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Joseph Heitman

Chair, Department of Molecular Genetics and Microbiology
Molecular Genetics and Microbiology
Duke Box 3546, Durham, NC 27710
322 Clin & Res Labs, Durham, NC 27710

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

Selected Grants


Tri-Institutional Molecular Mycology and Pathogenesis Training Program

Inst. Training Prgm or CMEPrincipal Investigator · Awarded by National Institutes of Health · 2024 - 2029

Calcineurin signaling cascades governing Cryptococcus virulence

ResearchPrincipal Investigator · Awarded by National Institute of Allergy and Infectious Diseases · 2023 - 2028

The Genetic Basis of Virulence in Cryptococcus Neoformans

ResearchCo-Principal Investigator · Awarded by National Institutes of Health · 2017 - 2028

Duke Preparing Research Scholars in Biomedical Sciences- Post-Baccalaureate Research Education Program

Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 2022 - 2027

Medical Scientist Training Program

Inst. Training Prgm or CMEPreceptor · Awarded by National Institute of General Medical Sciences · 2022 - 2027

Tri-Institutional Molecular Mycology and Pathogenesis Training Program

Inst. Training Prgm or CMEPrincipal Investigator · Awarded by National Institutes of Health · 2024 - 2029

Calcineurin signaling cascades governing Cryptococcus virulence

ResearchPrincipal Investigator · Awarded by National Institute of Allergy and Infectious Diseases · 2023 - 2028

The Genetic Basis of Virulence in Cryptococcus Neoformans

ResearchCo-Principal Investigator · Awarded by National Institutes of Health · 2017 - 2028

Duke Preparing Research Scholars in Biomedical Sciences- Post-Baccalaureate Research Education Program

Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 2022 - 2027

Medical Scientist Training Program

Inst. Training Prgm or CMEPreceptor · Awarded by National Institute of General Medical Sciences · 2022 - 2027

RNAi-dependent epimutation roles in antimicrobial drug resistance and pathogenesis

ResearchPrincipal Investigator · Awarded by National Institutes of Health · 2022 - 2027

Training Program in Developmental and Stem Cell Biology

Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 2001 - 2027

Cell and Molecular Biology Training Program

Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 2021 - 2026

Impact of RNAi and unisexual reproduction on Cryptococcus evolution, drug resistance, and pathogenesis

ResearchPrincipal Investigator · Awarded by National Institute of Allergy and Infectious Diseases · 1997 - 2026

Interdisciplinary Research Training Program in AIDS

Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 2010 - 2025

Genetic and Genomics Training Grant

Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 2020 - 2025

Therapeutic Agents Targeting Cryptococcal Infections

ResearchPrincipal Investigator · Awarded by Quercus Molecular Design · 2023 - 2025

Malassezia and Candida auris: skin microbiome dysbiosis and de-regulation of cutaneous homeostasis

ResearchPrincipal Investigator · Awarded by National Institute of Allergy and Infectious Diseases · 2023 - 2025

Unified Program for Therapeutics in Children

Inst. Training Prgm or CMEPreceptor · Awarded by National Institutes of Health · 2019 - 2024

Fungal Kingdom: Threats & Opportunities

ResearchPrincipal Investigator · Awarded by Canada Institute for Advanced Research · 2019 - 2024

Transplant Infectious Diseases Interdisciplinary Research Training Grant (TIDIRTG)

Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 2018 - 2023

Implications of mycoviral infection in Talaromyces marneffei: an analysis of human patient samples, RNAi, and hypermutation

ResearchPrincipal Investigator · Awarded by National Institutes of Health · 2021 - 2023

Structural Biological Development of Fungal-Specific Calcineurin Inhibitors

ResearchPrincipal Investigator · Awarded by National Institutes of Health · 2014 - 2022

Causes and Consequences of Hypermutability in Cryptococcus neoformans

FellowshipPrincipal Investigator · Awarded by National Institutes of Health · 2019 - 2022

Medical Scientist Training Program

Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 1997 - 2022

Structure-guided development of fungal specific calcineurin inhibitors

FellowshipPrincipal Investigator · Awarded by National Institutes of Health · 2020 - 2022

Mining the Coprophilous Mycobiome for new Cryptococcus Antiinfectives and Antifungal Synergists

