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TREM2 is down-regulated by HSV1 in microglia and involved in antiviral defense in the brain

Stefanie Fruhwürth1,2, Line S Reinert3, Carl Öberg2

  • 1Department of Rheumatology and Inflammatory Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

Science Advances
|August 18, 2023
PubMed

Insights

TREM2 (triggering receptor expressed on myeloid cells 2) is crucial for microglia's antiviral defense against herpes simplex virus type 1 (HSV1) in the brain. Its deficiency impairs viral clearance and increases infection susceptibility, potentially linking to Alzheimer's disease.

Area of Science:

  • Neuroimmunology
  • Virology
  • Cellular Biology

Background:

  • Microglia are key players in brain antiviral immunity.
  • Herpes simplex virus type 1 (HSV1) poses a significant threat to neurological health.
  • The role of TREM2 (triggering receptor expressed on myeloid cells 2) in microglial antiviral responses is not fully understood.

Purpose of the Study:

  • To investigate the function of TREM2 in microglial antiviral defense against HSV1.
  • To determine TREM2's role in the cGAS-STING pathway and phagocytosis during HSV1 infection.
  • To explore the implications of TREM2 alterations in HSV1-associated neurological diseases, including Alzheimer's disease.

Main Methods:

  • Utilized human induced pluripotent stem cell (hiPSC)-derived microglia.
  • Analyzed gene expression changes in microglia upon HSV1 infection.
  • Assessed the impact of TREM2 depletion on HSV1 infection in vitro (microglia-neuron cocultures) and in vivo (mouse brain).
  • Investigated TREM2's effect on the cGAS-STING signaling pathway.

Main Results:

  • HSV1 infection down-regulates TREM2 pathway gene expression in microglia.
  • TREM2 is essential for virus-induced interferon-beta (IFNB) production via the cGAS-STING pathway.
  • TREM2 mediates phagocytosis of HSV1-infected neurons.
  • TREM2 depletion enhances susceptibility to HSV1 infection in human microglia-neuron cocultures and the mouse brain.
  • TREM2 augments STING signaling and downstream activation of TBK1 and IRF3.

Conclusions:

  • TREM2 plays a critical role in the microglial antiviral immune response against HSV1.
  • TREM2's function in viral clearance and immune signaling is vital for protecting the brain from HSV1.
  • Dysregulation of TREM2 by genetic mutations or HSV1 infection may contribute to neurological pathologies like Alzheimer's disease.

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