Joseph Heitman

Overview:



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 GeneticsGenetics (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 BiologyCurrent BiologyCell 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).

Positions:

Chair, Department of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

James B. Duke Distinguished Professor of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Professor of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Professor in Medicine

Medicine, Infectious Diseases
School of Medicine

Professor in Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Education:

Ph.D. 1989

Rockefeller University

M.D. 1992

Cornell University

Grants:

Causes and Consequences of Hypermutability in Cryptococcus neoformans

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

The Genetic Basis of Virulence in Cryptococcus Neoformans

Administered By
Biology
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

The Genetic Basis of Virulence in Cryptococcus Neoformans

Administered By
Biology
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Genetics of Cryptococcus sexual reproduction

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Discovering novel antifungal agents via multi-species profiling of a structurally and stereochemically diverse, well-validated compound library

Administered By
Molecular Genetics and Microbiology
Role
Principal Investigator
Start Date
End Date

Publications:

Uncontrolled transposition following RNAi loss causes hypermutation and antifungal drug resistance in clinical isolates of Cryptococcus neoformans.

Cryptococcus neoformans infections cause approximately 15% of AIDS-related deaths owing to a combination of limited antifungal therapies and drug resistance. A collection of clinical and environmental C. neoformans isolates were assayed for increased mutation rates via fluctuation analysis, and we identified two hypermutator C. neoformans clinical isolates with increased mutation rates when exposed to the combination of rapamycin and FK506. Sequencing of drug target genes found that Cnl1 transposon insertions conferred the majority of resistance to rapamycin and FK506 and could also independently cause resistance to 5-fluoroorotic acid and the clinically relevant antifungal 5-flucytosine. Whole-genome sequencing revealed both hypermutator genomes harbour a nonsense mutation in the RNA-interference component ZNF3 and hundreds of Cnl1 elements organized into massive subtelomeric arrays on each of the fourteen chromosomes. Quantitative trait locus mapping in 28 progeny derived from a cross between a hypermutator and wild-type identified a locus associated with hypermutation that included znf3. CRISPR editing of the znf3 nonsense mutation abolished hypermutation and restored small-interfering-RNA production. We conclude that hypermutation and drug resistance in these clinical isolates result from RNA-interference loss and accumulation of Cnl1 elements.
Authors
Priest, SJ; Yadav, V; Roth, C; Dahlmann, TA; Kück, U; Magwene, PM; Heitman, J
MLA Citation
Priest, Shelby J., et al. “Uncontrolled transposition following RNAi loss causes hypermutation and antifungal drug resistance in clinical isolates of Cryptococcus neoformans.Nat Microbiol, vol. 7, no. 8, Aug. 2022, pp. 1239–51. Pubmed, doi:10.1038/s41564-022-01183-z.
URI
https://scholars.duke.edu/individual/pub1531626
PMID
35918426
Source
pubmed
Published In
Nature Microbiology
Volume
7
Published Date
Start Page
1239
End Page
1251
DOI
10.1038/s41564-022-01183-z

Infection and inflammation: New perspectives on Alzheimer's disease

Neuroinflammation has been recognized as a component of Alzheimer's Disease (AD) pathology since the original descriptions by Alois Alzheimer and a role for infections in AD pathogenesis has long been hypothesized. More recently, this hypothesis has gained strength as human genetics and experimental data suggest key roles for inflammatory cells in AD pathogenesis. To review this topic, Duke/University of North Carolina (Duke/UNC) Alzheimer's Disease Research Center hosted a virtual symposium: “Infection and Inflammation: New Perspectives on Alzheimer's Disease (AD).” Participants considered current evidence for and against the hypothesis that AD could be caused or exacerbated by infection or commensal microbes. Discussion focused on connecting microglial transcriptional states to functional states, mouse models that better mimic human immunity, the potential involvement of inflammasome signaling, metabolic alterations, self-reactive T cells, gut microbes and fungal infections, and lessons learned from Covid-19 patients with neurologic symptoms. The content presented in the symposium, and major topics raised in discussions are reviewed in this summary of the proceedings.
Authors
Whitson, HE; Colton, C; El Khoury, J; Gate, D; Goate, A; Heneka, MT; Kaddurah-Daouk, R; Klein, RS; Shinohara, ML; Sisodia, S; Spudich, SS; Stevens, B; Tanzi, R; Ting, JP; Garden, G; Aiello, A; Chiba-Falek, O; Heitman, J; Johnson, KG; Luftig, M; Moseman, A; Rawls, J; Swanstrom, R; Terrando, N
MLA Citation
Whitson, H. E., et al. “Infection and inflammation: New perspectives on Alzheimer's disease.” Brain, Behavior, and Immunity  Health, vol. 22, July 2022. Scopus, doi:10.1016/j.bbih.2022.100462.
URI
https://scholars.duke.edu/individual/pub1517953
Source
scopus
Published In
Brain, Behavior, & Immunity Health
Volume
22
Published Date
DOI
10.1016/j.bbih.2022.100462

