Dennis W. Metzger, PhD

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. His laboratory has developed highly effective intranasal prophylactic and therapeutic approaches for protection of neonatal and adult animals against pulmonary infectious disease, using a variety of bacteria and viruses as model pathogens. 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 have remained poorly understood. Dr. Metzger's laboratory has now demonstrated that pulmonary interferon (IFN)-gamma produced during T cell responses to influenza infection inhibits alveolar macrophage function and hence, bacterial clearance from the lung. This suppression of phagocytosis then leads to enhanced susceptibility to secondary bacterial infections. 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 extracellular pathogens (bacteria). Current work concentrates 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. In addition, since 9/11, the laboratory has focused on protective immunity against microbes that could be used for bioterrorism, in particular, pulmonary pathogens, and specifically, F. tularensis. Among our contributions, we have shown the prophylactic and therapeutic benefit of injected antibodies for prevention of disease in native animals and have identified a detrimental role of type 1 interferon and IL-10 in constraining effective immune protection. Most recently, since the emergence of the Covid-19 pandemic, we have used our expertise and availability of an ABSL-3 facility to study the pathogenesis of SARS-CoV-2 infection in both humans and mice.  We have shown that the presence of infectious virus in congregate care patients is correlated with SARS-CoV-2 RT-PCR detection only during early symptom onset and with very high viral genomic copy numbers and low antibody titers in non-immunosuppressed patients.  We have also obtained results in mice indicating that when seasonal respiratory infections such as pneumococcal infections and influenza return to their pre-pandemic levels, co-infections with these pathogens could lead to an increased incidence of lethal Covid-19 superinfections, especially among unvaccinated populations. The ultimate goal of our studies is to develop novel, safe and efficacious strategies for immune defense against emerging and re-emerging pathogens, as well as potential biothreat agents.