Dr. Metzger's research program concentrates on examining new approaches for induction of protective mucosal immune responses. Nearly all pathogens enter the body through mucosal surfaces, yet there are few vaccines that provide effective protection at these sites. A portion of his present work focuses on the role of interleukin-12 (IL-12) as an intranasal vaccine adjuvant for inducing immunity against respiratory viral and bacterial pathogens, including agents that could be potentially used for bioterrorism or biowarfare. IL-12 is a cytokine that is currently in clinical trials for the treatment of human disease. Its major effect is to induce T cells and natural killer cells to produce large amounts of interferon-gamma. Investigators in Dr. Metzger's laboratory have shown that IL-12 also acts as a powerful adjuvant for antibody responses and are directly examining the potential of IL-12 for increasing protection against mucosal pathogens, including influenza virus, HIV-1, pneumococci, and Francisella tularensis, a Category A Biothreat. For these studies, IL-12 is administered directly to mucosal surfaces and mice with defined genetic disruptions are used to determine the mechanisms responsible for protection. The antibodies that are induced by this vaccination procedure can prevent infection and can even protect the pulmonary tract in a therapeutic manner after pathogen exposure. As part of the long-standing interest in the development of new strategies for immune protection in the respiratory tract, the mechanisms responsible for viral-bacterial synergy in the lung are also being examined. It is well known that secondary bacterial infection often follows pulmonary virus infection and is a common cause of severe disease, especially during influenza pandemics in humans, including the 1918 Spanish flu pandemic. However, the reasons for this are only poorly understood. Dr. Metzger's laboratory has now demonstrated that pulmonary interferon (IFN)-gamma produced during T cell responses to influenza infection inhibits scavenger receptor expression by alveolar macrophages and hence, bacterial clearance from the lung. This suppression of phagocytosis then leads to enhanced susceptibility to secondary pneumococcal infection, which can be prevented by IFN-gamma neutralization following influenza infection Thus, the hypothesis of the work is that induction of an adaptive immune response against an intracellular pathogen in the lung (virus) results in significant impairment of innate alveolar macrophage-mediated protection against nonopsonized extracellular pathogens (bacteria). Current work is focused on characterizing functional changes in alveolar macrophages induced by influenza virus infection and on determining the mechanisms responsible for the inhibition of alveolar macrophage-mediated bacterial clearance. The ultimate goal is to develop novel, safe and efficacious strategies for biodefense against emerging and re-emerging pathogens, as well as potential biothreat agents.