Cell Host Microbe. 2020 Jan 8;27(1):104-114.e4.

Meaghan H Hancock ^{1, #}, Lindsey B Crawford^{1, #}, Andrew H Pham¹, Jennifer Mitchell¹, Hillary M Struthers¹, Andrew D Yurochko², Patrizia Caposio¹, Jay A Nelson³

1. Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA.
2. Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
3. Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA. Electronic address: nelsonj@ohsu.edu.

#Contributed equally

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-β production. Infection of HPCs with an HCMVΔmiR-US5-2 mutant resulted in decreased TGF-β expression and restoration of myelopoiesis. In contrast, we show that infected HPCs are refractory to TGF-β 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-β while protecting infected HPCs from TGF-β-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.

Presented by Meaghan Hancock