Joseph Heitman
Chair, Department of Molecular Genetics and Microbiology

Joseph Heitman was an undergraduate at the University of Chicago (1980-1984), graduating from the BS-MS program with dual degrees in chemistry and biochemistry with general and special honors. He then matriculated as an MD-PhD student at Cornell and Rockefeller Universities and worked with Peter Model and Norton Zinder on how restriction enzymes recognize specific DNA sequences and how bacteria respond to and repair DNA breaks and nicks. Dr. Heitman moved as an EMBO long-term fellow to the Biocenter in Basel Switzerland where, in studies with Mike Hall and Rao Movva, pioneered the use of yeast as a model for studies of immunosuppressive drug action. Their studies elucidated the central role of FKBP12 in forming complexes with FK506 and rapamycin that inhibit cell signaling and growth, discovered Tor1 and Tor2 as the targets of rapamycin, and contributed to the appreciation that immunosuppressive drugs inhibit signal transduction cascades that are conserved from yeasts to humans.

Dr. Heitman moved to Duke University in 1992, and is a member of the Department of Molecular Genetics and Microbiology where his studies focus on microorganisms addressing fundamental biological questions and unmet medical needs.  Dr. Heitman and colleagues focus on model and pathogenic yeasts including Cryptococcus neoformans and other diverse species from the fungal kingdom. Their studies with fungi as genetic models have revealed biological and genetic principles that can be generalized as models for eukaryotic cell and organism function. These include discovering FKBP12 and Tor1/2 as the targets of the immunosuppressive anti-proliferative natural product rapamycin, elucidating central roles of the calcium activated phosphatase calcineurin governing fungal virulence and morphogenesis and antifungal drug action, deciphering how cells sense and respond to nutrients via permeases, G protein coupled receptors, and the Tor signaling cascade, and illustrating how both model and pathogenic fungi sense both the environment and the infected host. In parallel, their studies address the evolution, structure, and function of fungal mating type loci as models for gene cluster and sex chromosome evolution.  The discovery of an ancestral sex determining locus in the basal fungal lineages involving two HMG domain proteins, SexM and SexP, homologous to the mammalian Sry sex determinant provides insights into both the origins of sex specification and its plasticity throughout the radiation of the fungal and metazoan kingdoms from their last shared common ancestor.  Their discovery of unisexual mating in fungi and subsequent analysis of its impact on the evolution of eukaryotic microbial pathogens provides insights into both microbial evolution and pathogenesis and how sexual reproduction may have first evolved.  Recent studies have unveiled novel mechanisms of antimicrobial drug resistance involving epimutations that silence drug-target genes via RNAi, functions of RNAi in genomic integrity of microbial pathogens, and loss of RNAi in hypervirulent outbreak lineages.

