Joseph Hetigman, MD, PhD
Principal Investigator
Joseph Heitman
Chair, Department of Molecular Genetics and Microbiology
James B. Duke Distinguished Professor of Molecular Genetics and Microbiology
Professor of Molecular Genetics and Microbiology
Professor of Cell Biology
Member of the Duke Cancer Institute
Professor in Medicine
Professor in Pharmacology & Cancer Biology
Contact Information

Box 3546 DUMC
Durham, N.C. 27710
Phone: (919) 684-2824
Fax: (919) 684-2790
Email: heitm001@duke.edu

Twitter

Location
322 CARL Building

Research

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) Rhoda Benham award talk 2018

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

Biography

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).

Lab Members

Konstantina Akritidou

Konstantina Akritidou

Student
Anna Floyd-Averette

Anna Floyd-Averette

Lab Research Analyst II
Zhuyun Bian

Zhuyun Bian

Postdoctoral Associate
"_"

Emma Cao

Undergraduate Researcher
Yeseul Choi

Yeseul Choi

Postdoctoral Associate
"_"

Jackson Cooke

Undergraduate Researcher
"_"

Sarah Croog

Undergraduate Researcher
Marcia David Palma

Marcia David Palma

Research Associate, Senior
Marco Coelho

Marco Antonio Dias Coelho

Assistant Research Professor
Sreethan Gajula

Sreethan Gajula

Nonduke Student/Intern
Jun Huang

Jun Huang

Postdoctoral Associate
Connor Larmore

Connor Larmore

Graduate Student
Anna Lehmann

Anna Lehmann

Graduate Student
Maria Isabel Navarro Mendoza

Maria Isabel Navarro Mendoza

Postdoctoral Associate
"_"

Melissa Palmer

Administrative Coordinator
Kirtan Patel

Kirtan Patel

Nonduke Student/Intern
Anushka Peer

Anushka Peer

Student
Carlos Perez Arques

Carlos Perez Arques

Postdoctoral Associate
" "

Patricia Peterson, PhD

Postdoctoral Associate
Moayad Shehadeh

Moayad Shehadeh

Undergraduate Researcher
Yeeun Son

Yeeun Son

Postdoctoral Associate
Sheng Sun

Sheng Sun

Associate Research Professor in Molecular Genetics and Microbiology
Gabby Walker

Gabby Walker

Student
Liping Xiong

Liping Xiong

Postdoctoral Associate
Ziyan Xu

Ziyan Xu

Research Technician II
Vikas Yadav

Vikas Yadav

Research Associate, Senior

Alumni

Featured Alumni:

Post-doctoral Fellows and Senior Research Associates:

Graduate Students:

Rotating Graduate Students:

Sabbatical Visitors:

Visiting Graduate Students and Scholars

Himeshi Samarasinghe – Xu Lab – McMaster University
Emmanuel Nnandi
Vikas Yadav – JNCASR, Bangalore India
Goh Pei Zhen Joleen – Agency for Science, Technology and Research (A*STAR), Singapore
Kyung-Tae Lee – Yonsei University, South Korea
Megan Truong – The University of Sydney, Australia
Jae-Hyung Jin – Yonsei University, South Korea
Carlos Perez Arques – University of Spain
Maribel Navarro – University of Spain 
Jin Young Kim – Yonsei University
Cecilia Miccoli –  Università degli Studi del Molise
Yeseul Choi - Yonsei University
Yujin Lee - Yonsei University
Xuefei Chen - McMaster University

 

 

Laboratory Research Analysts:

  • Cristl Arndt
  • Sheri Frank
  • Marie Josee-Boily
  • Zareen Kapadia
  • Shelly Clancey

Technicians:

Medical Students:

Undergraduate Students:

High School Interns:

  • Maggie Price

Publications

Selected Publications

Google Scholar Profile

Heitman, J. and Model, P. Site-specific methylases induce the SOS DNA repair response in Escherichia coli. J. of Bacteriology, 169: 3243-3250, 1987.

Heitman, J., Zinder, N.D. and Model, P. Repair of the Escherichia coli chromosome after in vivo scission by the EcoRI endonuclease. Proc. Natl. Acad. Sci. USA, 86: 2281-2285, 1989.

Heitman, J. and Model, P. Substrate recognition by the EcoRI endonuclease. Proteins: Struc, Func. and Genetics, 7: 185-197, 1990.

Heitman, J. and Model, P. Mutants of the EcoRI endonuclease with promiscuous substrate specificity implicate residues involved in substrate recognition. EMBO J., 9: 3369-3378, 1990.

Heitman, J., Movva, N.R., Hiestand, P.C., and Hall, M.N. FKBP proline rotamase is a target for the immunosuppressive agent FK506 in Saccharomyces cerevisiae, PNAS, 88:1948-1952, 1991.

Heitman, J., Movva, N.R., and Hall, M.N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast, Science, 253:905-909, 1991.

Breuder, T., Hemenway, C., Movva, N.R., Cardenas, M.E., and Heitman, J. Calcineurin is essential in cyclosporin A- and FK506-sensitive yeast strains. PNAS, 91: 5372-5376, 1994.

Cardenas, M.E., Hemenway, C., Muir, R.S., Ye, R.R., Fiorentino, D.F. and J. Heitman. Immunophilins interact with calcineurin in the absence of exogenous immunosuppressive ligands. EMBO J., 13:5 944-957, 1994.

Cardenas, M.E., Muir, R.S., Breuder, T., and Heitman, J. Targets of immunophilin-immunosuppressant complexes are distinct highly conserved regions of calcineurin A. EMBO J., 14: 2772-2783, 1995.

Cardenas, M.E., and Heitman, J. FKBP12-rapamycin target TOR2 is a vacuolar protein with an associated phosphatidylinositol-4 kinase activity. EMBO J., 14: 5892-5907, 1995.

Alarcon, C.M., Cardenas, M.E., and Heitman, J. Mammalian RAFT1 kinase domain provides rapamycin-sensitive TOR function in yeast. Genes & Development 10: 279-288, 1996.

Odom*, A., Muir*,R.S., Lim*, E., Tofalletti, D., Perfect, J., and Heitman, J. Calcineurin is required for virulence of Cryptococcus neoformans. EMBO J.,16: 2576-2589, 1997.

Dolinski, K., Muir, S., Cardenas, M.E., and Heitman, J. All cyclophilins and FKBPs are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae. PNAS, 94: 13093-13098, 1997.

Lorenz, M.C., and Heitman, J. Yeast pseudohyphal growth is regulated by GPA2, a G protein α homolog. EMBO J., 16: 7008-7018, 1997.

Alspaugh, J.A., Perfect, J.R., and Heitman, J. Cryptococcus neoformans mating and virulence are regulated by the G-protein α subunit GPA1 and cAMP. Genes & Development, 11:3206-3217, 1997.

Lorenz, M.C., and Heitman, J. The MEP2 ammonium permease regulates pseudohyphal differentiation in Saccharomyces cerevisiae. EMBO J., 17:1236-1247, 1998.

