Apoptosis Is Induced by Hantaviruses in Cultured Cells

Abstract

Hantaviruses replicate in primary and cultured animal cells with little or no cytopathic effect. We report here that the cultured Vero E6 cells infected by the Hantaan or by the Prospect Hill viruses exhibited characteristic features of apoptosis, including condensation and segmentation of nuclei and internucleosomal cleavage of nuclear DNA. Apoptosis was not seen in the cells adsorbed by UV-inactivated virus, indicating that the viral replication is required for the induction of apoptosis. Furthermore, level of the proto-oncogenic Bcl-2 protein was significantly reduced, whereas its mRNA level remained unchanged in Hantaan virus-infected cells, suggesting possible involvement and posttranscriptional regulation of this antiapoptotic protein in the process.

Bunyamwera Virus Nonstructural Protein NSs Counteracts Interferon Regulatory Factor 3-Mediated Induction of Early Cell Death

“…Little is known about the apoptotic pathways activated during infection by members of the Bunyaviridae family, the notable exception being the downregulation of the antiapoptotic protein Bcl-2 seen during Hantaan virus infection (27). Therefore we carried out a screen involving several well-characterized molecules and pathways in order to detect if differences exist between wild-type BUN and BUNdelNSs.…”

“…Our Apoptotic cell death induced by viruses of the Bunyaviridae family has been described previously. Hantaan and Prospect Hill hantaviruses have been shown to induce apoptosis in cultured cells (27), and, importantly, Hantaan virus activates IRF-3 (52). Similarly, La Crosse orthobunyavirus has been shown to induce apoptosis in a particular neuronal cell line and in BHK-21 cells (3,42).…”

“…It should be noted that we were unable to detect BUN-induced apoptosis in the mosquito cell line C3/36, which is in accordance with a recent finding with La Crosse virus (3). Little is known about the mechanisms and effector molecules involved in bunyavirus-induced apoptosis, but levels of the antiapoptotic protein Bcl-2 levels seemed to be decreased in Hantaan virus-infected cells (27). However, while molecules such as Bax and Bcl-2 intervene in a pathway involving mitochondria and release of cytochrome c (50), other negative-strand viruses such as respiratory syncytial virus and influenza A virus (17,41) seem to involve a death receptor pathway, the Fas/Fas ligand system.…”

Hantavirus Infection of Dendritic Cells

“…This is in accordance with studies demonstrating that hantaviruses replicate in endothelial cells and monocytes/ macrophages without causing cytopathic effects (59,75,79). Vero E6 cells, a cloned cell line derived from green monkeys, produce high peak viral titers 7 days after HTNV infection and undergo replication-dependent apoptosis (29). In contrast, the peak titer of HTNV replication in human DCs was lower (5 ϫ 10 4 FFU per ml), had already occurred at 4 days postinfection, and was not associated with cell death.…”

Hantavirus Infection

“…Host cells are not lysed by infection with pathogenic hantaviruses, and no increased permeability is induced in endothelial cell cultures (41,42). Apoptosis and expression of apoptosis-related genes in cells that were infected with pathogenic hantaviruses was reported for cultured VeroE6 and human embryonic kidney cells; however, in vivo, there is no evidence for programmed cell death in infected endothelial cells (43)(44)(45)(46). These data indicate that increased endothelial permeability during HFRS and HPS might be the result of the infection with pathogenic hantaviruses in combination with additional factors that are specific for the in vivo situation and that are not present in in vitro cell cultures.…”