Michael J. Mahan
Awards / Honors
- American Association for the Advancement of Science (AAAS) Newcomb-Cleveland Prize
- American Cancer Society Junior Faculty Research Award
- Beckman Young Investigator Award
- Harold J. Plous Award
- Faculty Distinguished Teaching Award
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.
Salmonella Pathogenesis / Immunity
Salmonella is the greatest foodborne-disease burden in the United States— responsible for the most infections, hospitalizations and deaths— causing 1.03 million illnesses annually. Our research is focused on the infection processes of Salmonella that can result in any of four distinct syndromes: enterocolitis/diarrhea, bacteremia, enteric (typhoid) fever and chronic asymptomatic carriage. The objective is to understand the molecular mechanisms underlying Salmonella pathogenesis, with the applied goal to develop intervention strategies for human and animal health as well as food safety. Salmonella have the capacity to deploy a wide variety of microbial virulence functions (adhesins, invasins, toxins) during the infective process and the expression of these virulence determinants changes as the infection proceeds in response to host inflammation, tissue breakdown, and immune responses. Additionally, Salmonella undergo global changes in microbial behavior upon dissemination to other host tissues as well as transmission to new hosts/environs. We have shown that Salmonella virulence gene expression is governed, in part, by the DNA adenine methylase (Dam). 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 to understand the mechanisms underlying microbial virulence and the host-pathogen interactions that compromise host immunity. Such analyses will 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.
Hypervirulent Salmonella Strains Derived from Natural Microbial Populations
The potential emergence of more virulent Salmonella strains poses a serious threat to human and animal health as well as to contamination of food and water supplies. We have isolated ‘hypervirulent’ Salmonella from natural microbial populations that are among the most virulent microbes encountered of this species. These strains are 100-times more virulent then other clinical isolates, are more capable of killing vaccinated animals, and are not detectable under standard laboratory test conditions as the hypervirulent state is only expressed during the infective process. The key to their identification was to assess virulence immediately after infection before their rapid transition to a less-virulent state outside of the animal. These hypervirulent strains utilize a ‘Trojan Horse’ strategy whereby virulence functions are only revealed during the infective process. Entry into an animal host induces distinct transcriptional responses in hypervirulent strains that were not altered, or altered to the same extent, in conventionally virulent strains. Such altered gene expression is characterized by elevated production of an actin cytotoxin and immunomodulatory molecules that, in combination, confer profound effects on microbial virulence and the capacity of the host to mount an effective immune response. Of particular concern is the likelihood that hypervirulent strains of other pathogens are present among natural microbial populations, posing a previously unrecognized risk to human health.
Host-dependent Induction of Transient Antibiotic Resistance: A Prelude to Treatment Failure
Although the standard 7-10 day antibiotic treatment regimen is usually sufficient to clear microbial infections, some patients fail to respond and require prolonged therapy, higher dosing or alternative antibiotics. This is particularly confounding in cases involving immune competent individuals where bacterial ID and AST results predict drug sensitivity. Why does this occur and what are the possible implications? Although bacteria may be susceptible to antibiotics in the laboratory, certain host sites may present a unique biochemical environment that induces changes in the bacterium so they become transiently resistant to high doses of certain antibiotics. This results in a large, transiently-resistant bacterial population from which permanent drug-resistant mutants may arise via standard mutational mechanisms. While it is likely that evolution this mechanism may predates antibiotic use, it is likely to play into the alarming rates of emerging antibiotic resistant bacteria. Even in the most advanced hospitals, high drug doses are given to infected patients without the knowledge that the host environment may render bacteria inherently resistant to the antibiotics prescribed to control them. These findings have two clinical outcomes: 1). When an antibiotic fails to clear an infection, rather than extending the current treatment or increasing the dose, a potentially more effective therapeutic option is prescription of another antibiotic. 2). Pharmaceutical chemical libraries may contain potent antibiotics to treat multidrug-resistant infections, but standard in vitro testing methods may have inadvertently excluded them. Thus, we have to revisit the way antibiotics are developed, tested and prescribed.