Dolinski, K.J, Cardenas, M.E., and Heitman, J. CNS1 encodes an essential p60/Sti1 homolog in Saccharomyces cerevisiae that suppresses cyclophilin 40 mutations and interacts with Hsp90, Mol. Cell. Biol., 18:7344-7352, 1998.

Cruz, M.C., Cavallo, L.M., Görlach, J.M., Cox, G., Perfect, J.R., Cardenas, M.E., and Heitman, J. Rapamycin antifungal action is mediated via conserved complexes with FKBP12 and TOR kinase homologs in Cryptococcus neoformans. Mol. Cell. Biol., 19:4101-4112, 1999.

Pan, X. and Heitman, J. Cyclic AMP dependent protein kinase regulates pseudohyphal differentiation in Saccharomyces cerevisiae. Mol. Cell. Biol., 19:4874-4887, 1999.

Cardenas, M.E., Cruz, M.C., Del Poeta, M., Chung, N., Perfect, J.R., and Heitman, J. Antifungal activities of antineoplastic agents: yeast as a model system to study drug action. Clin. Micro. Rev., 12:583-611, 1999.

Yue, C., Cavallo, L.M., Alspaugh, J.A., Wang, P., Cox, G.M., Perfect, J.R., and Heitman, J. The STE12α homolog is required for haploid filamentation but largely dispensable for mating and virulence in Cryptococcus neoformans. Genetics, 153:1601-1615, 1999.

Cardenas, M.E., Cutler, N.S., Lorenz, M.C., Di Como, C.J., and Heitman, J. The TOR signaling cascade regulates gene expression in response to nutrients. Genes & Development, 13:3271-3279, 1999.

Lorenz, M.C.*, Pan, X.*, Harashima, T.*, Cardenas, M.E., Xue, Y., Hirsch, J.P., and Heitman, J. The G protein-coupled receptor Gpr1 is a nutrient sensor that regulates pseudohyphal differentiation in Saccharomyces cerevisiae. Genetics, 154:609-622, 2000.

Wang, P., Perfect, J.R., and Heitman, J. The G-protein β subunit GPB1 is required for mating and haploid fruiting in Cryptococcus neoformans. Mol. Cell. Biol., 20:352-362, 2000.

Cruz, M.C.*, Sia, R.A.*, Olson, M., Cox, G.M., and Heitman, J. Roles of calcineurin in physiology and virulence in serotype D and serotype A strains of Cryptococcus neoformans. Infect. Immun., 68:982-985, 2000.

Liu, L., Zeng, M., Hausladen, A., Heitman, J., and Stamler, J.S. Protection from nitrosative stress by yeast flavohemoglobin. PNAS, 97:4672-4676, 2000.

Young, L.Y., Lorenz, M.C., and Heitman, J. A STE12 homolog is required for mating but dispensable for filamentation in Candida lusitaniae. Genetics, 155:17-29, 2000.

Sia, R.A., Lengeler, K.B., and Heitman, J. Diploid strains of the pathogenic basidiomycete Cryptococcus neoformans are thermally dimorphic. Fungal Genet. Biol., 29:153-163, 2000.

Arévalo-Rodríguez, M., Cardenas, M.E., Wu, X., Hanes, S.D. and Heitman, J. Cyclophilin A and Ess1 interact with and regulate silencing by the Sin3-Rpd3 histone deacetylase. EMBO J., 19:3739-3749, 2000.

Wu, X., Wilcox, C.B., Devashayam, G., Hackett, R. L., Arevalo-Rodriguez, M., Cardenas, M.E., Heitman, J., and Hanes, S.D. The mitotic Ess1 (Pin1) prolyl isomerase is linked to chromatin remodeling complexes and the general transcription machinery. EMBO J., 19:3727-3738, 2000.

Görlach, J., Fox, D.S., Cutler, N.S., Cox, G.M., Perfect, J.R. and Heitman, J. Identification and characterization of a highly conserved calcineurin binding protein, CBP1/calcipressin, in Cryptococcus neoformans. EMBO J., 19:3618-3638, 2000.

Pan, X. and Heitman, J. Sok2 regulates yeast pseudohyphal differentiation via a transcription factor cascade that regulates cell-cell adhesion. Mol. Cell. Biol. 22:8364-8372, 2000.

Lengeler, K.B., Wang, P., Cox, G.M., Perfect, J.R., and Heitman, J. Identification of the MATa mating-type locus of Cryptococcus neoformans reveals a serotype A MATa strain thought to have been extinct. PNAS, 97:14455-14460, 2000.

Davidson, R.C., Moore, T.D.E., Odom, A.R., and Heitman, J. Characterization of the MFα pheromone of the human fungal pathogen Cryptococcus neoformans. Mol. Microbiol., 38:1017-1026, 2000.

Lengeler, K.B., Davidson, R.C., D’Souza, C., Shen, W-C., Wang, P., Pan, X., Waugh, M., and Heitman, J. Signal transduction cascades regulating fungal development and virulence. MMBR 64:746-785, 2000.

Lengeler, K.B., Cox, G.M., and Heitman, J. Serotype AD strains of Cryptococcus neoformans are diploid or aneuploid and are heterozygous at the mating-type locus. Infect. Immunity, 69:115-122, 2001.

Fox, D.S., Cruz, M.C., Sia, R.A.L., Ke, H., Cox, G.M., Cardenas, M.E., and Heitman, J. Calcineurin regulatory subunit is essential for virulence and mediates interactions with FKBP12-FK506 in Cryptococcus neoformans. Mol. Microbiol., 39:835-849, 2001.

Cruz, M.C., Fox, D.S., and Heitman, J. Calcineurin is required for hyphal elongation during mating and haploid fruiting in Cryptococcus neoformans. EMBO J., 20:1020-1032, 2001.

D’Souza, C., Alspaugh, J.A., Yue, C., Harashima, T., Cox, G.M., Perfect, J.R., and Heitman, J. Cyclic AMP-dependent protein kinase controls virulence of the fungal pathogen Cryptococcus neoformans. Mol. Cell. Biol. 21:3179-3191, 2001.

Liu, L., Hausladen, A., Zeng, M., Que, L., Heitman, J., and Stamler, J.S. A metabolic enzyme for S-nitrosothiol conserved from bacteria to humans. Nature, 410:490-494, 2001.

Wang, P., Cardenas, M.E., Cox, G.M., Perfect, J.R., and Heitman, J. Two cyclophilin A homologs with shared and distinct functions important for growth and virulence of Cryptococcus neoformans. EMBO Rep., 2:511-518, 2001.

Cruz, M.C., Goldstein, A., Blankenship, J., Del Poeta, M., Perfect, J.R., McCusker, J.H., Bennani, Y.L., Cardenas, M.E., and Heitman, J. Rapamycin and nonimmunosuppressive analogs are toxic to Candida albicans and Cryptococcus neoformans via FKBP12-dependent inhibition of TOR. AAC 45:3162-3170, 2001.

