Hepatitis A Virus Suppresses Monocyte-to-Macrophage Maturation In Vitro

Abstract

To analyze the pathogenetic mechanism of hematopoietic dysregulation associated with hepatitis A virus (HAV) infections, we studied the influence of HAV on monocyte (MO)-to-macrophage (MAC) maturation in vitro. Exposure of peripheral blood-derived mononuclear cells (MNC) to HAV led to diminished adherence of MO to plastic. Furthermore, HAV inhibited the ability of peripheral blood MO to differentiate toward MAC. Freshly isolated and 14-day-old MO cultures demonstrated reduced differentiation and decreased phagocytic capacity after challenge with HAV. Viral replication in MO/MAC cultures was confirmed by titration of infectious virus. We also determined the influence of HAV on the MO/MAC population in human long-term bone marrow cultures (LTBMCs). Inoculation of bone marrow MNC with HAV suppressed the establishment of an adherent stromal layer containing a reduced number of MAC. Furthermore, increased MO numbers in the nonadherent fraction of HAV-challenged LTBMCs are indicative of the disturbance of MO adherence. These findings suggest that HAV infection leads to a disorder of the mononuclear phagocytic system which may contribute to functional abnormalities of the bone marrow stroma.Infections with hepatitis A virus (HAV) are associated with perturbations of hematopoietic regulation ranging from transient granulocytopenia to rare cases of aplastic anemia (AA) (5,7,9). The clinical syndrome of AA, which may also be caused by exposure to drugs, radiation, chemicals, or other hepatotropic viruses, is characterized by bone marrow hypocellularity and peripheral blood pancytopenia. The pathogenesis of AA associated with viral hepatitis is not well understood, although a variety of hematopoietic and immunoregulatory defects have been described, including direct infection of bone marrow progenitor cells and impairment of stromal function (6,11,14).The bone marrow stroma represents a heterogeneous cell pool, consisting of fibroblasts, endothelial cells, adipocytes, and macrophages (MAC). Growth and differentiation of the hematopoietic cell population is dependent on its close association with stromal cells, which produce regulatory cytokines necessary to control hematopoiesis. In previous studies with human long-term bone marrow cultures (LTBMCs), HAVinduced inhibition of hematopoiesis was demonstrated by granulocyte-macrophage colony formation assays, and sequential determination of virus titers in the supernatant provided evidence for HAV replication in LTBMCs (3, 4, 17). However, our knowledge about which cell types of the heterogeneous stromal cell population are permissive for HAV is limited. Whereas the HAV infection of fibroblasts is well characterized (16), very little is known about the interaction of HAV with MAC, endothelial cells, or adipocytes. In this study, we focused on the interaction of HAV with peripheral blood monocytes (MO) and MAC, using primary cultures of MO and LTBMCs. MATERIALS AND METHODS Virus.The virus used in this study was HAV strain GBM adapted to human fibroblasts.Cell isolation. Mononuc...

Impaired function of CD4+/CD25+ T regulatory lymphocytes characterizes the self‐limited hepatitis A virus infection

“…It is still unknown which mechanisms are related to suppression of CD3/CD4+/CD25+ T cells; HAV might have a direct activity on CD4+/CD25+ T cells' function as already reported for monocytes, 16 or it might be able to mediate the suppression of Tregs through some other cell subsets involving different mechanisms, as previously reported in other diseases 17,18 . In fact, it was of note that once the virus was cleared, after IgG seroconversion, the function of those T lymphocytes was restored to that of healthy individuals.…”

Phagocytosis of Apoptotic Cells and Immune Regulation

“…These results suggested that monocytic THP-1 cells were morphologically and functionally differentiated to macrophages by IV-infected apoptotic cells because of a soluble factor released from the apoptotic cells [50,51]. But, Brucella virus (Brucella genus) can prevent macrophage apoptosis [52,53]. Jimenez et al have shown that B. suis infection inhibits the spontaneously occurring apoptosis in human monocytes/macrophages [52].…”

Modulation of macrophages by infectious bursal disease virus

“…These cells play an indispensable role in regulating the interplay between innate and adaptive immune responses. Viral infections can modulate host immune responses by either enhancing or dampening the effector functions of macrophages, causing immunopathogenesis and/or immunoevasion (Biggs et al, 1995;Kedzierska et al, 2002;Wunschmann et al, 2002). Additionally, macrophages can also harbor infectious viruses, serving as reservoirs for further dissemination (Orenstein, 2001;Way et al, 2002).…”