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Published on: September 19, 2010
Microglia and macrophages alterations in the CNS during acute SIV infection: A single-cell analysis in rhesus
Xiaoke Xu1, Meng Niu1, Benjamin G Lamberty1
1Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
Abstract:
Human Immunodeficiency Virus (HIV) is widely acknowledged for its profound impact on the immune system. Although HIV primarily affects peripheral CD4 T cells, its influence on the central nervous system (CNS) cannot be overlooked. Within the brain, microglia and CNS-associated macrophages (CAMs) serve as the primary targets for HIV and the simian immunodeficiency virus (SIV) in nonhuman primates. This infection can lead to neurological effects and establish a viral reservoir. Given the gaps in our understanding of how these cells respond in vivo to acute CNS infection, we conducted single-cell RNA sequencing (scRNA-seq) on myeloid cells from the brains of three rhesus macaques 12 days after SIV infection, along with three uninfected controls. Our analysis revealed six distinct microglial clusters including homeostatic microglia, preactivated microglia, and activated microglia expressing high levels of inflammatory and disease-related molecules. In response to acute SIV infection, the homeostatic and preactivated microglia population decreased, while the activated and disease-related microglia increased. All microglial clusters exhibited upregulation of MHC class I molecules and interferon-related genes, indicating their crucial roles in defending against SIV during the acute phase. All microglia clusters also upregulated genes linked to cellular senescence. Additionally, we identified two distinct CAM populations: CD14lowCD16hi and CD14hiCD16low CAMs. Interestingly, during acute SIV infection, the dominant CAM population changed to one with an inflammatory phenotype. Specific upregulated genes within one microglia and one macrophage cluster were associated with neurodegenerative pathways, suggesting potential links to neurocognitive disorders. This research sheds light on the intricate interactions between viral infection, innate immune responses, and the CNS, providing valuable insights for future investigations.
Insights
Acute simian immunodeficiency virus (SIV) infection alters brain myeloid cells, increasing inflammatory microglia and macrophages. These changes, including senescence and neurodegeneration pathways, highlight the central nervous system
Area of Science:
- Neuroimmunology
- Virology
- Immunology
Background:
- Human Immunodeficiency Virus (HIV) significantly impacts the immune system, particularly CD4 T cells.
- HIV and simian immunodeficiency virus (SIV) infect microglia and CNS-associated macrophages (CAMs) in the brain, leading to neurological effects and viral reservoirs.
- Understanding in vivo myeloid cell responses during acute central nervous system (CNS) infection remains limited.
Purpose of the Study:
- To investigate the in vivo response of myeloid cells in the CNS to acute SIV infection.
- To characterize changes in microglial and CAM populations and their gene expression profiles during early SIV infection.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was performed on myeloid cells from the brains of SIV-infected and uninfected rhesus macaques.
- Analysis focused on identifying distinct cell clusters and differential gene expression patterns between infected and control groups.
Main Results:
- Six microglial clusters were identified, with a decrease in homeostatic/preactivated populations and an increase in activated, inflammatory, and disease-related microglia post-SIV infection.
- All microglial clusters showed upregulation of MHC class I and interferon-related genes, alongside genes linked to cellular senescence.
- Two distinct CAM populations were observed, with a shift towards an inflammatory phenotype in infected macaques; specific clusters showed upregulation of neurodegenerative pathway genes.
Conclusions:
- Acute SIV infection profoundly reshapes the brain's myeloid cell landscape, promoting inflammatory and senescent phenotypes in microglia and CAMs.
- Upregulation of specific genes suggests potential links between SIV-induced myeloid cell responses and neurocognitive disorders.
- The study provides critical insights into the early innate immune response within the CNS during viral infection.