Alspaugh, J.A., Pukkila-Worley, R., Harashima, T., Cavallo, L.M., Funnell, D., Cox, G.M., Perfect, J. R., Kronstad, J., and Heitman, J. Adenylyl cyclase functions downstream of the Gα protein Gpa1 and controls mating and virulence of Cryptococcus neoformans. Eukaryotic Cell, 1:75-84, 2002.

Cruz, M.C., Goldstein, A., Blankenship, J., Davis, D., Del Poeta, M., Cardenas, M.E., Perfect, J.R., McCusker, J.H., and Heitman, J. Calcineurin is essential for survival during membrane stress in Candida albicans. EMBO Journal, 21:546-559, 2002.

Wang, P.*, Nichols, C.B.*, Lengeler, K.B., Cardenas, M.E., Cox, G.M., Perfect, J.R., and Heitman, J. Mating type specific and nonspecific PAK kinases play shared and divergent roles in Cryptococcus neoformans. Eukaryotic Cell, 1:257-272, 2002.

Pan, X., and Heitman, J. Protein kinase A operates a molecular switch that governs yeast pseudohyphal differentiation. Mol. Cell. Biol., 22:3981-3993, 2002.

Shen, W.-C*, Davidson, R.C.*, Cox, G.M., and Heitman, J. Pheromones stimulate mating and differentiation via paracrine and autocrine signaling in Cryptococcus neoformans, Eukaryotic Cell, 3:366-377, 2002.

Harashima, T. and Heitman, J. The Gα protein Gpa2 controls yeast differentiation by interacting with kelch repeat proteins that mimic Gβ subunits, Molecular Cell 10: 163-173, 2002.

Davidson, R.C., Blankenship, J.R., Kraus, P.R., De Jesus-Berrios, M., Hull, C.M., D’Souza, C., Wang, P., and Heitman, J. A PCR-based strategy to generate integrative targeting alleles with large regions of homology, Microbiology, 148:2607-2615, 2002.

Schein, J.E., Tangen, K.L., Chiu, R., Shin, H., Lengeler, K.B., MacDonald, W.K., Bosdet, I., Heitman, J., Jones, S.J.M., Marra, M.A., and Kronstad, J.W. Physical maps for sequence analysis of the genomes of serotype A and D strains of the fungal pathogen Cryptococcus neoformans, Genome Research, 12:1445-1453, 2002.

Hull, C.M., Davidson, R.C., and Heitman, J. Cell identity and sexual development in Cryptococcus neoformans are controlled by the mating type-specific homeodomain protein Sxilα. Genes & Dev., 16:3046-3060, 2002.

Lengeler, K.B., Fox, D.S., Fraser, J.A., Allen, A., Forrester, K., Dietrich, F., and Heitman, J. Mating-type locus of Cryptococcus neoformans: a step in the evolution of sex chromosomes. Eukaryotic Cell 1:704-718, 2002.

Hull, C.M. and Heitman, J. Genetics of Cryptococcus neoformans. Annual Review of Genetics, 36:557-615, 2002.

Kraus, P.R., Fox, D.S., Cox, G.M., and Heitman, J. The Cryptococcus neoformans MAP kinase Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin function, Molecular Microbiology, 48:1377-1387, 2003.

Blankenship, J.R., Wormley, F.L., Boyce, M.K., Schell, W.A., Filler, S.G., Perfect, J.R., and Heitman, J. Calcineurin is essential for Candida albicans survival in serum and virulence, Eukaryotic Cell, 2:422-430, 2003.

Davidson, R.C., Nichols, C.B., Cox, G.M., Perfect, J.R., and Heitman, J. A MAP kinase cascade composed of cell type specific and non-specific elements controls mating and differentiation of the fungal pathogen Cryptococcus neoformans. Molecular Microbiology, 49:469-485, 2003.

Fox, D.S., Cox, G.M., and Heitman, J. Phospholipid-binding protein Cts1 controls septation and functions coordinately with calcineurin in Cryptococcus neoformans. Eukaryotic Cell, 2:1025-1035, 2003.

Fraser, J.A., Subaran, R.L., Nichols, C.B., and Heitman J. Recapitulation of the sexual cycle of the primary fungal pathogen C. neoformans var. gattii: Implications for an outbreak on Vancouver Island. Eukaryotic Cell, 2:1036-1045, 2003.

De Jesus-Berrios, M., Liu, L., Nussbaum, J., Cox, G.M., Stamler, J.S., and Heitman, J. Enzymes that counteract nitrosative stress promote fungal virulence. Current Biology, 13:1963-1968, 2003.

Litvintseva, A.P., Marra, R., Nielsen, K., Heitman, J, Vilgalys, R., and Mitchell, T.G. Evidence of sexual recombination among isolates of Cryptococcus neoformans serotype A in sub-saharan Africa. Eukaryotic Cell, 2:1162-1168, 2003.

Nielsen, K., Cox, G.M., Wang, P., Toffaletti, D.L., Perfect, J.R., and Heitman, J. Sexual cycle of Cryptococcus neoformans var. grubii and virulence of congenic a and alpha isolates. Infect Immun., 71:4831-4841, 2003.

Idnurm, A., Reedy, J.L., Nussbaum, J.C., and Heitman, J. Cryptococcus neoformans virulence gene discovery through insertional mutagenesis. Eukaryotic Cell, 3:420-429, 2004.

Fraser, J. A., Diezmann, S., Subaran, R.L., Allen, A., Lengeler, K.B., Dietrich, F.S. and Heitman, J. Convergent evolution of chromosomal sex-determining regions in the animal and fungal kingdoms. PLoS Biol., 2:e384, 2004.

Kraus, P. R., M. J. Boily, S. S. Giles, J. E. Stajich, A. Allen, G. M. Cox, F. S. Dietrich, J. R. Perfect, and J. Heitman. Identification of Cryptococcus neoformans temperature-regulated genes with a genomic-DNA microarray. Eukaryot Cell, 3:1249-1260, 2004.

Nichols, C. B., J. A. Fraser, and J. Heitman. PAK kinases Ste20 and Pak1 govern cell polarity at different stages of mating in Cryptococcus neoformans. Mol Biol Cell, 15:4476-89, 2004.

Marra, R. E., J. C. Huang, E. Fung, K. Nielsen, J. Heitman, R. Vilgalys, and T. G. Mitchell. A genetic linkage map of Cryptococcus neoformans variety neoformans serotype D (Filobasidiella neoformans). Genetics, 167:619-31, 2004.

Arevalo-Rodriguez, M., and J. Heitman. Cyclophilin A is localized to the nucleus and controls meiosis in Saccharomyces cerevisiae. Eukaryot Cell, 4:17-29, 2005.

