Bio

Professor Michael Mahan's research concerns the molecular mechanisms of bacterial pathogenesis; and innate and adaptive immune responses to infection. He received his B.S. degree in Biochemistry and M.S. degree in Genetics from the University of California, Davis; and a Ph.D. in Genetics from the University of Utah. He was a NIH post-doctoral fellow at Harvard Medical School where he began his work on the molecular mechanisms of underlying Salmonella pathogenesis. Dr. Mahan joined the UCSB faculty in 1993. Dr. Mahan shared the American Association for the Advancement of Science (AAAS) Newcomb-Cleveland Prize for the outstanding paper published in Science. He is a recipient of an American Cancer Society Junior Faculty Research Award; Beckman Young Investigator Award; Harold J. Plous Award; USDA National Impact Paper; and Faculty Distinguished Teaching Award. Dr. Mahan served on the Editorial Board for the Journal of Molecular Medicine was Co-founder and Director of Remedyne Corporation, a biotech company in Santa Barbara, California.

Research

Microbial Pathogenesis

Emerging infectious diseases continue to compromise human health, animal welfare, and modern agriculture. The numbers of multi-drug resistant bacterial pathogens are increasing at a rapid rate, creating sometimes hopeless situations for patients unfortunate enough to become infected with one of these organisms. Consequently, it is imperative that we thoroughly investigate alternative avenues to control emerging pathogens. By gaining a better understanding of the mechanisms underlying microbial virulence and the host-pathogen interactions that compromise host immunity, we can facilitate the design of novel vaccine and therapeutic strategies that impair the infecting microbe or modify the host immune responses involved in microbial pathogenesis and/or adverse clinical disease outcomes.

Salmonella

Salmonellosis is a principal health and economic burden due to the endemic prevalence of salmonellae in food and water supplies and emergent multi-drug resistant strains associated with increased incidence and severity of disease. The goal of our research is to understand the molecular mechanisms underlying Salmonella pathogenesis during growth or association with the host. We have shown that Salmonella virulence gene expression is governed, in part, by the DNA adenine methylase (Dam) regulatory protein. Salmonella dam mutants are attenuated for virulence, modify cytokine responses in infected hosts, and promote protective immunity in vaccinated animals. We are continuing our efforts in the investigation of the molecular mechanisms underlying microbial pathogenesis during growth or association with the host, and the global microbial changes that occur during transmission to other hosts and to the environment.

Vaccine Development

Immunity conferred by conventional vaccines is restricted to a narrow range of closely-related strains, highlighting the unmet medical need for the development of vaccines that elicit protection against multiple pathogenic serotypes. Safety and efficacy studies by our laboratory have shown that Salmonella vaccines deficient in the DNA adenine methylase (dam) gene are safe, well tolerated, and confer significant cross-protective immunity against multiple strains of Salmonella. Cross-protective immunity directly correlated with increased levels of cross-reactive opsonizing antibodies and memory T cells along with a diminished expansion of myeloid-derived suppressor cells (MDSCs) that are responsible for immune suppression. These data suggest that pronounced stimulation of B and T cells is a requisite for the development of vaccines that confer cross-protective immunity against multiple pathogenic serotypes.

Emerging Infectious Diseases

A recent global screen of Salmonella clinical isolates of human and animal origin has revealed a novel class of hyperinfectious bacteria that can override the protection previously conferred by vaccination. These data indicate that hyperinfectious strains are present in current natural bacterial populations and, as such, may pose increased public health and economic risks due to potential impacts on human and animal disease, epidemic spread, and infection of immunized populations. Our overall goal is to define the molecular mechanisms that engender the heightened virulence exhibited by hyperinfectious strains and the host-microbe interactions that compromise host immune responses following infection with these strains.

Host Immune Responses to Microbial Infection

Host innate immune responses to microbial infection are stimulated by the recognition of conserved pathogen-associated molecular patterns via host Toll-like receptors. Such recognition leads to the induction of cytokines, chemokines, and interferon (IFN) system genes. We have focused our efforts on the characterization of the altered innate immune responses to Salmonella infection as well as to those that occur during infection/immunization with Salmonella dam vaccines. Infection of mice with the dam vaccine showed reduced multi-tissue innate immune cytokine responses relative to wild type, which may contribute to the reduced disease manifestations and protective immunity observed in vaccinated animals. Investigation into the role of host responses to infection will provide insight into the molecular basis of microbial pathogenesis and enable the design of therapeutics to either control the infecting microbe or the host immune responses that may contribute to pathogenesis.