TUMOR-NECROSIS-FACTOR-ALPHA PROMOTES REPLICATION AND PATHOGENICITY OFRAT CYTOMEGALOVIRUS

We investigated the role of tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of rat cytomegalovirus (RCMV) infection. TNF-alpha l evels found in the sera of radiation-immunosuppressed rats in the cour se of infection (>350 pg/ml) correlated with the development of RCMV d isease. Administration of anti-TNF-alpha antibodies strongly reduced t he severity of pneumonia and led to a reduction in virus titers. In im munocompetent rats, anti-TNF-alpha antibodies also significantly suppr essed viral replication. Conversely, administration of TNF-alpha augme nted RCMV replication and aggravated the disease signs. In vitro, TNF- alpha 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-alpha also favored lymphoid and hematopoietic tissue reconstitution after irradi ation, which may contribute to antiviral resistance and survival. This finding demonstrates the protean nature of TNF-alpha, with both benef icial and adverse effects for the host. Our results suggest that TNF-a lpha plays an important role in modulating the pathogenesis of RCMV in fection.