Abstract
Myeloid cells are important sites of lytic and latent infection by human cytomegalovirus (CMV). We previously showed that only a small subset of myeloid cells differentiated from CD34+ hematopoietic stem cells is permissive to CMV replication, underscoring the heterogeneous nature of these populations. The exact identity of resistant and permissive cell types, and the cellular features characterizing the latter, however, could not be dissected using averaging transcriptional analysis tools such as microarrays and, hence, remained enigmatic. Here, we profile the transcriptomes of ∼7000 individual cells at day 1 post-infection using the 10× genomics platform. We show that viral transcripts are detectable in the majority of the cells, suggesting that virion entry is unlikely to be the main target of cellular restriction mechanisms. We further show that viral replication occurs in a small but specific sub-group of cells transcriptionally related to, and likely derived from, a cluster of cells expressing markers of Colony Forming Unit – Granulocyte, Erythrocyte, Monocyte, Megakaryocyte (CFU-GEMM) oligopotent progenitors. Compared to the remainder of the population, CFU-GEMM cells are enriched in transcripts with functions in mitochondrial energy production, cell proliferation, RNA processing and protein synthesis, and express similar or higher levels of interferon-related genes. While expression levels of the former are maintained in infected cells, the latter are strongly down-regulated. We thus propose that the preferential infection of CFU-GEMM cells may be due to the presence of a pre-established pro-viral environment, requiring minimal optimization efforts from viral effectors, rather than to the absence of specific restriction factors. Together, these findings identify a potentially new population of myeloid cells permissive to CMV replication, and provide a possible rationale for their preferential infection.
Highlights
Infection by human cytomegalovirus (CMV) is common and usually asymptomatic in healthy individuals, but can be the source of serious disease in hosts with naïve or compromised immune functions such as fetuses, newborns, AIDS patients, and solid organ or bone marrow transplant recipients (Pass, 2001; Griffiths et al, 2013)
We previously showed that culture of cord blood CD34+ hematopoietic stem cells (HSC) in the presence of cytokines known to instruct their differentiation into Langerhans cells (Strobl et al, 1997, 2018), gives rise to a population of cells capable of restricting infection progress at multiple steps of the viral replication cycle (Lauron et al, 2014; Coronel et al, 2015, 2016), providing an outstanding model to study the cellular determinants of CMV tropism
To identify cellular factors potentially involved in regulating myeloid cells permissiveness to CMV infection, we sought to analyze the transcriptome of a representative population of activated cells differentiated from CD34+ HSC in vitro
Summary
Infection by human cytomegalovirus (CMV) is common and usually asymptomatic in healthy individuals, but can be the source of serious disease in hosts with naïve or compromised immune functions such as fetuses, newborns, AIDS patients, and solid organ or bone marrow transplant recipients (Pass, 2001; Griffiths et al, 2013). We previously showed that culture of cord blood CD34+ HSC in the presence of cytokines known to instruct their differentiation into Langerhans cells (Strobl et al, 1997, 2018), gives rise to a population of cells capable of restricting infection progress at multiple steps of the viral replication cycle (Lauron et al, 2014; Coronel et al, 2015, 2016), providing an outstanding model to study the cellular determinants of CMV tropism. We took advantage of the most recent developments in single-cell RNA sequencing technologies to provide the first transcriptional profiling of a population of myeloid cells permissive to CMV lytic infection, and the first comparison of cellular gene expression changes occurring in cells expressing high levels of a large variety of viral genes versus cells containing lower levels (viral transcript low) or undetectable levels (viral transcript−) of viral transcripts, all co-existing in the same population
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