On Fruits and Fungi: A Risk of Antifungal Usage in Food Storage and Distribution in Driving Drug Resistance in Candida auris.

The continuous emergence of antifungal drug resistance is a mounting concern for the treatment of fungal infections worldwide. While many pathogenic fungi exhibit some level of antifungal drug resistance, the identification of Candida auris has brought this phenomenon to the fore in recent years. C. auris exhibits resistance to all antifungal drugs used for treatment, and it does so at a very high rate, with more than 90% of isolates being resistant to at least one drug and roughly 4% being panresistant. However, the environmental factors driving this exceptionally high antifungal drug resistance remain unidentified. The presence of C. auris on stored apples that are treated with antifungals during storage suggests a possible route to selection of drug-resistant C. auris isolates that may have contributed to the evolution of this deadly pathogen. This study further suggests that the adage "an apple a day keeps the doctor away" may need to be revisited in light of the discovery of C. auris on the surface of apples.
Authors
Yadav, V; Heitman, J
MLA Citation
Yadav, Vikas, and Joseph Heitman. “On Fruits and Fungi: A Risk of Antifungal Usage in Food Storage and Distribution in Driving Drug Resistance in Candida auris.Mbio, vol. 13, no. 3, June 2022, p. e0073922. Pubmed, doi:10.1128/mbio.00739-22.
URI
https://scholars.duke.edu/individual/pub1521319
PMID
35575501
Source
pubmed
Published In
Mbio
Volume
13
Published Date
Start Page
e0073922
DOI
10.1128/mbio.00739-22

Structure-Guided Synthesis of FK506 and FK520 Analogs with Increased Selectivity Exhibit In Vivo Therapeutic Efficacy against Cryptococcus.

Calcineurin is an essential virulence factor that is conserved across human fungal pathogens, including Cryptococcus neoformans, Aspergillus fumigatus, and Candida albicans. Although an excellent target for antifungal drug development, the serine-threonine phosphatase activity of calcineurin is conserved in mammals, and inhibition of this activity results in immunosuppression. FK506 (tacrolimus) is a naturally produced macrocyclic compound that inhibits calcineurin by binding to the immunophilin FKBP12. Previously, our fungal calcineurin-FK506-FKBP12 structure-based approaches identified a nonconserved region of FKBP12 that can be exploited for fungus-specific targeting. These studies led to the design of an FK506 analog, APX879, modified at the C-22 position, which was less immunosuppressive yet maintained antifungal activity. We now report high-resolution protein crystal structures of fungal FKBP12 and a human truncated calcineurin-FKBP12 bound to a natural FK506 analog, FK520 (ascomycin). Based on information from these structures and the success of APX879, we synthesized and screened a novel panel of C-22-modified compounds derived from both FK506 and FK520. One compound, JH-FK-05, demonstrates broad-spectrum antifungal activity in vitro and is nonimmunosuppressive in vivo. In murine models of pulmonary and disseminated C. neoformans infection, JH-FK-05 treatment significantly reduced fungal burden and extended animal survival alone and in combination with fluconazole. Furthermore, molecular dynamic simulations performed with JH-FK-05 binding to fungal and human FKBP12 identified additional residues outside the C-22 and C-21 positions that could be modified to generate novel FK506 analogs with improved antifungal activity. IMPORTANCE Due to rising rates of antifungal drug resistance and a limited armamentarium of antifungal treatments, there is a paramount need for novel antifungal drugs to treat systemic fungal infections. Calcineurin has been established as an essential and conserved virulence factor in several fungi, making it an attractive antifungal target. However, due to the immunosuppressive action of calcineurin inhibitors, they have not been successfully utilized clinically for antifungal treatment in humans. Recent availability of crystal structures of fungal calcineurin-bound inhibitor complexes has enabled the structure-guided design of FK506 analogs and led to a breakthrough in the development of a compound with increased fungal specificity. The development of a calcineurin inhibitor with reduced immunosuppressive activity and maintained therapeutic antifungal activity would add a significant tool to the treatment options for these invasive fungal infections with exceedingly high rates of mortality.
Authors
Hoy, MJ; Park, E; Lee, H; Lim, WY; Cole, DC; DeBouver, ND; Bobay, BG; Pierce, PG; Fox, D; Ciofani, M; Juvvadi, PR; Steinbach, W; Hong, J; Heitman, J
MLA Citation
Hoy, Michael J., et al. “Structure-Guided Synthesis of FK506 and FK520 Analogs with Increased Selectivity Exhibit In Vivo Therapeutic Efficacy against Cryptococcus.Mbio, vol. 13, no. 3, June 2022, p. e0104922. Pubmed, doi:10.1128/mbio.01049-22.
URI
https://scholars.duke.edu/individual/pub1521547
PMID
35604094
Source
pubmed
Published In
Mbio
Volume
13
Published Date
Start Page
e0104922
DOI
10.1128/mbio.01049-22

