Dataset Information

Human Cytomegalovirus miRNAs Regulate TGF-? to Mediate Myelosuppression while Maintaining Viral Latency in CD34⁺ Hematopoietic Progenitor Cells.

ABSTRACT: Infection with human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality following hematopoietic stem cell transplant (HSCT) because of various hematologic problems, including myelosuppression. Here, we demonstrate that latently expressed HCMV miR-US5-2 downregulates the transcriptional repressor NGFI-A binding protein (NAB1) to induce myelosuppression of uninfected CD34⁺ hematopoietic progenitor cells (HPCs) through an increase in TGF-? production. Infection of HPCs with an HCMV?miR-US5-2 mutant resulted in decreased TGF-? expression and restoration of myelopoiesis. In contrast, we show that infected HPCs are refractory to TGF-? signaling as another HCMV miRNA, miR-UL22A, downregulates SMAD3, which is required for maintenance of latency. Our data suggest that latently expressed viral miRNAs manipulate stem cell homeostasis by inducing secretion of TGF-? while protecting infected HPCs from TGF-?-mediated effects on viral latency and reactivation. These observations provide a mechanism through which HCMV induces global myelosuppression following HSCT while maintaining lifelong infection in myeloid lineage cells.

SUBMITTER: Hancock MH

PROVIDER: S-EPMC6952548 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Human Cytomegalovirus miRNAs Regulate TGF-β to Mediate Myelosuppression while Maintaining Viral Latency in CD34<sup>+</sup> Hematopoietic Progenitor Cells.

Hancock Meaghan H MH Crawford Lindsey B LB Pham Andrew H AH Mitchell Jennifer J Struthers Hillary M HM Yurochko Andrew D AD Caposio Patrizia P Nelson Jay A JA

Cell host & microbe 20191219 1

Infection with human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality following hematopoietic stem cell transplant (HSCT) because of various hematologic problems, including myelosuppression. Here, we demonstrate that latently expressed HCMV miR-US5-2 downregulates the transcriptional repressor NGFI-A binding protein (NAB1) to induce myelosuppression of uninfected CD34<sup>+</sup> hematopoietic progenitor cells (HPCs) through an increase in TGF-β production. Infection ...[more]

PMID: 31866424

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Project description:The establishment of human cytomegalovirus (HCMV) latency and persistence relies on the successful infection of hematopoietic cells, which serve as sites of viral persistence and contribute to viral spread. Here, using blocking antibodies and pharmacological inhibitors, we document that HCMV activation of the epidermal growth factor receptor (EGFR) and downstream phosphatidylinositol 3-kinase (PI3K) mediates viral entry into CD34+ human progenitor cells (HPCs), resulting in distinct cellular trafficking and nuclear translocation of the virus compared to that in other immune cells, such as we have documented in monocytes. We argue that the EGFR allows HCMV to regulate the cellular functions of these replication-restricted cells via its signaling activity following viral binding. In addition to regulating HCMV entry/trafficking, EGFR signaling may also shape the early steps required for the successful establishment of viral latency in CD34+ cells, as pharmacological inhibition of EGFR increases the transcription of lytic IE1/IE2 mRNA while curbing the expression of latency-associated UL138 mRNA. EGFR signaling following infection of CD34+ HPCs may also contribute to changes in hematopoietic potential, as treatment with the EGFR kinase (EGFRK) inhibitor AG1478 alters the expression of the cellular hematopoietic cytokine interleukin 12 (IL-12) in HCMV-infected cells but not in mock-infected cells. These findings, along with our previous work with monocytes, suggest that EGFR likely serves as an important determinant of HCMV tropism for select subsets of hematopoietic cells. Moreover, our new data suggest that EGFR is a key receptor for efficient viral entry and that the ensuing signaling regulates important early events required for successful infection of CD34+ HPCs by HCMV.IMPORTANCE HCMV establishes lifelong persistence within the majority of the human population without causing overt pathogenesis in healthy individuals. Despite this, reactivation of HCMV from its latent reservoir in the bone marrow causes significant morbidity and mortality in immunologically compromised individuals, such as bone marrow and solid organ transplant patients. Lifelong persistent infection has also been linked with the development of various cardiovascular diseases in otherwise healthy individuals. Current HCMV therapeutics target lytic replication, but not the latent viral reservoir; thus, an understanding of the molecular basis for viral latency and persistence is paramount to controlling or eliminating HCMV infection. Here, we show that the viral signalosome activated by HCMV binding to its entry receptor, EGFR, in CD34+ HPCs initiates early events necessary for successful latent infection of this cell type. EGFR and associated signaling players may therefore represent promising targets for mitigating HCMV persistence.

Dataset Information

Human Cytomegalovirus miRNAs Regulate TGF-? to Mediate Myelosuppression while Maintaining Viral Latency in CD34⁺ Hematopoietic Progenitor Cells.

Publications

Human Cytomegalovirus miRNAs Regulate TGF-β to Mediate Myelosuppression while Maintaining Viral Latency in CD34<sup>+</sup> Hematopoietic Progenitor Cells.

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Dataset Information

Human Cytomegalovirus miRNAs Regulate TGF-? to Mediate Myelosuppression while Maintaining Viral Latency in CD34+ Hematopoietic Progenitor Cells.

Publications

Human Cytomegalovirus miRNAs Regulate TGF-β to Mediate Myelosuppression while Maintaining Viral Latency in CD34<sup>+</sup> Hematopoietic Progenitor Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Human Cytomegalovirus miRNAs Regulate TGF-? to Mediate Myelosuppression while Maintaining Viral Latency in CD34⁺ Hematopoietic Progenitor Cells.