Mechanisms of cytomegalovirus-mediated myelosuppression: perturbation of stromal cell function versus direct infection of myeloid cells.

Abstract

Infection with cytomegalovirus (CMV) continues to be one of the most common complications following allogeneic bone marrow transplantation. To study the role of CMV in the suppression of hemopoiesis that frequently accompanies infection, we investigated the effect ofCMV on the growth ofisolated committed myeloid progenitors and on hemopoiesis in long-term bone marrow cultures. Laboratory strain AD169 had no effect on the growth and development of progenitor cells. In contrast, 40% of clinical isolates of CMV inhibited colony formation by up to 100%. In long-term bone marrow cultures all CMV isolates resulted in myelosuppression, which in the majority of cases was associated with the infection of stromal elements. Analysis of RNA from stromal cells infected with AD169 and one clinical isolate demonstrated a specific deficiency of granulocyte colony-stimulating factor transcripts. For a small proportion of the clinical isolates tested in long-term bone mlarrow cultures, suppression of hemopoiesis was correlated Okh infection of developing granulocytes. These studies suggest that CMV can impair hemopoiesis either through infection of stromal cells and consequent perturbation of growth factor production or by direct infection of myeloid cells.Human cytomegalovirus (CMV), a member of the herpesvirus family, infects the majority ofthe population by adulthood (1). The consequences of CMV infection ranges from subclinical asymptomatic illness to a rapidly progressive disseminated disease in immunocompromised individuals. In patients undergoing bone marrow transplants, CMV can be associated with delayed platelet engraftment (2), phenotypically abnormal peripheral blood leukocytes (3), and graft failure (4).Several mechanisms acting alone or in combination could mediate the myelosuppression associated with CMV. Hemopoietic progenitor cells or accessory cells such as monocytes and T lymphocytes, hypothesized to provide growth factors, may be targets for infection (5-8). Alternatively, since the maintenance of primitive hemopoietic progenitor cells is crucially dependent on their interactions with stromal cells of the marrow microenvironment (9), the perturbation of stromal cell function by CMV could also result in myelosuppression.We studied the myelosuppressive effects of CMV in vitro using a laboratory-adapted strain and low-passage clinical isolates to infect human long-term bone marrow cultures (LTBMC) (Table 1). AD169 and 12 of 19 clinical isolates had no effect on the growth of colonies nor was viral IEA detected in cytospin preparations. However, 8 clinical isolates inhibited growth of CFU-GM, BFU-E, and CFU-Mix colonies, ranging from 17% to 100% of growth obtained in mock-infected control cultures.Addition of CMV to LTBMCs: Effects on Hemopoiesis. CMV has been demonstrated to infect and replicate in bone marrow-derived stromal cells of simian and human origin (21,22). To investigate whether infection with CMV impaired the ability of marrow stromal cells to maintain hemopoietic development, LTBMCs establi...

Depletion of immature B cells duringTrypanosoma cruzi infection: involvement of myeloid cells and the cyclooxygenase pathway

“…Despite the many clinical and experimental observations showing hematopoietic abnormalities associated with infections [26][27][28][29], most studies have focused on documenting pathogen-induced effects on myeloid and erythroid lineages. Surprisingly, there are few reports on alterations in BM lymphocytes during infection [25,30].…”

Human Cytomegalovirus (HCMV) Infection in Osteosarcoma Cell Line Suppresses GM‐CSF Production by Induction of TGF‐β

“…A decreased production of hemopoietic growth factors from HCMV-infected bone marrow stroma has been described (1,16). The hemopoietic microenvironment plays an important role in supporting and regulating the proliferation and differentiation of hemopoietic cells.…”

“…Transient neutropenia and thrombocytopenia may occur in the course of acute HCMV infections, particularly in immunocompromised patients (19,21), newborn infants (22), and congenitally infected infants (20). The mechanism by which HCMV disease causes immunosuppression is unclear but may either directly or indirectly involve the infection of hemopoietic cells (14,16,17).…”

Fulminant pancytopenia due to cytomegalovirus infection in an immunocompetent adult

“…11 In addition, it has been suggested that CMV infection results in downregulation of G-CSF and hematopoietic suppression. 12 In our case, bone marrow aspiration showed normal cellularity and CMV antigen was not detected. Therefore, this mechanism should not be the cause of pancytopenia.…”