ResearchCollaborator · Awarded by University of Iowa · 2017 - 2020

Genetics Training Grant

Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 1979 - 2020

Organization and Function of Cellular Structure

Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 1975 - 2020

Temperature-dependent transposon mobilization in Cryptococcus neoformans

ResearchConsultant · Awarded by National Institutes of Health · 2017 - 2020

Mechanism to evade host immunity by Mucorales fungi

ResearchCollaborator · Awarded by National Institutes of Health · 2018 - 2020

Thermo Lumos Tribrid High-Resolution Accurate-Mass Tandem Mass Spectrometer

EquipmentMajor User · Awarded by National Institutes of Health · 2018 - 2019

Structural Biological Development of Fungal-Specific Calcineurin Inhibitors

ResearchPrincipal Investigator · Awarded by National Institutes of Health · 2014 - 2019

Duke Research Training Program for Pediatricians

Inst. Training Prgm or CMETraining Faculty · Awarded by National Institutes of Health · 2002 - 2018

Center for Molecular & Cellular Studies of Ped Disease

Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 2003 - 2018

The Genetic Architecture of Virulence in Cryptococcus Neoformans

ResearchCo-Principal Investigator · Awarded by National Institutes of Health · 2017 - 2017

Institutional Training Grant in Pediatric Infectious Disease

Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 2011 - 2016

A Computer Modeling Approach to Create an Antifungal to Improve the Treatment of Cryptococcal Infections

ResearchPrincipal Investigator · Awarded by Amplyx Pharmaceuticals, Inc. · 2014 - 2016

Improvement of genetic analysis in the pathogenic zygomycete Mucor circinelloides

ResearchCo Investigator · Awarded by National Institutes of Health · 2016 - 2016

A Combination Therapy Approach to Treating Drug Resistant Fungal Infections

ResearchPrincipal Investigator · Awarded by Amplyx Pharmaceuticals, Inc. · 2014 - 2016

Cancer Biology Training Grant

Inst. Training Prgm or CMEMentor · Awarded by National Cancer Institute · 1993 - 2016

Clinical Oncology Research Career Development Program

ResearchMentor · Awarded by National Institutes of Health · 2009 - 2015

Instrumentation for Quantitative Phosphoproteomics and Acetylomics

EquipmentMajor User · Awarded by National Institutes of Health · 2014 - 2015

Novel Antifungal Therapeutic Approaches

ResearchPrincipal Investigator · Awarded by National Institutes of Health · 2001 - 2014

A Computer Modeling Approach to Create an Antifungal to Improve the Treatment of Cryptococcal Infections

ResearchPrincipal Investigator · Awarded by Amplyx Pharmaceuticals, Inc. · 2012 - 2014

A Structural Approach for Treating Drug Resistant Fungal Pathogens

ResearchPrincipal Investigator · Awarded by Amplyx Pharmaceuticals, Inc. · 2012 - 2014

Pulmonary Surfactant and Lung Homeostasis

ResearchCollaborator · Awarded by National Institutes of Health · 1993 - 2014

Sexual reproduction and virulence of zygomycete fungi

ResearchPrincipal Investigator · Awarded by National Institutes of Health · 2010 - 2013

Role of Calcineurin in Fungal Virulence

ResearchPrincipal Investigator · Awarded by National Institutes of Health · 2004 - 2010

Genetic analysis of Cryptococcus neoformans virulence

ResearchPrincipal Investigator · Awarded by National Institutes of Health · 2005 - 2010

GPCR signaling cascades in Cryptococcus neoformans

ResearchPrincipal Investigator · Awarded by National Institutes of Health · 2007 - 2009

Genetic molecular biology of virulence in C. neoformans

ResearchCo Investigator · Awarded by National Institutes of Health · 1991 - 2008

Same

ResearchPrincipal Investigator · Awarded by National Institutes of Health · 1998 - 2003

Same

ResearchPrincipal Investigator · Awarded by National Institutes of Health · 1997 - 2001

Novel Antifungal Drug Targets In Cryptococcus Neoformans

ResearchPrincipal Investigator · Awarded by National Institutes of Health · 1997 - 1999

Immunosuppressant Targets In Cryptococcus Neoformans

ResearchPrincipal Investigator · Awarded by National Institutes of Health · 1997 - 1999

External Relationships


  • CIFAR
  • Yonsei University Seoul Korea
  • stock owned in a variety of companies, about $300,000 total in about 60 different companies

This faculty member (or a member of their immediate family) has reported outside activities with the companies, institutions, or organizations listed above. This information is available to institutional leadership and, when appropriate, management plans are in place to address potential conflicts of interest.