Loftus, B. J., E. Fung, P. Roncaglia, D. Rowley, P. Amedeo, D. Bruno, J. Vamathevan, M. Miranda, I. J. Anderson, J. A. Fraser, J. E. Allen, I. E. Bosdet, M. R. Brent, R. Chiu, T. L. Doering, M. J. Donlin, C. A. D’Souza, D. S. Fox, V. Grinberg, J. Fu, M. Fukushima, B. J. Haas, J. C. Huang, G. Janbon, S. J. Jones, H. L. Koo, M. I. Krzywinski, J. K. Kwon-Chung, K. B. Lengeler, R. Maiti, M. A. Marra, R. E. Marra, C. A. Mathewson, T. G. Mitchell, M. Pertea, F. R. Riggs, S. L. Salzberg, J. E. Schein, A. Shvartsbeyn, H. Shin, M. Shumway, C. A. Specht, B. B. Suh, A. Tenney, T. R. Utterback, B. L. Wickes, J. R. Wortman, N. H. Wye, J. W. Kronstad, J. K. Lodge, J. Heitman, R. W. Davis, C. M. Fraser, and R. W. Hyman. The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans. Science, 307:1321-1324, 2005.

Idnurm, A. and Heitman, J. Light controls growth and development via a conserved pathway in the fungal kingdom. PLoS Biol., 3:e95, 2005.

Lin, X., Hull, C.M., and Heitman, J. Sexual reproduction between partners of the same mating type in Cryptococcus neoformans. Nature, 434:1017-1021, 2005.

Nielsen, K., Marra, R.E., Hagen, F., Boekhout, T., Mitchell, T.G., Cox, G.M, and Heitman, J. Interaction between genetic background and the mating-type locus in Cryptococcus neoformans virulence potential. Genetics, 171:975-983, 2005.

Harashima, T. and Heitman, J. Galpha subunit Gpa2 recruits kelch repeat subunits that inhibit receptor-G protein coupling during cAMP-induced dimorphic transitions in Saccharomyces cerevisiae. Mol Biol Cell., 16:4557-4571, 2005.

Nielsen, K. Cox, G.M., Litvintseva, A.P., Mylonakis, E., Mallaris, S.D., Benjamin, D.K. Jr., Giles, S.S., Mitchell, T.G., Casadevall, A., Perfect, J.R., and Heitman, J. Cryptococcus neoformans {alpha} strains preferentially disseminate to the central nervous system during coinfection. Infect Immun., 73:4922-4933, 2005.

Campbell, L.T., Fraser, J.A., Nichols, C.B., Dietrich, F.S., Carter, D., and Heitman, J. Clinical and environmental isolates of Cryptococcus gattii from Australia that retain sexual fecundity. Eukaryotic Cell, 4:1410-1419, 2005.

Campbell, L.T., Currie, B.J., Krockenberger, M., Malik, R., Meyer, W., Heitman, J., and Carter, D. Clonality and recombination in genetically differentiated subgroups of Cryptococcus gattii. Eukaryotic Cell, 4:1403-1409, 2005.

Fan, W., Kraus, P.R., Boily, M.J., and Heitman, J. Cryptococcus neoformans gene expression during murine macrophage infection. Eukaryotic Cell, 4:1420-1433, 2005.

Fox, D.S. and Heitman, J. Calcineurin-binding protein Cbp1 directs the specificity of calcineurin-dependent hyphal elongation during mating in Cryptococcus neoformans. Eukaryotic Cell, 4:1526-1538, 2005.

Idnurm, A., Bahn, Y.S., Nielsen, K., Lin, X., Fraser, J.A., and Heitman, J. Deciphering the model pathogenic fungus Cryptococcus neoformans. Nat Rev Microbiol., 3:753-764, 2005.

Blankenship, J.R. and Heitman, J. Calcineurin is required for Candida albicans to survive calcium stress in serum. Infect Immun., 73:5767-5774, 2005.

Walton, F.J., Idnurm, A., and Heitman, J. Novel gene functions required for melanization of the human pathogen Cryptoccocus neoformans. Mol Microbiol., 57:1381-1396, 2005.

Fraser, J.A., Giles, S.S., Wenink, E.C., Guenes-Boyer, S.G., Wright, J.R., Diezmann, S., Allen, A., Stajich, J.E., Dietrich, F.S., Perfect, J.R., and Heitman, J. Same-sex mating and the origin of the Vancouver Island Cryptococcus gattii outbreak. Nature, 437:1360-1364, 2005.

Bahn Y.S., Cox G.M., Perfect J.R., Heitman J. Carbonic anhydrase and CO2 sensing during Cryptococcus neoformans growth, differentiation, and virulence. Curr Biol., 15:2013-20, 2005.

Xue C., Bahn Y.S., Cox G.M., Heitman J. G protein-coupled receptor Gpr4 senses amino acids and activates the cAMP-PKA pathway in Cryptococcus neoformans. Mol Biol Cell., 17:667-79, 2006.

Idnurm A., Rodriguez-Romero J., Corrochano L.M., Sanz C., Iturriaga E.A., Eslava A.P., Heitman J. The Phycomyces madA gene encodes a blue-light photoreceptor for phototropism and other light responses. Proc Natl Acad Sci U S A., 103:4546-51, 2006.

Bahn Y.S., Kojima K., Cox G.M., and Heitman J. A unique fungal two-component system regulates stress responses, drug sensitivity, sexual development, and virulence of Cryptococcus neoformans. Mol Biol Cell., 17:3122-35, 2006.

Harashima T., Anderson S., Yates J.R. III, and Heitman J.
The kelch proteins Gpb1 and Gpb2 inhibit Ras activity via association with the yeast RasGAP neurofibromin homologs Ira1 and Ira2. Mol Cell., 22:819-30, 2006.

Lin, X., Huang, J.C., Mitchell, T.G., and Heitman, J. Virulence attributes and hyphal growth of C. neoformans are quantitative traits and the MATα allele enhances filamentation. PLoS Genet., 2:e187, 2006.

Hsueh, Y.P., Idnurm, A., and Heitman, J. Recombination hotspots flank the Cryptococcus mating-type locus: Implications for the evolution of a fungal sex chromosome. PLoS Genet., 2:e184, 2006.

Heitman, J. Sexual reproduction and the evolution of microbial pathogens. Curr Biol., 16:R711-25, 2006.

Onyewu, C. and Heitman, J. Unique applications of novel antifungal drug combinations. Anti-infective Agents in Medicinal Chemistry, 6:3-15, 2007. [Free Open Access]

Steinbach, W.J., Reedy, J.L., Cramer, R.A., Perfect, J.R., and Heitman, J. Harnessing calcineurin as a novel anti-infective against fungal infections. Nature Rev Microbiol., 5:418-430, 2007.

Fan, W., Idnurm, A., Breger, J., Mylonakis, E., and Heitman, J. Ecal, a sarco/endoplasmic reticulum Ca2+-ATPase, is involved in stress tolerance and virulence in Cryptococcus neoformans. Infect Immun., 75:3394-3405, 2007.

Nielsen, K. and Heitman, J. Sex and virulence of human pathogenic fungi. Adv Genet., 57:143-173, 2007.