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 strains. The development of cross-protective vaccines against salmonellosis is a high priority for human and animal health due to the large number of pathogenic serotypes, the emergence of multi-drug resistant strains, the difficulties associated with preventing Salmonella contamination of food and water supplies, and the potential for the emergence of strain variants that exhibit enhanced pathogenicity in humans and/or animals. We have shown that modified live attenuated Salmonella that harbor loss of function mutations in the gene encoding the DNA adenine methylase (dam) are capable of eliciting protection against a diversity of salmonellae and are well tolerated when applied as modified live vaccines in mice, poultry, sheep and calves. Induction of immunity is rapid and the vaccine can be administered via drinking water for low-cost and low-stress immunization of livestock populations. These findings indicate that the development of livestock vaccines based on altered Dam levels is a viable approach for the prevention of human and animal disease from several zoonotic pathogens.
We plan to continue our investigation into the molecular mechanisms underlying microbial pathogenesis and the associated innate and adaptive immune responses that increase disease and compromise host immunity. This information can be translated into effective therapies against microbial infection such as the design of novel vaccine and therapeutic strategies that control the infecting pathogen or modulate host immune responses that disrupt the microbial lifestyle and/or suppress adverse clinical disease outcomes. We plan to continue our efforts to understand the mechanisms underlying host-dependent induction of antibiotic resistance with the applied goal of identifying drugs that can be useful in treating multidrug-resistant infections.
Ersoy, S. C., D. M. Heithoff, L. Barnes V, G. K. Tripp, J. K. House, J. D. Marth, J. W. Smith, and M. J. Mahan. (2017). Correcting a fundamental flaw in the paradigm for antimicrobial susceptibility testing. EbioMedicine. doi.org/10.1016/j.ebiom.2017.05.026.
Mahan, M. J., D. M. Heithoff, L. Barnes, 5th, R. L. Sinsheimer. (2017). Epigenetic programming by microbial pathogens and impacts on acute and chronic disease, p. 89-112. In: Epigenetics and infectious diseases. Series: Epigenetics and Human Health, W. Doerfler and J. Casadesús (eds.). Springer Intl, doi.10.1007/978-3-319-55021-3_5.
Kubicek-Sutherland, J. Z., D. M. Heithoff, S. C. Ersoy, W. R. Shimp, J. K. House, J. D. Marth, J. W. Smith, and M. J. Mahan. (2015). Host-dependent induction of transient antibiotic resistance: a prelude to treatment failure. EBioMedicine, 2:1169–1178. doi.org/10.1016/j.ebiom.2015.08.012.
Yang, W.H., P.V. Aziz, D. M. Heithoff, M. J. Mahan, J. W. Smith, and J. D. Marth. (2015). An intrinsic mechanism of secreted protein aging and turnover. Proc. Natl. Acad. Sci. USA. www.pnas.org/cgi/doi/10.1073/pnas.1515464112.
Heithoff, D. M., J. K. House, P. C. Thomson and M. J. Mahan. (2015). Development of a Salmonella cross-protective vaccine for food animal production systems. Vaccine 33:100–107.
Kubicek-Sutherland, J. Z., D. M. Heithoff, S. C. Ersoy, W. R. Shimp, and M. J. Mahan. (2014). Immunization with a DNA adenine methylase over-producing Y. pseudotuberculosis vaccine confers robust cross-protection against heterologous pathogenic serotypes. Vaccine 32:1451-1459.
Patterson, A. S., D. M. Heithoff, B. S. Ferguson, H. T. Soh, M. J. Mahan, and K. W. Plaxco. (2013). Microfluidic chip-based detection and intraspecies strain discrimination of Salmonella serovars derived from whole blood of septic mice. Appl. Environ. Microbiol., 79: 2302-2311.
