significantly impacted these responses, resulting in impaired immunity to the microbiota and its associated tissue repair function. Conversely, a lipid-enriched diet primed the skin for heightened ERV- expression in response to commensal colonization, leading to increased immune responses and tissue inflammation. Together, our results support the idea that the host may have co-opted its endogenous virome as a means to communicate with the exogenous microbiota, resulting in a multi-kingdom dialog that controls both tissue homeostasis and inflammation.

Original languageEnglish (US)
Pages (from-to)3794-3811.e19
JournalCell
Volume184
Issue number14
DOIs
StatePublished - Jul 8 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology

Keywords

  • STING
  • Staphylococcus epidermidis
  • T cells
  • antiretroviral
  • endogenous retrovirus
  • high fat diet
  • keratinocytes
  • microbiota
  • skin immunity
  • tissue repair

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