Fraser, J.A., Stajich, J.E., Tarcha, E.J., Cole, G.T., Inglis, D.O., Sil, A., and Heitman, J. Evolution of the mating type locus: Insights gained from the dimorphic primary fungal Pathogens Histoplasma capsulatum, Coccidioides immitis, and Coccidioides posadasii. Eukaryot Cell., 6:622-629, 2007.

Hicks, J.K. and Heitman, J. Divergence of protein kinase A catalytic subunits in Cryptococcus neoformans and Cryptococcus gattii illustrates evolutionary reconfiguration of a signaling cascade. Eukaryot Cell., 6:413-420, 2007.

Bahn, Y.S., Xue, C., Idnurm, A., Rutherford, J.C., Heitman, J., and Cardenas, M.E. Sensing the environment: Lessons from fungi. Nat Rev Microbiol., 5:57-69, 2007.

Xue, C., Tada, Y., Dong, X., and Heitman, J. The human fungal pathogen Cryptococcus neoformans can complete its sexual cycle during a pathogenic association with plants. Cell Host and Microbe, 1:263-273, 2007.

Nielsen, K., DeObaldia, A.L., and Heitman, J.Cryptococcus neoformans mates on pigeon guano: Implications for the realized ecological niche and globalization. Eukaryot Cell., 6:949-959, 2007.

Onyewu, C., Eads, E., Schell, W.A., Perfect, J.R., Ullmann, Y., Kaufman, G., Horwitz, B.A., Berdicevesky, I., and Heitman, J. Targeting the calcineurin pathway enhances ergosterol biosynthesis inhibitors againsTrichophyton mentagrophytes in vitro and in a human skin infection model. Antimicrob Agents Chemother. 51:3743-3746, 2007.

Upton, A., Fraser, J.A., Kidd, S.E., Bretz, C., Bartlett, K.H., Heitman, J. and Marr, K.A. First contemporary case of human infection with Cryptococcus gattii in Puget Sound: Evidence for spread of the Vancouver Island outbreak. J Clin Microbiol. 45:3086-3088, 2007.

Hseuh, Y.P., Xue, C., and Heitman, J. G protein signaling governing cell fate decisions involves opposing G{alpha} subunits in Cryptococcus neoformans. Mol Biol Cell. 18:3237-3249, 2007.

Litvintseva, A.P., Lin, X., Templeton, I., Heitman, J., and Mitchell, T.G. Many globally isolated AD hybrid strains of Cryptococcus neoformans originated in Africa. PLoS Pathogens. 8:e114, 2007.

Lin, X., Litvintseva, A.P., Nielsen, K., Patel, S., Floyd, A., Mitchell, T.G., and Heitman, J. alphaADalpha hybrids of Cryptococcus neoformans: Evidence of same-sex mating in nature and hybrid fitness. PLoS Genet. 3:e186, 2007.

Idnurm, A., Walton, F.J., Floyd, A. and Heitman, J. Identification of the sex genes in an early diverged fungus. Nature, 451:193-196, 2008.

Rutherford, J.C., Lin, X., Nielsen, K. and Heitman, J. Amt2 permease is required to induce ammonium-responsive invasive growth and mating in Cryptococcus neoformans. Eukaryot Cell. 7:237-246, 2008.

Rutherford, J.C., Chua, G., Hughes, T., Cardenas, M.E. and Heitman, J. A Mep2-dependent transcriptional profile links permease function to gene expression during pseudohyphal growth in Saccharomyces cerevisiae. Mol Biol Cell. 19:3028-3039, 2008.

Lin, X., Nielsen, K., Patel, S. and Heitman, J. Impact of mating type, serotype, and ploidy on the virulence of Cryptococcus neoformans. Infect Immun. 76:2923-2938, 2008.

Bui, T., Lin, X., Malik, R., Heitman, J. and Carter, D. Isolates of Cryptococcus neoformans from infected animals reveal genetic exchange in unisexual, alpha mating type populations. Eukaryot Cell. 7:1771-1780, 2008.

Hsueh, Y.P., Fraser, J.A. and Heitman, J. Transitions in sexuality: Recapitulation of an ancestral tri- and tetrapolar mating system in Cryptococcus neoformans. Eukaryot Cell. 7:1847-1855, 2008.

Xue, C., Hsueh, Y.P., Chen, L. and Heitman, J. The RGS protein Crg2 regulates both pheromone and cAMP signalling in Cryptococcus neoformans. Mol Microbiol. 70:379-395, 2008.

Lee, S.C., Corradi, N., Byrnes, E.J. III, Torres-Martinez, S., Dietrich, F.S., Keeling, P.J. and Heitman, J. Microsporidia evolved from ancestral sexual fungi. Curr Biol. 18:1675-1679, 2008.

Findley, K., Rodriguez-Carres, M., Metin, B., Kroiss, J., Fonseca, A., Vilgalys, R., and Heitman, J. Phylogeny and phenotypic characterization of Cryptococcus species and closely related saprobic taxa in the Tremellales. Eukaryotic Cell, 8:353-361, 2009.

Bastidas, R.J., Heitman, J., and Cardenas, M.E. The protein kinase Tor1 regulates adhesin expression in Candida albicans. PLoS Pathogens, e1000294, 2009.

Lin, X., Patel, S., Litvintseva, A.P., Floyd, A., Mitchell, T.G., and Heitman, J. Diploids in the Cryptococcus neoformans serotype A population homozygous for the alpha mating type originate via unisexual mating. PLoS Pathogens, e1000283, 2009.

Byrnes, E.J., Bildfell, R., Frank, S., Mitchell, T.G., Marr, K., and Heitman, J. Molecular evidence that the Vancouver Island C. gattii outbreak has expanded into the United States Pacific Northwest. Journal of Infectious Diseases, 99:1081-1086, 2009.

Shapiro, R.S., Uppuluri, P., Zaas, A.K., Collins, C., Senn, H., Perfect, J.R., Heitman, J., and Cowen, L.E. Hsp90 orchestrates temperature-dependent Candida albicans morphogenesis via Ras1-PKA signaling. Curr Biol. 19:621-629, 2009.

Hsueh, Y.P., Xue, C., and Heitman, J. A constitutively active GPCR governs morphogenic transitions in Cryptococcus neoformans. EMBO J. 28:1220-1233, 2009.

Sanz, C., Rodriguez-Romero, J., Idnurm, A., Christie, J.M., Heitman, J., Corrochano, L.M., and Eslava, A.P. Phycomyces MADB interacts with MADA to form the primary photoreceptor complex for fungal phototropism. Proc Natl Acad Sci USA. 106:7095-7100, 2009.

Reedy, J.L., Floyd, A.M., and Heitman, J. Mechanistic plasticity of sexual reproduction and meiosis in the Candida pathogenic species complex. Curr Biol. 19:891-899, 2009.