Dr. Heitman is a recipient of the Burroughs Wellcome Scholar Award in Molecular Pathogenic Mycology (1998-2005), the 2002 ASBMB AMGEN award for significant contributions using molecular biology to our understanding of human disease, and the 2003 Squibb Award from the Infectious Diseases Society of America (IDSA) for outstanding contributions to infectious disease research, the 2018 Korsmeyer Award from the American Society for Clinical Investigation, and the 2018 Rhoda Benham Award from the Medical Mycological Society of the Americas.  He is the recipient of an NIH/NIAID MERIT award 2011-2021 in support of studies on fungal unisexual reproduction in microbial pathogen evolution, a Duke University translational research mentoring award in 2012, and a Dean’s Award for Excellence in Mentoring from the Duke Graduate School in 2018.  He has served as an instructor in residence since 1998 for the Molecular Mycology Course at the Marine Biological Laboratory at Woods Hole, MA. Dr. Heitman is an editor for the journals PLOS Genetics, Genetics (2012-2017), PLOS Pathogens (Pearls review editor), Current Genetics (2001-2014), mBio, and Fungal Genetics and Biology; a member of the editorial boards of PLOS Biology, Current Biology, Cell Host and Microbe, and PeerJ; former editor for PLOS Pathogens (mycology section editor, 2008-2011) and Eukaryotic Cell (2002-2012); an advisory board member for the Fungal Genome Initiative at the Broad Institute, the Fungal Kingdom Genome Project at the Department of Energy Joint Genome Institute, the NIAID Genomic Sequencing Centers for Infectious Diseases, and for the Integrated Microbial Biodiversity Program at the Canadian Institute for Advanced Research (CIFAR); co-chair for the Duke Chancellor’s Science Advisory Council (2009-2010); and co-chair/chair for the FASEB summer conference on Microbial Pathogenesis: Mechanisms of Infectious Disease (2011, 2013).  He was elected a member of the American Society for Clinical Investigation (ASCI) in 2003, a fellow of the Infectious Diseases Society of America (IDSA) in 2003, a fellow of the American Academy of Microbiology in 2004, a fellow of the American Association for the Advancement of Science (AAAS) in 2004, a member of the Association of American Physicians (AAP) in 2006, and a member of the American Academy of Arts & Sciences in 2020.  Dr. Heitman was an investigator with the Howard Hughes Medical Institute from 1992 to 2005. Dr. Heitman served as the director for the Duke University Program in Genetics and Genomics (UPGG) from 2002-2009 (including writing two funded competitive renewals for the T32 NIH training grant and establishing the annual program retreat). He was the founding director for the Center for Microbial Pathogenesis (now called the Center for Host-Microbial Interactions, CHoMI) and served in this capacity January 2002-October 2014.  He is currently the director of the Tri-institutional (Duke, UNC-CH, NC State) Molecular Mycology and Pathogenesis Training Program (MMPTP) (since July 1, 2012), and Chair of the Department of Molecular Genetics and Microbiology (since September 1, 2009).

Current Research Interests

Sexual reproduction and the emergence and evolution of microbial pathogens

Our studies focus on the human fungal pathogen Cryptococcus, which causes life-threatening infections of the central nervous system in both immunocompromised and immunocompetent hosts. This organism is a basidiomycete and therefore divergent from other common human fungal pathogens and model fungi. We contributed to define the sexual cycle involving haploid alpha anda cells, and to apply Falkow’s molecular postulates of virulence employing gene disruption approaches and robust animal virulence models. These efforts have defined the molecular basis for antifungal drug action and synergistic combinations and elucidated roles for calcineurin in fungal virulence and drug tolerance in C. neoformans, Candida albicans, and Aspergillus fumigatus. We are currently exploring the potential of combining calcineurin or Hsp90 inhibitors with existing antifungal agents against a panel of pathogenic fungi in infectious settings including systemic, ocular, and cutaneous models. We have participated in championing and organizing the fungal kingdom genome sequencing project. These efforts are nearly completed for five strains representing three related but divergent varieties of Cryptococcus, all of which are pathogenic in humans and have unique environmental and virulence attributes. In addition, we contributed to enlist the Broad Fungal Genome initiative to sequence a group of Candida species related to Candida albicans to explore their potential for sexual reproduction, including meiosis, and detailed molecular and genetic studies are in progress for the species Candida lusitaniaeon the functions of the mating type locus and conserved meiotic machinery. Finally, the fungal genome initiative of the Department of Energy Joint Genome Institute is currently sequencing the basidiomycete Tremella mesenterica, and Keisha Findley in our group serves as the community coordinator for this genome project.

Parallel studies have focused on the structure, function, and evolution of the fungal mating type locus, which is linked to differentiation and virulence potential in Cryptococcus. Signaling cascades that control virulence and mating have been defined, and the a and alpha alleles of the mating type locus have been cloned and sequenced from two varieties and the sibling species C. gattii. The MAT locus spans over 100 kb and contains more than 20 genes, several of which function in differentiation and virulence. The MAT alleles are composed of divergent sets of the same genes that evolved by extensive remodeling from a common ancestral DNA region. The only MAT allele specific genes encode two homeodomain proteins, Sxi1alpha and Sxi2a, which physically interact and are necessary and sufficient to govern post-fusion events enabling completion of the sexual cycle. A detailed model has been developed for the evolution of MAT from an ancestral tetrapolar mating system, revealing parallels with the evolution and features of sex chromosomes of plants and animals. We have contributed to define the structure of the mating type locus from the human dimorphic fungal pathogens, Histoplasma capsulatum, Coccidioides immitis and C. posadasii, revealing that all three retain both mating types, consistent with extant sexual cycles that remain to be explored. These studies also reveal how genes have been captured into the MAT locus, with implications for expansions of MAT that have occurred in other pathogenic fungi, including C. albicans and C. neoformans and C. gattii. Finally, we have defined the structure of the mating type locus in Phycomyces blakesleeanus, the first representative of the Zygomycete phylum in which MAT has been identified. This reveals that the sexM andsexP loci each contain only a single gene, and each encodes a divergent HMG domain transcription factor homolog, with implications for the origins of sex determination and the evolution of sex chromosomes.

