Xu Xiaoke, Niu Meng, Lamberty Benjamin G, Emanuel Katy, Trease Andrew J, Tabassum Mehnaz, Lifson Jeffrey D, Fox Howard S
Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
bioRxiv. 2024 Apr 4:2024.04.04.588047. doi: 10.1101/2024.04.04.588047.
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, as well as for the simian immunodeficiency virus (SIV) in nonhuman primates. This infection can lead to neurological effects and the establishment of a viral reservoir. Given the gaps in our understanding of how these cells respond 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 population of homeostatic and preactivated microglia 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: CD14CD16 and CD14CD16 CAMs. Interestingly, during acute SIV infection, the dominant CAM population changed to one with an inflammatory phenotype. Notably, 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.
人类免疫缺陷病毒（HIV）因其对免疫系统的深远影响而广为人知。尽管HIV主要影响外周CD4 T细胞，但其对中枢神经系统（CNS）的影响也不容忽视。在大脑中，小胶质细胞和中枢神经系统相关巨噬细胞（CAMs）是HIV以及非人灵长类动物中的猿猴免疫缺陷病毒（SIV）的主要靶细胞。这种感染可导致神经学效应并建立病毒库。鉴于我们对这些细胞如何应对急性中枢神经系统感染的认识存在差距，我们在三只恒河猴感染SIV 12天后，对其大脑中的髓样细胞以及三只未感染的对照猴进行了单细胞RNA测序（scRNA-seq）。我们的分析揭示了六个不同的小胶质细胞簇，包括稳态小胶质细胞、预激活小胶质细胞和表达高水平炎症和疾病相关分子的激活小胶质细胞。响应急性SIV感染，稳态和预激活小胶质细胞群体减少，而激活和疾病相关小胶质细胞增加。所有小胶质细胞簇均表现出MHC I类分子和干扰素相关基因的上调，表明它们在急性期抵御SIV中起关键作用。所有小胶质细胞簇还上调了与细胞衰老相关的基因。此外，我们鉴定出两种不同的CAM群体：CD14CD16和CD14CD16 CAMs。有趣的是，在急性SIV感染期间，占主导地位的CAM群体转变为具有炎症表型的群体。值得注意的是，一个小胶质细胞簇和一个巨噬细胞簇内特定上调的基因与神经退行性途径相关，提示与神经认知障碍的潜在联系。这项研究揭示了病毒感染、先天免疫反应和中枢神经系统之间的复杂相互作用，为未来的研究提供了有价值的见解。
