Figure 1. Ross River virus (RRV) replication in joint associated tissues of infected mice. 14 day old mice were infected subcutaneously with 103 pfu of a recombinant RRV expressing green fluorescent protein. Frozen sections were analyzed by fluorescent microscopy. Green cells indicate viral infection. 200 x magnification. A. Synovial cavity in foot, 48 hours post infection. B. Synovial cavity in ankle, 48 hours post infection. C. Synovial cavity in knee, 48 hours post infection. D. Periosteum adjacent to knee, 72 hours post infection.

Figure 2. Ross River virus (RRV)-induced inflammation in joint-associated tissues. 14 day old mice were either mock infected or infected with 103 pfu of RRV subcutaneously. On day 7 post infection, hind limbs were sectioned and H+E stained. Periosteum adjacent to ankle joint of RRV infected mouse exhibits inflammation (lower panel), while the ankle of the mock infected animal appears normal. 200x magnification.

Our laboratory has developed two different model systems involving alphavirus infection of mice to study the pathogenesis of alphavirus-induced encephalitis and arthritis. The first model involves the use of two closely related alphaviruses, one of which causes lethal encephalitis in mice while the other is avirulent. We have begun using infectious cDNA clones of these two viruses to map viral genetic elements that are involved in the development of disease. The long term goals of these studies is to define the mechanisms by which these virulence determinants act to promote virus-induced disease and to evaluate the role of specific host immune factors in protecting against viral disease. The second model system focuses on identifying viral and host determinants that are involved in the development of virus-induced arthritis. Ross River virus, an Australian virus associated with several thousand cases of infectious poly-arthritis a year, causes a macrophage-mediated inflammatory disease in the muscle and joints of infected mice. This system provided us with a useful model to investigate the viral and host genetic elements that lead to virus-induced arthritis and should also increase our understanding of the basic mechanisms involved in the generation and resolution of the inflammatory response to viral infection.

In addition to studying viral pathogenesis, we are also extremely interested in using alphavirus-based vectors for gene delivery. We are currently attempting to develop replicon-based vaccines against several hemorrhagic fever viruses. These studies are focused on modifying both the replicons and the expressed antigens to generate an optimal host immune response.