Endogenous retroviruses promote homeostatic and inflammatory responses to the microbiota

Cell. 2021 Jul 8;184(14):3794-3811.e19. doi: 10.1016/j.cell.2021.05.020. Epub 2021 Jun 23.

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.

Keywords: STING; Staphylococcus epidermidis; T cells; antiretroviral; endogenous retrovirus; high fat diet; keratinocytes; microbiota; skin immunity; tissue repair.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteria / metabolism
  • Chromosomes, Bacterial / genetics
  • Diet, High-Fat
  • Endogenous Retroviruses / physiology*
  • Homeostasis*
  • Inflammation / immunology
  • Inflammation / microbiology*
  • Inflammation / pathology*
  • Inflammation / virology
  • Interferon Type I / metabolism
  • Keratinocytes / metabolism
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Microbiota*
  • Nucleotidyltransferases / metabolism
  • Retroelements / genetics
  • Signal Transduction
  • Skin / immunology
  • Skin / microbiology
  • T-Lymphocytes / immunology
  • Transcription, Genetic

Substances

  • Interferon Type I
  • Membrane Proteins
  • Retroelements
  • Sting1 protein, mouse
  • Nucleotidyltransferases
  • cGAS protein, mouse