Geunes-Boyer, S., Oliver, T.N., Janbon, G., Lodge, J.K., Heitman, J., Perfect, J.R., and Wright, J.R. Surfactant protein D increases phagocytosis of hypocapsular Cryptococcus neoformans by murine macrophages and enhances fungal survival. Infect Immun. 77:2783-2794, 2009.

Butler et al, Evolution of pathogenicity and sexual reproduction in eight Candida genomes. Nature 459:657-662, 2009.

Velagapudi, R., Hsueh, Y.P., Geunes-Boyer, S., Wright, J.R., and Heitman, J. Spores as infectious propagules of Cryptococcus neoformans. Infect Immun. 77:4345-4355, 2009.

Li, W., Metin, B., White, T.C., and Heitman, J. Organization and evolutionary trajectory of the mating type (MAT) locus in dermatophyte and dimorphic fungal pathogens. Eukaryot Cell. 9:46-58, 2010.

Kozubowski, L. and Heitman, J. Septins enforce morphogenetic events during sexual reproduction and contribute to virulence of Cryptococcus neoformans. Mol Microbiol. 75:658-675, 2010.

Byrnes, E.J. III, Li, W., Lewit, Y., Ma, H., Voelz, K., Ren, P., Carter, D.A., Chaturvedi, V., Bildfell, R.J., May, R.C., and Heitman, J. Emergence and pathogenicity of highly virulent Cryptococcus gattii genotypes in the northwest United States. PLoS Pathogens. 6:e1000850, 2010.

Lee, S.C., Corradi, N., Doan, S., Dietrich, F.S., Keeling, P.J., and Heitman, J. Evolution of the sex-related locus and genomic features shared in microsporidia and fungi. PLoS One. 5:e10539, 2010.

Lin, X., Jackson, J.C., Feretzaki, M., Xue, C., and Heitman, J. Transcription factors Mat2 and Znf2 operate cellular circuits orchestrating opposite- and same-sex mating in Cryptococcus neoformans. PLoS Genetics. 6:e1000953, 2010.

Metin, B., Findley, K., and Heitman, J. The mating type locus (MAT) and sexual reproduction of Cryptococcus heveanensis: Insights into the evolution of sex and sex-determining chromosomal regions in fungi. PLoS Genetics. 6:e1000961, 2010.

Lee, S.C., Ni, M., Li, W., Shertz, C., and Heitman, J. The evolution of sex: A perspective from the fungal kingdom. Microbiology and Molecular Biology Reviews. 74:298-340, 2010.

Heitman, J. Evolution of eukaryotic microbial pathoens via covert sexual reproduction. Cell Host Microbe. 8:86-99, 2010.

Okagaki, L.H., Strain, A.K., Neilsen, J.N., Charlier, C., Baltes, N.J., Chretien, F. Heitman, J., Dromer, F., and Nielsen, K. Cryptococcal cell morphology affect host cell interactions and pathogenicity. PLoS Pathog. 6:e1000953, 2010.

Xue, C., Liu, T., Chen, L., Li, W., Liu, I., Kronstad, J.W., Seyfang, A., and Heitman, J. Role of an expanded inositol transporter repertoire in Cryptococcus neoformans sexual reproduction and virulence. mBio. 1:e00084-10, 2010.

Wang, X., Hsueh, Y.P., Li, W., Floyd, A., Skalsky, R., and Heitman, J. Sex-induced silencing defends the genome of Cryptococcus neoformans via RNAi. Genes Dev. 24:2566-2582, 2010. [Abstract] [PDF@Journal]

Gryganskyi, A.P., Lee, S.C., Litvintseva, A.P., Smith, M.E., Bonito, G., Porter, T.M., Anishchenko, I.M., Heitman, J., and Vilgalys, R. Structure, function, and phylogeny of the mating locus in the Rhizopus oryzaecomplex. PLoS One. 5:e15273, 2010. [Abstract] [PDF@Journal]

D’Souza, C.A., Kronstad, J.W., Taylor, G., Warren, R., Yuen, M., Hu, G., Jung, W.H., Sham, A., Kidd, S.E., Tangen, K., Lee, N., Zeilmaker, T., Sawkins, J., McVicker, G., Shah, S., Gnerre, S., Griggs, A., Zeng, Q., Bartlett, K., Li, W., Wang, X., Heitman, J., Stajich, J.E., Fraser, J.A., Meyer, W., Carter, D., Schein, J., Krzywinski, M., Kwon-Chung, K.J., Varma, A., Wang, J., Brunham, R., Fyfe, M., Ouellette, B.F., Siddiqui, A., Marra, M., Jones, S., Holt, R., Birren, B.W., Galagan, J.E., Cuomo, C.A. Genome variation in Cryptococcus gattii, an emerging pathogen of immunocompetent hosts. mBio. 2:e00342-10, 2011. [Abstract] [PDF@Journal]

Chen, Y.L., Brand, A., Morrison, E.L., Silao, F.G., Bigol, U.G., Malbas, F.F. Jr., Nett, J.E., Andes, D.R., Solis, N.V., Filler, S.G., Averette, A., and Heitman, J. Calcineurin controls drug tolerance, hyphal growth, and virulence in Candida dubliniensis. Eukaryot Cell. 10:803-819, 2011. [Epub 2011 Apr 29]. [Abstract] [PDF@Journal]

Li, C.H., Cervantes, M., Springer, D.J., Boekhout, T., Ruiz-Vazquez, R.M., Torres-Martinez, S.R., Heitman, J., and Lee, S.C. Sporangiospore size dimorphism is linked to virulence of Mucor circinelloides. PLoS Pathog. 7:e1002086, 2011. [Epub 2011 Jun 16]. [Abstract] [PDF@Journal]

Kozubowski, L., Aboobakar, E.F., Cardenas, M.E., and Heitman, J. Calcineurin co-localizes with P-bodies and stress granules during thermal stress in Cryptococcus neoformans. Eukaryot Cell. 10:1396-1402, 2011. [Abstract] [PDF@Journal]

Byrnes, E.J., Li, W., Ren, P., Lewit, Y., Voelz, K., Fraser, J.A., Dietrich, F.S., May, R.C., Chaturvedi, S., Chaturvedi, V., and Heitman, J. A diverse population of Cryptococcus gattii molecular type VGIII in southern Californian HIV/AIDS patients. PLoS Pathogens 7:e1002205, 2011. [Abstract] [PDF@Journal]

Ni, M., Feretzaki, M., Sun, S., Wang, X., and Heitman, J. Sex in fungi. Annu Rev Genet 45:405-430, 2011. [Abstract] [PDF@Journal]

Aboobakar, E.F., Wang, X., Heitman, J., and Kozubowski, L. The C2 domain protein Cts1 functions in the calcineurin signaling circuit during high-temperature stress responses in Cryptococcus neoformans. Eukaryotic Cell 10:1714-1723, 2011. [Abstract] [PDF@Journal]

Semighini, C.P., Averette, A.F., Perfect, J.R., and Heitman, J. Deletion of Cryptococcus neoformans AIF ortholog promotes chromosome aneuploidy and fluconazole-resistance in a metacaspase-independent manner. PLoS Pathogens 7:e1002364, 2011. [Abstract] [PDF@Journal]

