Host cytosolic RNA sensing pathway promotes T Lymphocyte-mediated mycobacterial killing in macrophages

PLoS Pathog. 2020 May 28;16(5):e1008569. doi: 10.1371/journal.ppat.1008569. eCollection 2020 May.

Abstract

Mycobacterial infection leads to activation of the RIG-I/MAVS/TBK1 RNA sensing pathway in macrophages but the consequences of this activation remains poorly defined. In this study, we determined that activation of this RNA sensing pathway stimulates ICAM-1 expression in M.avium-infected macrophage through the inhibition of the E3 ubiquitin ligase CRL4COP1/DET1. CRL4 when active targets the transcription factor ETV5 for degradation by the ubiquitin-proteasome system. In the absence of the ETV5 transcription factor, ICAM-1 expression is significantly decreased. The M.avium-induced ICAM-1 production is required for the formation of immune synapse between infected macrophages and antigen-specific CD4+ T lymphocytes, and is essential for CD4+ T lymphocyte-mediated mycobacterial killing in vitro and in mice. This study demonstrates a previously undefined mechanism by which a host cytosolic RNA sensing pathway contributes to the interplay between mycobacteria infected macrophages and antigen-specific T lymphocytes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology*
  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / microbiology
  • CD4-Positive T-Lymphocytes / pathology
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / immunology*
  • Macrophages* / immunology
  • Macrophages* / microbiology
  • Macrophages* / pathology
  • Mice
  • Mice, Knockout
  • Mycobacterium avium / immunology*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / immunology*
  • Tuberculosis / genetics
  • Tuberculosis / immunology*
  • Tuberculosis / pathology

Substances

  • Adaptor Proteins, Signal Transducing
  • IPS-1 protein, mouse
  • Tbk1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Ddx58 protein, mouse
  • DEAD Box Protein 58