Mahan, M. J., J. K. Kubicek-Sutherland, and D. M. Heithoff. (2013). Rise of the microbes. Virulence, 4: 213–222.
Heithoff, D. M., W. R. Shimp, J. K. House, Y. Xie, B. C. Weimer, R. L. Sinsheimer, and M. J. Mahan. (2012). Intraspecies variation in emergence of hyperinfectious bacterial strains in nature. PLoS Pathogens. 8(4): e1002647. doi:10.1371/journal.ppat.1002647
Mohler, V. L., D. M. Heithoff, M. J. Mahan, M.A. Hornitzky, P.C. Thomson, and J. K. House. (2012). Development of a novel in-water vaccination protocol for DNA adenine methylase deficient Salmonella enterica serovar Typhimurium vaccine in adult sheep. Vaccine 30:1481 1491.
Mahan, M. J., D. M. Heithoff, and J. K. House. (2012). Salmonella cross-protective vaccines: fast-forward to the next generation of food safety. Future Micobiol. 7(7):1-4.
Mohler, V. L., D. M. Heithoff, M. J. Mahan, K. H. Walker, M.A. Hornitzky, L. Gabor, A. Thompson, J. K. House. (2011). Protective immunity conferred by a DNA adenine methylase deficient Salmonella enterica serovar Typhimurium vaccine when delivered in-water to sheep challenged with Salmonella enterica serovar Typhimurium. Vaccine. 29:3571-3582.
Mahan, M. J., R. L. Sinsheimer, W. R. Shimp, and D. M. Heithoff. (2010). Covert operations: the adaptable plan of attack deployed by pathogenic bacteria. In: The lure of bacterial genetics: a tribute to John Roth, S. Maloy, K. T. Hughes, J. Casadesus, ed., Amer. Soc. Microbiol., Washington, D.C. pg. 185-200.
Heithoff D. M., E. Y. Enioutina, D. Bareyan, R. A. Daynes, and M. J. Mahan. (2008). Conditions that diminish myeloid-derived suppressor cell activities stimulate cross-protective immunity. Infect. Immun. 76:5191-5199.
Heithoff, D. M., W. R. Shimp, P. W. Lau, G. Badie, E. Y. Enioutina, R. A. Daynes, B. A. Byrne, J. K. House, and M. J. Mahan. (2008). Human Salmonella clinical isolates that are distinct from those of animal origin. Appl. Environ. Microbiol. 74:1757-1766.
Mohler, V. L., D. M. Heithoff, M. J. Mahan, K. H., Walker, L. W. C., Shum, K. J., Makin, J. K. House. (2008). Cross-protective immunity conferred by a DNA adenine methylase deficient Salmonella enterica serovar Typhimurium vaccine in calves challenged with Salmonella enterica serovar Newport. Vaccine 26:1751-1758.
Simon, R., D. M. Heithoff, M. J. Mahan, and C. E. Samuel. (2007). Tissue-selective proinflammatory gene induction in mice infected with wild type compared to DNA adenine methylase- or flagella- deficient mutant Salmonella. Infect. Immun. 75:5627-5639.
Badie, G., D. M. Heithoff, R. L. Sinsheimer, and M. J. Mahan. (2007). Altered levels of Salmonella DNA adenine methylase are associated with defects in gene expression, motility, flagellar synthesis, and bile resistance in pathogenic strain 14028, but not in laboratory strain, LT2. J. Bacteriol. 189:1556-1564.
Heithoff, D. M., G. Badie, S. M. Julio, E. Y. Enioutina, R. A. Daynes, R. L. Sinsheimer, M. J. Mahan. (2007). In vivo-selected mutations in methyl-directed mismatch repair suppress the virulence attenuation of Salmonella dam mutant strains following intraperitoneal, but not oral, infection of naÃ¯ve mice. J. Bacteriol. 189: 4708-4717.