US researchers have reported the mechanism by which human cytomegalovirus (HCMV) causes complications following haematopoietic stem cell transplant. Their work could lead to new treatments to improve the success rates of stem cell transplantation.
Dr Jay Nelson at Oregon University, USA, and colleagues examined HCMV infection of human haematopoietic stem cells. They found that HCMV reduces the activity of a transcription factor called NAB1, which then induces myelosuppression of uninfected CD34+ hematopoietic progenitor cells by increasing transforming growth factor beta (TGF-β) production.
The team then further investigated the mechanism by which HCMV infection causes these effects. They infected of haematopoietic progenitor cells with a mutated version of HCMV, which had a small piece of genetic material called miR-US5-2 removed. This led to decreased TGF-β expression, and restored healthy production of bone marrow and blood cells, highlighting the role of miR‑US5‑2 in this process.
Writing in the journal Cell Host & Microbe recently, the team state: “Our data suggest that latently expressed viral miRNAs manipulate stem cell homeostasis by inducing secretion of TGF‑β, while protecting infected haematopoietic progenitor cells from TGF‑β-mediated effects on viral latency and reactivation.
“These observations provide a mechanism through which HCMV induces global myelosuppression following [haematopoietic stem cell transplant] while maintaining lifelong infection in myeloid lineage cells.”
Dr Nelson says: “We've known for about 40 years that cytomegalovirus is key to many of the complications transplant patients experience. But it wasn't until now that we were able to determine exactly how it causes these problems.”
Hancock MH, Crawford LB, Pham AH, Mitchell J, Struthers HM, Yurochko AD, Caposio P, Nelson JA (2020) “Human Cytomegalovirus miRNA Regulation of TGF-beta Expression and Signaling Mediates Myelosuppression and Latency in CD34+ Hematopoietic Progenitor Cells”, Cell Host & Microbe, doi: 10.1016/j.chom.2019.11.013