Bastidas, R.J., Shertz, C.A., Lee, S.C., Heitman, J., and Cardenas, M.E. Rapamycin exerts antifungal activity in vitro and in vivo against Mucor circinelloides via FKBP12-dependent inhibition of Tor. Eukaryotic Cell 2011 Dec 30 [Epub ahead of print] [Abstract]

Findley, K., Sun, S., Fraser, J.A., Hsueh, Y.P., Averette, A.F., Li, W., Dietrich, F.S., and Heitman, J.  Discovery of a modified tetrapolar sexual cycle in Cryptococcus amylolentus and the evolution of MAT in the Cryptococcus species complex. PLOS Genetics 8:e1002528, 2012. [Abstract] [PDF@Journal]

Wang, X., Wang, P., Sun, S., Darwiche, S., Idnurm, A., and Heitman, J.  Mitotic transgene silencing in Cryptococcus neoformans. PLOS Genetics8:e1002885, 2012. [Abstract] [PDF@Journal]

Sun, S., Hsueh, Y.P., and Heitman, J. Gene conversion occurs within the mating-type locus of Cryptococcus neoformans during sexual reproduction. PLOS Genetics 8:e1002810, 2012. [Abstract] [PDF@Journal]

Floudas et al. The Paleozoic origin of enzymatic lignin decomposition reconstructed from 31 fungal genome. Science 336:1715-1719, 2012. [Abstract] [PDF@Journal]

Martinez et al. Comparative genomic analysis of Trichophyton rubrum and related dermatophytes reveals candidate genes involved in infection. mBio 3:e00259-12, 2012. [Abstract] [PDF@Journal]

Lee, S.C., Phadke, S., Sun, S., and Heitman, J. Pseudohyphal growth of Cryptococcus neoformans is a reversible dimorphic transition in response to ammonium that requires the Amt1/2 ammonium permeases. Eukaryotic Cell 11:1391-1398, 2012. [Abstract] [PDF@Journal]

Li*, W., Sullivan*,T.D., Walton, E., Averette, A.F., Sakthikumar, S., Cuomo, C.A., Klein, B.S., and Heitman, J. Identification of the mating type (MAT) locus that controls sexual reproduction of Blastomyces dermatitidis, Eukaryotic Cell [Epub 9 Nov 2012]. [Abstract] [PDF@Journal]

Heitman, J., Sun, S., and James, T.Y. Evolution of fungal sexual reproduction. Mycologia [Epub 25 Oct 2012] in press January 2013. [Abstract] [PDF@Journal]

Feretzaki, M., and Heitman, J. Genetic circuits that govern bisexual and unisexual reproduction in Cryptococcus neoformans. PLoS Genet. 9(8):e1003688, 2013. [Abstract] [PDF@Journal]

Lee, S.C., Li, A., Calo, S., and Heitman, J. Calcineurin plays key roles in the dimorphic transition and virulence of the human pathogenic zygomycete Mucor circinelloides. PLoS Pathog. 9(9):e1003625, 2013. [Abstract] [PDF@Journal]

Voelz, K., Ma, H., Phadke, S., Byrnes, E.J., Zhu, P., Mueller, O., Farrer, R.A., Henk, D.A., Lewit, Y., Hsueh, Y.P., Fisher, M.C., Idnurm, A., Heitman, J., and May, R.C. Transmission of hypervirulence traits via sexual reproduction within and between lineages of the human fungal pathogen Cryptococcus gattii. PLoS Genet. 9(9):e1003771, 2013. [Abstract] [PDF@Journal]

Ni, M., Feretzaki, M, Li, W., Floyd-Averette, A., Mieczkowski, P., Dietrich, F.S., and Heitman, J. Unisexual and heterosexual meiotic reproduction generate aneuploidy and phenotypic diversity de novo in the yeast Cryptococcus neoformans. PLoS Biol. Sep;11(9):e1001653, 2013. [Abstract] [PDF@Journal]

Feretzaki, M. and Heitman, J. Unisexual reproduction drives evolution of eukaryotic microbial pathogens. PLoS Pathog. Oct;9(10):e1003674, 2013. [Abstract] [PDF@Journal]

Janbon G., Ormerod K.L., Paulet D., Byrnes E.J. 3rd, Yadav V., Chatterjee G., Mullapudi N., Hon C.C., Billmyre R.B., Brunel .F, Bahn Y.S., Chen W., Chen Y., Chow E.W., Coppée J.Y., Floyd-Averette A., Gaillardin C., Gerik K.J., Goldberg J., Gonzalez-Hilarion S., Gujja S., Hamlin J.L., Hsueh Y.P., Ianiri G., Jones S., Kodira C.D., Kozubowski L., Lam W., Marra M., Mesner L.D., Mieczkowski P.A., Moyrand F., Nielsen K., Proux C., Rossignol T., Schein J.E., Sun S., Wollschlaeger C., Wood I.A., Zeng Q., Neuvéglise C., Newlon C.S., Perfect J.R., Lodge J.K., Idnurm A., Stajich J.E., Kronstad J.W., Sanyal K., Heitman J., Fraser J.A., Cuomo C.A., Dietrich F.S.  Analysis of the genome and transcriptome of Cryptococcus neoformans var. grubii reveals complex RNA expression and microevolution leading to virulence.  PLoS Genet. Apr 17;10(4):e1004261, 2014. [PDF@Journal]

Billmyre R.B., Croll D., Li W., Mieczkowski P., Carter D.A., Cuomo C.A., Kronstad J.W., Heitman J. Highly recombinant VGII Cryptococcus gattii population develops clonal outbreak clusters through both sexual macroevolution and asexual microevolution. mBio. Jul 29;5(4):e01494-14. 2014. [PDF@Journal]

Calo S., Shertz-Wall C., Lee S.C., Bastidas R.J., Nicolás F.E., Granek J.A., Mieczkowski P., Torres-Martínez S., Ruiz-Vázquez R.M., Cardenas M.E., Heitman J. Antifungal drug resistance evoked via RNAi-dependent epimutations.  Nature.  Sep 28;513(7519):555-8. 2014. [PDF@Journal]

Springer D.J., Billmyre R.B., Filler E.E., Voelz K., Pursall R., Mieczkowski P.A., Larsen R.A., Dietrich F.S., May R.C., Filler S.G., Heitman J. Cryptococcus gattii VGII isolates causing infections in HIV/AIDS patients in Southern California: identification of the local environmental source as arboreal.  PLOS Pathog. Aug 21;10(8):e1004285 2014. [PDF@Journal]

Sun S., Billmyre R.B., Mieczkowski P.A., Heitman J.  Unisexual reproduction drives meiotic recombination and phenotypic and karyotypic plasticity in Cryptococcus neoformans. PLoS Genet. Dec 11;10(12):e1004849. 2014. [PDF@Journal]

