Xu Xiaoke, Niu Meng, Lamberty Benjamin G, Emanuel Katy, Apostol Moses Jedd Facun, Fox Howard S
Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Res Sq. 2024 Sep 18:rs.3.rs-4916594. doi: 10.21203/rs.3.rs-4916594/v1.
The primary immune constituents in the brain, microglia and macrophages, are the target for HIV in people and simian immunodeficiency virus (SIV) in nonhuman primates. This infection can lead to neurological dysfunction, known as HIV-associated neurocognitive disorder (HAND). Given the gaps in our knowledge on how these cells respond in vivo to CNS infection, we performed single-cell multiomic sequencing, including gene expression and ATAC-seq, on myeloid cells from the brains of rhesus macaques with SIV-induced encephalitis (SIVE) as well as uninfected controls. We found that the myeloid cell populations were significantly changed by SIVE. In SIVE microglia-like cells express high levels of chemoattractants capable of recruiting highly activated CAM-like cells to the site of infection/inflammation. A unique population of microglia-like cells was found in which the chromatin accessibility of genes diverged from their RNA expression. Additionally, we observed a dramatic shift of upstream gene regulators and their targets in brain myeloid cells during SIVE. In summary, this study further uncovers the transcriptome, gene regulatory events and potential roles of different brain myeloid phenotypes in SIVE.
大脑中的主要免疫成分——小胶质细胞和巨噬细胞，是人类感染HIV以及非人灵长类动物感染猴免疫缺陷病毒（SIV）的靶标。这种感染会导致神经功能障碍，即HIV相关神经认知障碍（HAND）。鉴于我们对这些细胞在体内如何应对中枢神经系统感染的认识存在差距，我们对患有SIV诱导性脑炎（SIVE）的恒河猴以及未感染的对照猴大脑中的髓样细胞进行了单细胞多组学测序，包括基因表达和ATAC测序。我们发现，SIVE显著改变了髓样细胞群体。在SIVE中，小胶质细胞样细胞表达高水平的趋化因子，能够将高度活化的CAM样细胞招募到感染/炎症部位。我们发现了一种独特的小胶质细胞样细胞群体，其中基因的染色质可及性与其RNA表达不同。此外，我们观察到在SIVE期间，大脑髓样细胞中的上游基因调节因子及其靶标发生了显著变化。总之，这项研究进一步揭示了SIVE中不同大脑髓样细胞表型的转录组、基因调控事件和潜在作用。
