Single-cell and spatiotemporal transcriptomic profiling of brain immune infiltration following Venezuelan equine encephalitis virus infection

Front Immunol. 2024 Dec 19:15:1497839. doi: 10.3389/fimmu.2024.1497839. eCollection 2024.

Abstract

Neurotropic alphaviruses such as Venezuelan equine encephalitis virus (VEEV) are critical human pathogens that continually expand to naïve populations and for which there are no licensed vaccines or therapeutics. VEEV is highly infectious via the aerosol route and is a recognized weaponizable biothreat that causes neurological disease in humans. The neuropathology of VEEV has been attributed to an inflammatory immune response in the brain yet the underlying mechanisms and specific immune cell populations involved are not fully elucidated. This study uses single-cell RNA sequencing to produce a comprehensive transcriptional profile of immune cells isolated from the brain over a time course of infection in a mouse model of VEEV. Analyses reveal differentially activated subpopulations of microglia, including a distinct type I interferon-expressing subpopulation. This is followed by the sequential infiltration of myeloid cells and cytotoxic lymphocytes, also comprising subpopulations with unique transcriptional signatures. We identify a subpopulation of myeloid cells that form a distinct localization pattern in the hippocampal region whereas lymphocytes are widely distributed, indicating differential modes of recruitment, including that to specific regions of the brain. Altogether, this study provides a high-resolution analysis of the immune response to VEEV in the brain and highlights potential avenues of investigation for therapeutics that target neuroinflammation in the brain.

Keywords: Venezuelan equine encephalitis virus (VEEV); encephalitis; neuroimmunology; single cell RNA sequencing; spatial trancriptomics.

MeSH terms

  • Animals
  • Brain* / immunology
  • Brain* / pathology
  • Brain* / virology
  • Disease Models, Animal
  • Encephalitis Virus, Venezuelan Equine* / genetics
  • Encephalitis Virus, Venezuelan Equine* / immunology
  • Encephalomyelitis, Venezuelan Equine* / immunology
  • Encephalomyelitis, Venezuelan Equine* / virology
  • Female
  • Gene Expression Profiling*
  • Mice
  • Mice, Inbred C57BL
  • Microglia / immunology
  • Microglia / virology
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Myeloid Cells / virology
  • Single-Cell Analysis*
  • Transcriptome*

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Funding for this research was provided by internal Lawrence Livermore National Laboratory Directed Research and Development funds (22-ERD-038 to D.R.W.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Security, LLC, Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.