Single-cell RNA sequencing reveals microglia-like cells in cerebrospinal fluid during virologically suppressed HIV

Abstract

Central nervous system (CNS) immune activation is an important driver of neuronal injury during several neurodegenerative and neuroinflammatory diseases. During HIV infection, CNS immune activation is associated with high rates of neurocognitive impairment, even during sustained long-term suppressive antiretroviral therapy (ART). However, the cellular subsets that drive immune activation and neuronal damage in the CNS during HIV infection and other neurological conditions remain unknown, in part because CNS cells are difficult to access in living humans. Using single-cell RNA sequencing (scRNA-seq) on cerebrospinal fluid (CSF) and blood from adults with and without HIV, we identified a rare (<5% of cells) subset of myeloid cells that are found only in CSF and that present a gene expression signature that overlaps significantly with neurodegenerative disease-associated microglia. This highlights the power of scRNA-seq of CSF to identify rare CNS immune cell subsets that may perpetuate neuronal injury during HIV infection and other conditions.

Comprehensive mapping of the human cytokine gene regulatory network

“…The HIV data was downloaded from the GEO repository GSE117397 (Farhadian et al, 2018). The Crohn's disease data was downloaded from the GEO repository GSE134809 (Martin et al, 2019).…”

“…Canonical markers for immune cell types were used to find different immune cell types. For the HIV dataset, we used the following markers described in the original article (Farhadian et al, 2018) T cells: CD2, CD3D, CD3G, CD4, CD5, CD7, CD8A, IL2RA, CD27, CD28, PTPRC For the Crohn's disease dataset, we used the following markers described in the original article (Martin et al, 2019) to identify intestinal epithelial cells, dendritic cells,…”

“…To find supporting evidence for our predicted TF-cytokine-disease associations, we integrated scRNA-seq expression data to reveal correlated TF-cytokine pairs at the single-cell level that may contribute to pathogenesis of the disease. As a proof-of-concept, we focused on HIV given its importance in human health and the availability of scRNAseq data from healthy and infected individuals (Farhadian et al, 2018). The HIVassociated PDI network contains 171 PDIs between 15 cytokines associated with HIV (reported in DisGeNET, GWAS, or MGI) and 102 TF interactors ( Figure 4C and Table S5).…”

CD11c+CD88+CD317+myeloid cells are critical mediators of persistent CNS autoimmunity

“…Interestingly, our human CSF transcriptome analyses placed CD11c + CD88 + CD317 + cells within a population of myeloid cells that was previously defined as CSF microglia 11,[32][33][34] . We found that activated, but not naive murine microglia concomitantly express CD11c, CD88, and CD317.…”

“…Characteristic gene expression markers were employed to assign cellular identities to each cluster of myeloid populations in blood (Figure 5A) and CSF (Figure 5B). Recent studies identified myeloid cells within the CSF using scRNA-seq that resembled microglia 11,[32][33][34] , which are characterized by the expression of signature genes including CX3CR1, CSF1R, SLC2A5, MARCKS, and P2RY13 [35][36][37] .…”