Obligate sexual reproduction of a homothallic fungus closely related to the Cryptococcus pathogenic species complex.

<title>eLife digest</title>. Fungi are enigmatic organisms that flourish in soil, on decaying plants, or during infection of animals or plants. Growing in myriad forms, from single-celled yeast to multicellular molds and mushrooms, fungi have also evolved a variety of strategies to reproduce. Normally, fungi reproduce in one of two ways: either they reproduce asexually, with one individual producing a new individual identical to itself, or they reproduce sexually, with two individuals of different 'mating types' contributing to produce a new individual. However, individuals of some species exhibit 'homothallism' or self-fertility: these individuals can produce reproductive cells that are universally compatible, and therefore can reproduce sexually with themselves or with any other cell in the population. Homothallism has evolved multiple times throughout the fungal kingdom, suggesting it confers advantage when population numbers are low or mates are hard to find. Yet some homothallic fungi been overlooked compared to heterothallic species, whose mating types have been well characterised. Understanding the genetic basis of homothallism and how it evolved in different species can provide insights into pathogenic species that cause fungal disease. With that in mind, Passer, Clancey et al. explored the genetic basis of homothallism in Cryptococcus depauperatus, a close relative of C. neoformans, a species that causes fungal infections in humans. A combination of genetic sequencing techniques and experiments were applied to analyse, compare, and manipulate C. depauperatus' genome to see how this species evolved self-fertility. Passer, Clancey et al. showed that C. depauperatus evolved the ability to reproduce sexually by itself via a unique evolutionary pathway. The result is a form of homothallism never reported in fungi before. C. depauperatus lost some of the genes that control mating in other species of fungi, and acquired genes from the opposing mating types of a heterothallic ancestor to become self-fertile. Passer, Clancey et al. also found that, unlike other Cryptococcus species that switch between asexual and sexual reproduction, C. depauperatus grows only as long, branching filaments called hyphae, a sexual form. The species reproduces sexually with itself throughout its life cycle and is unable to produce a yeast (asexual) form, in contrast to other closely related species. This work offers new insights into how different modes of sexual reproduction have evolved in fungi. It also provides another interesting case of how genome plasticity and evolutionary pressures can produce similar outcomes, homothallism, via different evolutionary paths. Lastly, assembling the complete genome of C. depauperatus will foster comparative studies between pathogenic and non-pathogenic Cryptococcus species.
Authors
Passer, AR; Clancey, SA; Shea, T; David-Palma, M; Averette, AF; Boekhout, T; Porcel, BM; Nowrousian, M; Cuomo, CA; Sun, S; Heitman, J; Coelho, MA
MLA Citation
Passer, Andrew Ryan, et al. “Obligate sexual reproduction of a homothallic fungus closely related to the Cryptococcus pathogenic species complex.Elife, vol. 11, June 2022. Pubmed, doi:10.7554/eLife.79114.
URI
https://scholars.duke.edu/individual/pub1525031
PMID
35713948
Source
pubmed
Published In
Elife
Volume
11
Published Date
DOI
10.7554/eLife.79114