The rockefeller university

Event Details

Type

Friday Lecture Series

Speaker(s)

Joseph Heitman, M.D., Ph.D., James B. Duke Distinguished Professor and Chair, department of molecular genetics and microbiology, Duke University School of Medicine

Speaker bio(s)

Microorganisms evolve via sexual/parasexual reproduction, mutators, aneuploidy, Hsp90, or prions. Mechanisms that are detrimental can be repurposed to generate diversity. Microbes are known to evolve resistance to antimicrobial agents (AMR) via pathways involving both stable and unstable genetic mechanisms, such as aneuploidy underlying azole resistance in Candida albicans and Cryptococcus neoformans. The Heitman lab discovered a new mechanism conferring antifungal drug resistance in the human fungal pathogen Mucor. Spontaneous resistance to the antifungal drug FK506 was found to evolve via two distinct mechanisms. One involves Mendelian mutations in the known drug targets (FKBP12, calcineurin A or B) conferring stable drug resistance. The second occurs via epigenetic processes involving RNAi or ectopic heterochromatin (with or without RNAi) resulting in unstable, transient drug resistance. In murine infection models both RNAi-dependent and heterochromatin epimutants were found to be largely stable throughout the course of infection. Recent studies reveal RNAi epimutations are inheritable following sexual reproduction and meiosis. These studies uncover a novel, reversible, transient epigenetic epimutation mechanism controlling phenotypic plasticity, with implications for antimicrobial drug resistance, in vivo mechanisms of pathogenesis, and RNAi-regulatory mechanisms in fungi and other eukaryotes. These studies reveal inheritable genetic information transmitted by RNA, which may reflect facets of an RNA world hypothesized to have existed during the origins of life, predating the evolution of DNA as the central conduit of inherited genetic information. The full impact of epimutations in this and other genetic systems and species may have eluded discovery previously given their inherently unstable nature.

Joseph Heitman, M,D., Ph.D. is James B. Duke Professor and Chair, Department of Molecular Genetics and Microbiology, Duke University. He serves as co-director with Leah Cowen for the CIFAR program Fungal Kingdom: Threats & Opportunities. His research studies model and pathogenic fungi addressing fundamental questions of scientific and medical importance. Pioneering studies with Baker’s yeast revealed how immunosuppressive natural products interdict signaling cascades via FKBP12-drug complexes (in collaboration with Mike Hall and Rao Movva), and discovered TOR as a globally conserved nutrient sensor targeted by the immunosuppressive/antiproliferative drug rapamycin. His research discovered unisexual reproduction of pathogenic microbes, with implications for pathogen emergence, how sex generates diversity, and how sex evolved. Dr. Heitman’s lab has further developed genetic/genomic approaches elucidating molecular principles of fungal virulence, identifying therapeutic targets, and illustrating convergent evolution of fungal mating-type loci with mammalian, insect, and plant sex chromosomes. His studies have defined the calcium activated protein phosphatase calcineurin as a globally conserved fungal virulence factor and are harnessing structural biology to develop fungal specific inhibitors as novel therapeutic leads. They have elucidated functions of RNAi in microbial pathogen genome integrity, RNAi loss in hypervirulent outbreak lineages, and novel RNAi roles evoking drug resistance via epimutations silencing genes. His research program has championed fungal genomics, advanced the field, and mentored numerous students and fellows to impactful independent careers in medicine and science.  

Dr. Heitman was a Burroughs-Wellcome Scholar and HHMI investigator, received the Gustavo Cudkowicz Prize, AMGEN award (ASBMB), Squibb award (IDSA), NIH MERIT award (2011-2021), Korsmeyer Award (ASCI), the Rhoda Benham Award (MMSA), the Edward Novitski Prize (GSA), the ASM Basic Science Award, the Distinguished Mycologist Award (MSA), and the Lucille Georg Medal (ISHAM). He is an elected fellow or member of the American Academy of Microbiology, the American Society for Clinical Investigation, the Association of American Physicians, the American Association for the Advancement of Science, the American Academy of Arts and Sciences, the National Academy of Sciences, the German National Academy of Sciences – Leopoldina, and the National Academy of Medicine. He is an editor for PLOS Genetics, PLOS Pathogens, and Fungal Genetics & Biology, an editorial board member for PLOS Biology, Current Biology, and Cell Host & Microbe, and has edited 7 textbooks. He received B.S./M.S. degrees from the University of Chicago, M.D./Ph.D. degrees from Cornell and Rockefeller Universities (graduate studies with Peter Model and Norton Zinder at Rockefeller), and was an EMBO long-term fellow at the Biocenter in Basel, Switzerland.

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