We have defined the sexual cycles for the most common pathogenic variety of Cryptococcus (serotype A, variety grubii), recapitulated the sexual cycle for the divergent gattii variety that infects immunocompetent hosts with implications for an unusually fertile clonal alpha isolate causing an outbreak on Vancouver Island, and contributed to the discovery of a unique population of serotype A strains undergoing active recombination in sub-Saharan Africa. Recent studies have demonstrated that sexual reproduction occurs on Pigeon guano medium, and during a pathogenic association with plants, two common environmental niches in which Cryptococcus may complete its sexual cycle in nature to produce infectious spores. Our studies reveal an enhanced virulence potential of alpha strains during co-infection with a strains, and the molecular basis for this enhanced virulence is being explored involving pheromone production and sensing via cell-cell signaling analogous to quorum sensing in bacteria and other fungi. This model is being examined in detail in both murine virulence models and in heterologous hosts, including insects. Our investigations have revealed that monokaryotic fruiting represents a modified form of the sexual cycle that can occur between partners of only one mating type, and which involves a ploidy shift, meiosis, and production of recombinant haploid progeny that may represent the infectious propagules. Recent population genetic studies implicate this laboratory defined same sex mating cycle in the origin and ongoing outbreak of Cryptococcus gattii on Vancouver Island. In collaboration with Kieren Marr, we have identified the first index case for expansion of the Vancouver Island outbreak into the United States, and further studies of environmental, veterinary, and human isolates are ongoing. Our studies of unusual hybrid isolates of Cryptococcus neoformans(alphaADalpha) demonstrate that same sex mating occurs in nature and has given rise to hybrids which exhibit hybrid fitness and are pathogenic. Analysis of a different hybrid lineage (aADalpha) provides evidence that these isolates descend from a mating event in sub-Saharan Africa that gave rise to a hybrid that emigrated worldwide and is a common cause of infection. Taken together, these complementary lines of investigation illustrate the potential roles of sexual recombination in the evolution and virulence of a species cluster of human fungal pathogens with implications for other eukaryotic microbial pathogens, including fungi, parasites, and bacterial pathogens.

E Pluribus Unum: The Fungal Kingdom as a Rosetta Stone for Biology and Medicine.

How Model and Pathogenic Fungi Sense the Environment and the Host

Sex and the evolution of microbial pathogens

Sex and emerging pathogens- Vancouver Island Cryptococcus gattii outbreak expands

Evolution of Gene Clusters: The Mating Type Locus Paradigm

Antifungal Drug Action and the Elucidation of Drug Targets in Fungi

Read an article presenting Dr. Heitman’s reflections on the MD-PhD program and the importance of discovery and serendipity in science. Read more (Originally published: Beyond the Bench, The Rockefeller University, February 1993)

On the discovery of TOR as the Target of Rapamycin, Science Matters Series, PLOS Pathogens, Joseph Heitman

Weill Cornell Medicine Magazine on the Lasker Prize for the Discovery of TOR as the Target of Rapamycin by Joseph Heitman, Rao Movva, and Michael Hall

JCI Insight interview with Joe Heitman and Rao Movva on the Discovery of TOR as the Target of Rapamycin

JCI interview with Joe Heitman on research, mentoring, and receipt of the 2018 Korsmeyer Award from the ASCI

Medical Mycological Society of the Americas (MMSA) Rhoda Benham award talk 2018

Medical Mycological Society of the Americas (MMSA) banquet Rhoda Benham Dinner Talk – June 9, 2018

Current Appointments & Affiliations

Contact Information

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