EFFECT OF MACROPHAGE SOURCE AND ACTIVATION ON SUSCEPTIBILITY IN AN AGE-DEPENDENT MODEL OF MURINE HEPATITIS CAUSED BY A PHLEBOVIRUS, PUNTA TORO

The Adames strain of a bunyavirus, Punta Toro virus (PTV), is an hepatotrophic virus that has been described to produce an age-dependent lethal hepatic necrosis in 3-4 week old C57BL/6 mice, but 8 week old mice survive with minimal necrosis. The course of PTV infection in vitro in macrophages derived from these mice served as a model to study the pathogenesis of phlebovirus infection. Peripheral blood monocytes, resident or elicited peritoneal macrophages, and Kupffer cell liver macrophages, as well as hepatocytes, were able to support replication of PTV in vitro to a variable extent. Kupffer cells were the only population of macrophages, however, that expressed an age-related ability to affect viral infection and replication in vitro, suggesting that liver macrophages may have a unique modulatory effect on the occurrence and severity of PTV-induced hepatitis in mice. Whereas PTV showed minimal replication in resident peritoneal macrophages, the virus could replicate effectively in peritoneal macrophages elicited by thioglycolate. Activation of peritoneal macrophages with endotoxin resulted in a significant inhibition of intrinsic PTV replication (p < 0.001), and a modest extrinsic inhibitory effect on PTV replication in cocultured hepatocytes. Both effects persisted in the presence of anti-interferon. These results indicate that the source and state of activation of macrophage/monocyte populations can influence the course of infection in vitro by the phlebovirus, Punta Toro, and can modulate infection in cocultured target cells.