Perivascular Stromal Cells as a Potential Reservoir of Human Cytomegalovirus

Abstract

Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality among both solid organ and hematopoietic stem cell transplant recipients. Identification of cells throughout the body that can potentially serve as a viral reservoir is essential to dissect mechanisms of cell tropism and latency and to develop novel therapies. Here, we tested and compared the permissivity of liver-, brain-, lung (LNG)- and bone marrow (BM)-derived perivascular mesenchymal stromal cells (MSC) to HCMV infection and their ability to propagate and produce infectious virus. Perivascular MSC isolated from the different organs have in common the expression of CD146 and Stro-1. While all these cells were permissive to HCMV infection, the highest rate of HCMV infection was seen with LNG-MSC, as determined by viral copy number and production of viral particles by these cells. In addition, we showed that, although the supernatants from each of the HCMV-infected cultures contained infectious virus, the viral copy number and the quantity and timing of virus production varied among the various organ-specific MSC. Furthermore, using quantitative polymerase chain reaction, we were able to detect HCMV DNA in BM-MSC isolated from 7 out of 19 healthy, HCMV-seropositive adults, suggesting that BM-derived perivascular stromal cells may constitute an unrecognized natural HCMV reservoir.

The N Terminus of Human Cytomegalovirus Glycoprotein O Is Important for Binding to the Cellular Receptor PDGFRα

“…This assumption is supported by our finding that both mutations conferring resistance also reduced penetration into fibroblasts. Although the role of fibroblasts in HCMV pathogenesis within the host is not fully resolved, fibroblasts are a predominant target cell of HCMV in various organ tissues and were suggested as reservoirs for virus dissemination (1,56,57). In the murine CMV model, it was demonstrated that the gH/gL/gO complex is important for transmission of the virus to new hosts as well as spread within the host (58,59).…”

The silent war of CMV in aging and HIV infection

“…Indeed, CMV can infect a host of different cell types, including fibroblasts, endothelial cells, muscle cells, and brain-derived pericytes. Recent studies have added perivascular mesenchymal stromal cells within multiple organs to this list (Soland et al, 2014). These cells are present not only within the hematopoietic microenvironmental niche, but also as cells that encircle capillaries and vessels throughout the body, allowing intimate contact with circulating lymphocytes as they extravasate across vessel walls (Soland et al, 2014).…”

“…Recent studies have added perivascular mesenchymal stromal cells within multiple organs to this list (Soland et al, 2014). These cells are present not only within the hematopoietic microenvironmental niche, but also as cells that encircle capillaries and vessels throughout the body, allowing intimate contact with circulating lymphocytes as they extravasate across vessel walls (Soland et al, 2014). These observations may explain the fact that the magnitude of the CD8 T cell response during even clinical latency is extraordinarily high, ranging from 10–20% in otherwise healthy adults, and reaches levels of 50% in the HIV-infected population.…”

“…However, it should be noted that CMV also negatively impacts other clinical situations. For example, in the case of inflammatory bowel disease, CMV is associated with steroid resistance (Wu et al, 2015); in kidney transplant patients, CMV induces activation of several human endogenous retroviruses (Bergallo et al, 2015), and in stem cell transplant recipients, CMV is an important cause of mortality (Soland et al., 2014). A recent, highly relevant finding is the consistent association between unfavorable glucose and lipid profiles with the accumulation of late stage CD8 T cells in a large cohort (n=400) of CMV+ individuals, as compared to uninfected controls that were matched for age, sex, sociodemographic variables and lifestyle factors.…”

Mesenchymal stem cells and infectious diseases: Smarter than drugs

“…By infusing CMV positive MSCs into such recipients, we may inadvertently deliver an exogenous pool of CMV and cause unwanted infectious complications [49].…”