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Multiomic spatial landscape of innate immune cells at human central nervous system borders

ABSTRACT: The innate immune system of the human central nervous system (CNS) is highly diverse already during homeostasis. Several immune cell populations such as macrophages that are frequent in the brain parenchyma (microglia) and less numerous at the brain interfaces as CNS-associated macrophages (CAMs) constitute the local immune compartment. Due to their scantiness and particular location, little is known about the presence of temporally and spatially restricted CAM subclasses during development, health and perturbation. Here, we combined several high-dimensional technologies, such as single-cell RNA-sequencing, time-of-flight mass cytometry and single-cell spatial transcriptomics with fate mapping and advanced immunohistochemistry to comprehensively characterize the immune system at human CNS interfaces. We also provide a comprehensive analysis of resident and engrafted myeloid cells in the brains of individuals with peripheral blood stem cell transplantation, revealing remarkable dynamics. These approaches enabled us to identify a previously unappreciated spectrum of transcriptional classes of human CAMs and to decipher their turnover with circulating cells. CAM signatures profoundly changed during ontogeny and pathology. Our results highlight myeloid diversity at the interfaces of the human CNS with the periphery and provide new insights into the human brain’s immune system.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245311 | GEO | 2023/12/20

REPOSITORIES: GEO

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Project description:Human immunodeficiency virus (HIV) is widely recognized for its striking impact on the immune system, and it also significantly impacts the central nervous system (CNS). The primary immune constituents in the brain, microglia and macrophages, are the target for HIV in people and the simian immunodeficiency virus (SIV) in nonhuman primates. This infection can lead to neurological dysfunction, known as HIV-associated neurocognitive disorder (HAND) and pathological entities such as HIV-induced encephalitis (HIVE). 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 two rhesus macaques with SIV-induced encephalitis (SIVE) as well as two uninfected controls. We used both RNA expression and chromatin accessibility to identify cell clusters. We found that the myeloid cell populations were significantly changed by SIVE, which differed greatly from those found in the uninfected brains. We categorized myeloid cells in the SIVE brains into two primary phenotypes: microglia-like and CAM-like, which were different from each other regarding trancriptomic profile and chromatin accessibility. We found that these microglia-like cells express high levels of chemoattractants for capable of recruiting highly the activated CAM-like cells to the site of infection/inflammation. Additionally, we observed a dramatic shift of upstream gene regulators and their targets in brain myeloid cells during SIVE. The transcription factors (TFs) highly enriched in SIVE-specific cell clusters were related to IRF/STAT and NF-κB mediated interferon and other proinflammatory cytokines production. Interestingly, some of these TF binding sites were also enriched in the open chromatin identified in the SIV DNA provirus in infected myeloid cells, indicating the immune activation in the host cells might also promote HIV/SIV gene expression and regulation . In summary, this study further uncover the trancriptome, gene regulaory events and potenital roles of differenet brain myeloid phenotypes in SIVE.

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Multiomic spatial landscape of innate immune cells at human central nervous system borders

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