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JEV Infection Induces M-MDSC Differentiation Into CD3+ Macrophages in the Brain

Nan Zhang1,2,3,4, Xiaochen Gao1,2,3,4, Weijia Zhang1,2,3,4

  • 1State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.

Frontiers in Immunology
|May 9, 2022
PubMed

Insights

Japanese encephalitis virus (JEV) infection induces monocytic myeloid-derived suppressor cells (M-MDSCs) that suppress T cell proliferation. These M-MDSCs, originating from bone marrow, migrate to the CNS and differentiate, exacerbating JEV pathogenicity.

Area of Science:

  • Immunology
  • Virology
  • Neuroscience

Background:

  • Japanese encephalitis virus (JEV) is a significant flavivirus causing zoonotic disease with considerable socioeconomic impact.
  • The interplay between JEV-induced immunosuppression and inflammatory responses remains incompletely understood.
  • Investigating these mechanisms is crucial for understanding JEV pathogenesis and developing effective treatments.

Purpose of the Study:

  • To elucidate the role of myeloid-derived suppressor cells (MDSCs) in JEV infection.
  • To identify the cellular origins and migration pathways of JEV-induced MDSCs.
  • To explore the molecular mechanisms regulating MDSC induction and differentiation during JEV infection.

Main Methods:

  • Isolation and characterization of infiltrating cells in JEV-infected mouse brains.
  • Co-culture assays with T cells to assess MDSC function.
  • Splenectomy models to trace MDSC origins.
  • Transcriptome analysis and studies using IRF7-deficient mice.
  • Investigation of chemokine and cytokine involvement in MDSC migration and differentiation.

Main Results:

  • Monocytic MDSCs (M-MDSCs) were identified as key infiltrating cells in the JEV-infected brain, differentiating into CD3+ macrophages.
  • Both splenic and brain-infiltrating M-MDSCs from JEV-infected mice inhibited T cell proliferation via ARG1 and iNOS.
  • JEV-induced M-MDSCs originate from bone marrow and migrate to the spleen and central nervous system (CNS).
  • The ZBP1-IRF7 signaling pathway, activated by JEV RNA, is critical for M-MDSC induction.
  • M-MDSC CNS infiltration is mediated by astrocyte-derived CCL2, and their differentiation into macrophages involves M-CSF, IL-6, and IFN-γ.

Conclusions:

  • JEV infection induces M-MDSCs that suppress T cell responses and differentiate into macrophages within the CNS.
  • The ZBP1-IRF7 pathway and astrocyte-derived chemokines are essential for M-MDSC regulation during JEV infection.
  • Understanding JEV-induced M-MDSC dynamics offers potential therapeutic targets for Japanese encephalitis.
Keywords:
CCL2CD3 macrophagesIRF7Japanese encephalitis virusM-MDSCs

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