HCMV miR-US22 down-regulation of EGR-1 regulates CD34+ hematopoietic progenitor cell proliferation and viral reactivation

English version

Autoři: Iliyana Mikell ^aff001; Lindsey B. Crawford ^aff001; Meaghan H. Hancock ^aff001; Jennifer Mitchell ^aff001; Jason Buehler ^aff002; Felicia Goodrum ^aff002; Jay A. Nelson ^aff001
Působiště autorů: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, United States of America ^aff001; Department of Immunobiology, BIO5 Institute, University of Arizona, Tucson, Arizona, United States of America ^aff002
Vyšlo v časopise: HCMV miR-US22 down-regulation of EGR-1 regulates CD34+ hematopoietic progenitor cell proliferation and viral reactivation. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1007854
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1007854

Souhrn

Reactivation 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.

Klíčová slova:

Bone marrow cells – Cell differentiation – Human cytomegalovirus – MicroRNAs – Stem cells – Transcription factors – Viral persistence and latency – Viral replication

Zdroje

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