| The Arenaviridae are enveloped negative-stranded RNA viruses that often elicit cell-mediated immunity in mice and can be biothreat agents in primates. Five years ago our laboratory began infections of rhesus macaques with the prototype arenavirus, lymphocytic choriomeningitis virus (LCMV) using the WE strain that has been known to cause both encephalopathy and multifocal hemorrhage. Our initial study established that intravenously-inoculated monkeys developed signs of fatal hemorrhagic fever, whereas monkeys inoculated by the intragastric route had subclinical infections and no gross or microscopic lesions.; In a second study, a high dose of LCMV-WE was delivered intragastrically or intravenously to rhesus macaques. This study contradicted the generally held notion that hemorrhagic fever was characterized by a burst of pro-inflammatory cytokines because we showed that pro-inflammatory cytokines TNF-alpha and IL-1beta were not detected in plasma of infected animals, and that increased gamma interferon could only be detected late in the plasma of fatally infected animals. We proposed that certain pro-inflammatory cytokines like IL-6 were instigators in liver repair, and that disease was due to virus inhibition of repair mechanisms. We observed increases in IL-6, sIL-6R, sTNFR, and proliferation antigen in liver that are similar to the profile of incipient liver regeneration. Although IL-6 was not directly induced by virus infection in vitro, peripheral blood mononuclear cells from acutely infected monkeys produced higher levels of IL-6 than did healthy controls. Our data confirmed that acute infection is associated with weak inflammatory responses in tissues and initiates a program of liver regeneration in primates.; In a final study we characterized infection after mucosal inoculation and further lethal challenge. I used plaque neutralization, ELISA, lymphocyte proliferation, real time RT-PCR, flow-cytometry and chromium-release assays to monitor protective immune responses, and cross-protection between virulent (LCMV-WE) and avirulent (LCMV-ARM) strains. Three out of seven monkeys that experienced protection were also the three with the strongest cell-mediated immunity. Overall, the studies presented in this thesis validate the importance of the mucosally-infected macaque as a valuable model for the pathogenesis of hemorrhagic fever, for characterizing immune responses, and for testing vaccine candidates for Lassa Fever virus. |
