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Single cell analysis reveals human cytomegalovirus drives latently infected cells towards an anergic-like monocyte state.

ABSTRACT: Human cytomegalovirus (HCMV) causes a lifelong infection through establishment of latency. Although reactivation from latency can cause life-threatening disease, our molecular understanding of HCMV latency is incomplete. Here we use single cell RNA-seq analysis to characterize latency in monocytes and hematopoietic stem and progenitor cells (HSPCs). In monocytes, we identify host cell surface markers that enable enrichment of latent cells harboring higher viral transcript levels, which can reactivate more efficiently, and are characterized by reduced intrinsic immune response that is important for viral gene expression. Significantly, in latent HSPCs, viral transcripts could be detected only in monocyte progenitors and were also associated with reduced immune-response. Overall, our work indicates that regardless of the developmental stage in which HCMV infects, HCMV drives hematopoietic cells towards a weaker immune-responsive monocyte state and that this anergic-like state is crucial for the virus ability to express its transcripts and to eventually reactivate.

SUBMITTER: Shnayder M

PROVIDER: S-EPMC7039680 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Single cell analysis reveals human cytomegalovirus drives latently infected cells towards an anergic-like monocyte state.

Shnayder Miri M Nachshon Aharon A Rozman Batsheva B Bernshtein Biana B Lavi Michael M Fein Noam N Poole Emma E Avdic Selmir S Blyth Emily E Gottlieb David D Abendroth Allison A Slobedman Barry B Sinclair John J Stern-Ginossar Noam N Schwartz Michal M

eLife 20200122

Human cytomegalovirus (HCMV) causes a lifelong infection through establishment of latency. Although reactivation from latency can cause life-threatening disease, our molecular understanding of HCMV latency is incomplete. Here we use single cell RNA-seq analysis to characterize latency in monocytes and hematopoietic stem and progenitor cells (HSPCs). In monocytes, we identify host cell surface markers that enable enrichment of latent cells harboring higher viral transcript levels, which can react ...[more]

PMID: 31967545

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Project description:Epstein-Barr virus (EBV) and Plasmodium falciparum have a well described role in the development of endemic Burkitt lymphoma (BL), yet the mechanisms involved remain unknown. A major hallmark of malarial disease is hemolysis and bystander eryptosis of red blood cells, which causes release of free heme in large quantities into peripheral blood. We hypothesized that heme released during malaria infection drives differentiation of latently infected EBV-positive B cells, resulting in viral reactivation and release of infectious virus. To test this hypothesis, we used the EBV-positive Mutu I B-cell line and treated with hemin (the oxidized form of heme) and evaluated evidence of EBV reactivation. Hemin treatment resulted in the expression of EBV immediate early, early and late lytic gene transcripts. In addition, expression of CD138, a marker of plasma cells was co-expressed with the late lytic protein gp350 on hemin treated Mutu I cells. Finally, DNase-resistant EBV DNA indicative of virion production was detected in supernatant. To assess the transcriptional changes induced by hemin treatment, RNA sequencing was performed on mock- and hemin-treated Mutu I cells, and a shift from mature B cell transcripts to plasma cell transcripts was identified. To identify the mechanism of hemin-induced B cell differentiation, we measured levels of the plasma cell transcriptional repressor, BACH2, that contains specific heme binding sites. Hemin treatment caused significant degradation of BACH2 by 24 hours post-treatment in four BL cell lines (two EBV positive, two EBV negative). Knockdown of BACH2 in Mutu I cells using siRNAs significantly increased CD138+gp350+ cells to levels similar to treatment with hemin. This suggested that hemin induced BACH2 degradation was responsible for plasma cell differentiation and viral reactivation. Together, these data support a model where EBV reactivation can occur during malaria infection via heme modulation, providing a mechanistic link between malaria and EBV.

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Single cell analysis reveals human cytomegalovirus drives latently infected cells towards an anergic-like monocyte state.

Publications

Single cell analysis reveals human cytomegalovirus drives latently infected cells towards an anergic-like monocyte state.

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