HCMV miR-US22 down-regulation of EGR-1 regulates CD34+ hematopoietic progenitor cell proliferation and viral reactivation
Crawford, Lindsey B
Hancock, Meaghan H
Nelson, Jay A
AffiliationUniv Arizona, Dept Immunobiol, BIO5 Inst
MetadataShow full item record
PublisherPUBLIC LIBRARY SCIENCE
CitationMikell I, Crawford LB, Hancock MH, Mitchell J, Buehler J, Goodrum F, et al. (2019) HCMV miR-US22 down-regulation of EGR-1 regulates CD34+ hematopoietic progenitor cell proliferation and viral reactivation. PLoS Pathog 15(11): e1007854. https://doi.org/10.1371/journal. ppat.1007854
RightsCopyright © 2019 Mikell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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AbstractReactivation of latent Human Cytomegalovirus (HCMV) in CD34(+) hematopoietic progenitor cells (HPCs) is closely linked to hematopoiesis. Viral latency requires maintenance of the progenitor cell quiescence, while reactivation initiates following mobilization of HPCs to the periphery and differentiation into CD14(+) macrophages. Early growth response gene 1 (EGR-1) is a transcription factor activated by Epidermal growth factor receptor (EGFR) signaling that is essential for the maintenance of CD34(+) HPC self-renewal in the bone marrow niche. Down-regulation of EGR-1 results in mobilization and differentiation of CD34(+) HPC from the bone marrow to the periphery. In the current study we demonstrate that the transcription factor EGR-1 is directly targeted for down-regulation by HCMV miR-US22 that results in decreased proliferation of CD34(+) HPCs and a decrease in total hematopoietic colony formation. We also show that an HCMV miR-US22 mutant fails to reactivate in CD34(+) HPCs, indicating that expression of EGR-1 inhibits viral reactivation. Since EGR-1 promotes CD34(+) HPC self-renewal in the bone marrow niche, HCMV miR-US22 down-regulation of EGR-1 is a necessary step to block HPC self-renewal and proliferation to induce a cellular differentiation pathway necessary to promote reactivation of virus.
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VersionFinal published version
SponsorsNational Institute of Allergy and Infectious DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [AI21640, P01AI127335, R01 AI079059]; American Cancer Society Post-Doctoral Research Fellowship [129842-PF-16-212-01-TBE]
- Human Cytomegalovirus US28 Ligand Binding Activity Is Required for Latency in CD34<sup>+</sup> Hematopoietic Progenitor Cells and Humanized NSG Mice.
- Authors: Crawford LB, Caposio P, Kreklywich C, Pham AH, Hancock MH, Jones TA, Smith PP, Yurochko AD, Nelson JA, Streblow DN
- Issue date: 2019 Aug 20
- Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34<sup>+</sup> Human Progenitor Cells.
- Authors: Kim JH, Collins-McMillen D, Buehler JC, Goodrum FD, Yurochko AD
- Issue date: 2017 Mar 1
- Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation.
- Authors: Crawford LB, Kim JH, Collins-McMillen D, Lee BJ, Landais I, Held C, Nelson JA, Yurochko AD, Caposio P
- Issue date: 2018 Apr 24
- Human Cytomegalovirus miRNAs Regulate TGF-β to Mediate Myelosuppression while Maintaining Viral Latency in CD34<sup>+</sup> Hematopoietic Progenitor Cells.
- Authors: Hancock MH, Crawford LB, Pham AH, Mitchell J, Struthers HM, Yurochko AD, Caposio P, Nelson JA
- Issue date: 2020 Jan 8
- Host signaling and EGR1 transcriptional control of human cytomegalovirus replication and latency.
- Authors: Buehler J, Carpenter E, Zeltzer S, Igarashi S, Rak M, Mikell I, Nelson JA, Goodrum F
- Issue date: 2019 Nov