Tumor necrosis factor α promotes replication and pathogenicity of rat cytomegalovirus

Abstract

We investigated the role of tumor necrosis factor alpha (TNF-α) in the pathogenesis of rat cytomegalovirus (RCMV) infection. TNF-α levels found in the sera of radiation-immunosuppressed rats in the course of infection (> 350 pg/ml) correlated with the development of RCMV disease. Administration of anti-TNF-α antibodies strongly reduced the severity of pneumonia and led to a reduction in virus titers. In immunocompetent rats, anti-TNF-α antibodies also significantly suppressed viral replication. Conversely, administration of TNF-α augmented RCMV replication and aggravated the disease signs. In vitro, TNF-α enhanced RCMV replication in the macrophage, whereas a reduction of viral replication was observed in fibroblasts, indicating that the effect on viral replication is cell type specific. Besides activation of viral replication and exacerbation of RCMV disease, TNF-α also favored lymphoid and hematopoietic tissue reconstitution after irradiation, which may contribute to antiviral resistance and survival. This finding demonstrates the protean nature of TNF-α, with both beneficial and adverse effects for the host. Our results suggest that TNF-α plays an important role in modulating the pathogenesis of RCMV infection.