Bone marrow failure by cytomegalovirus is associated with an in vivo deficiency in the expression of essential stromal hemopoietin genes

Abstract

Bone marrow (BM) failure associated with cytomegalovirus (CMV) infection is a feared complication after clinical BM transplantation. Experiments in long-term BM cultures have indicated that BM stromal cells (BMSC) are targets of productive CMV infection, but an in situ infection of BM stroma remained to be documented, and the pathomechanism is open to question. Here we describe a murine in vivo model of lethal CMV aplastic anemia (CMV-AA). The reconstitution of hematopoietic progenitor cells expressing stem cell factor (SCF) receptor was found to be defective in CMV-AA. While murine CMV replication in permissive parenchymal tissues is cytolytic, the hematopoietic cord was found to be a site of very limited virus production with foci of reticular BMSC expressing the intranuclear viral IE1 protein, but with only a few BMSC positive for viral genome in the in situ hybridization. XX-XY BM chimeras were established in order to quantitate Y-chromosome-tagged BMSC by a PCR specific for the male-sex-determining gene Tdy. This approach revealed that murine CMV infection is not associated with a significant loss of BMSC. Despite the physical integrity of the stromal network, the functional integrity of the stroma was impaired. While housekeeping genes were expressed normally in BMSC of infected mice, the expression of genes encoding the essential hemopoietins SCF, granulocyte colony-stimulating factor, and interleukin-6 was markedly reduced. In conclusion, the mechanism of BM failure is not a stromal lesion but an insufficient stromal function. These findings explain CMV-AA as a manifestation of multiple hemopoietin deficiency.

Interaction of human herpesvirus 6 with human CD34 positive cells

“…One, the virus directly suppresses hematopoietic progenitors [Rakusan et al, 1989;Sing and Ruscetti, 1990;MacKintosh et al, 1993;Movassagh et al, 1996;Sindre et al, 1996]. Two, the virus indirectly suppresses the cell population by cytokine production from accessory cells [Apperley et al, 1989;Busch et al, 1991;Lagneaux et al, 1994Lagneaux et al, , 1996aMayer et al, 1997;Steffens et al, 1998]. In this study, we determined the effect of HHV-6 on the purified CD34þ cells.…”

CD8 T cells induce destruction of bone marrow stromal niches and hematopoietic stem cell dysfunction in chronic viral infections

“…It is also conceivable that defective BM stromal cell function may only become functionally relevant in the context of secondary stress. Intriguingly, latent chronic CMV infections are reactivated during myeloablative conditioning regimens in BM transplant patients, and are a common cause of engraftment failure (SIMMONS et al, 1990;Reddehase et al, 1992;Mayer et al, 1997).…”

“…CMV infects both hematopoietic as well as stromal cell populations (SIMMONS et al, 1990;Mayer et al, 1997). Thus, infections with chronic LCMV-cl13 may represent a valid model to shed light on how underlying infection-mediated stromal deficiencies contribute to this highly relevant clinical burden.…”

Fatal ongoing human cytomegalovirus reactivation during high‐dose melphalan and autologous stem cell transplantation

“…HCMV is associated frequently with graft failure and cytopenias involving all hematopoietic lineages, but thrombocytopenia is the hematologic complication reported most commonly [Sing and Ruscetti, 1995]. HCMV inhibits the engraftment of HSCs by downregulating expression of MIP-1a, TGF-b 1 [Taichman et al, 1997], interleukin-3 (IL-3), IL-6, granulocytemacrophage and granulocyte colony-stimulating factors (GM-CSF and G-CSF) [Lagneaux et al, 1994], but not IL-6 [Reddehase et al, 1992;Taichman et al, 1997], in recipient stroma [Mayer et al, 1997;Steffens et al, 1998].…”