Lee S.C., Li A., Calo S., Inoue M., Tonthat N.K., Bain J.M., Louw J., Shinohara M.L., Erwig L.P., Schumacher M.A., Ko D.C., Heitman J.  Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungusMucor circinelloides.  Mol Microbiol. Sep;97(5):844-65  PLoS Genet. 2015. [PDF@Journal]

Farrer R.A., Desjardins C.A., Sakthikumar S., Gujja S., Saif S., Zeng Q., Chen Y., Voelz K., Heitman J., May R.C., Fisher M.C., Cuomo C.A.  Genome evolution and innovation across the four major lineages of Cryptococcus gattii.  mBio.  Sep 1;6(5):e00868-15.  2015  [PDF@Journal]

Wu G., Zhao H., Li C., Rajapakse M.P., Wong W.C., Xu J., Saunders C.W., Reeder N.L., Reilman R.A., Scheynius A., Sun S., Billmyre B.R., Li W., Averette A.F., Mieczkowski P., Heitman J., Theelen B., Schröder M.S., De Sessions P.F., Butler G., Maurer-Stroh S., Boekhout T., Nagarajan N., Dawson T.L. Jr.  Genus-wide comparative genomics of Malassezia delineates its phylogeny, physiology, and niche adaptation on human skin.  PLoS Genet.  Nov 5;11(11):e1005614.  2015.  [PDF@Journal]

Heitman J.  On the discovery of TOR as the target of Rapamycin.  PLoS Pathog.  Nov 5;11(11):e1005245.  2015.  [PDF@Journal]

Feretzaki, M.*, Billmyre, R.B.*, Clancey, S.A., Wang, X., and Heitman, J. Gene network polymorphism illuminates loss and retention of novel RNAi silencing components in the Cryptococcus pathogenic species complex, PLOS Genetics, 12: e1005868, 2016.

Tonthat, N.K., Juvvadi, P.R., Zhang, H., Lee, S.C., Venters, R., Spicer, L., Steinbach, W.J., Heitman, J., and Schumacher, M.A.  Structures of pathogenic fungal FKBP12 proteins reveal possible self-catalysis function, mBio, 7: e00492-16, 2016.

Corrochano et al, Expansion of signal transduction pathways in fungi by extensive gene duplication, Current Biology, 26: 1577-1584, 2016.

Park, H.-S., Chow, E.W.L., Soderblom, E.J., Moseley, M.A., Heitman, J., and Cardenas, M.E.  Calcineurin targets involved in stress survival and fungal virulence, PLOS Pathogens, 12: e1005873, 2016.

Ianiri, G., Averette, A., Kingsbury, J.M., Heitman, J., and Idnurm, A.  Gene function analysis in the ubiquitous human commensal and pathogen Malassezia genus, mBio, 7: e01853-16, 2016.

Lee et al, Systematic functional analysis of kinases in the fungal pathogen Cryptococcus neoformans, Nature Communications, 7: 12766, 2016.

Zhu et al, Proteogenomics produces comprehensive and highly accurate protein-coding gene annotation in a complete genome assembly of Malassezia sympodialis, Nucleic Acids Research, 45: 2629-2643, 2017.

Calo, S.*, Nicolás, F.E.*, Lee, S.C., Vila, A., Cervantes, M., Torres-Martinez, S., Ruiz-Vazquez, R.M., Cardenas, M.E., and Heitman, J.  A non-canonical RNA degradation pathway suppresses RNAi-dependent epimutations in the human fungal pathogen Mucor circinelloides, PLOS Genetics 13: e1006686, 2017.

Chow, E.W.L., Clancey, S.A., Billmyre, R.B., Averette, A.F., Granek, J.A., Mieczkowski, P., Cardenas, M.E., and Heitman, J.  Elucidation of the calcineurin-Crz1 stress response network in the human fungal pathogen Cryptococcus neoformans, PLOS Genetics, 13: e1006667, 2017.

Desjardins, C.A., Giamberardino, C., Sykes, S.M., Yu, C.-H., Tenor, J.L., Chen, Y., Yang, T., Jones, A.M., Sun, S., Haverkamp, M.R., Heitman, J., Litvintseva, A.P., Perfect, J.R., and Cuomo, C.A.  Population genomics and the evolution of virulence in the fungal pathogen Cryptococcus neoformans, Genome Research, 27: 1207-1219, 2017.

Sun, S., Yadav, V., Billmyre, R.B., Cuomo, C.A., Nowrousian, M., Wang, L., Souciet, J.-L., Boekhout, T., Porcel, B., Wincker, P., Granek, J.A., Sanyal, K., and Heitman, J.  Fungal genome and mating system transitions facilitated by chromosomal translocations involving intercentromeric recombination, PLOS Biology, 15: e2002527, 2017.

Billmyre, R.B., Clancey S.A., and Heitman, J.  Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii, eLife, 2017 Sep 26;6. pii: e28802. doi: 10.7554/eLife.28802.

Ianiri, G., Applen Clancey, S., Lee, S.C., and Heitman, J.  FKBP12-dependent inhibition of calcineurin mediates immunosuppressive antifungal drug action in Malassezia, mBio, 8: pii: e01752-17. doi: 10.1128/mBio.01752-17, 2017.

Honors and Awards

  • Gustavo Cudkowicz Memorial Prize in Immunobiology, Cornell University Medical College (1991)
  • Investigator, Howard Hughes Medical Institute (1992-2005)
  • Burroughs Wellcome Scholar in Molecular Pathogenic Mycology (1998-2005)
  • AMGEN Award, American Society for Biochemistry and Molecular Biology, for significant achievements in the understanding of human disease, including studies in model yeasts defining targets and modes of action for immunosuppressive drugs  (2002)
  • Squibb Award, Infectious Diseases Society of America, in recognition of outstanding achievement in the field of infectious diseases (2003)
  • Fellow, American Society for Clinical Investigation (2003)
  • Fellow, American Association for the Advancement of Science (2004)
  • Fellow, American Academy of Microbiology (2004)
  • Fellow, Association of American Physicians (2006)
  • Duke University Presidential Meritorious Service Award in Executive Leadership (2007)
  • MERIT Award, NIH/NIAID for discovery of, and studies on, fungal unisexual reproduction (2011-2021)
  • Faculty of 1000, Faculty member of the year (2011, 2013, 2015, 2018)
  • Faculty of 1000, Outstanding faculty member of the year (2014, 2017)
  • Duke University Research Mentoring Award for translational research (2012)
  • Elected to the Alpha Omega Alpha (AOA) medical honorific society as a faculty member (2014)
  • Visiting International Professorship, Ruhr University Bochum, Germany (2015-2019)
  • Stanley J. Korsmeyer Award, American Society for Clinical Investigation, for key contributions to understanding how microbial pathogens evolve, cause disease, and develop drug resistance and discovery of TOR and FKBP12 as targets of rapamycin (2018)
  • Dean’s Award for Excellence in Mentoring, Graduate School, Duke University (2018)
  • Rhoda Benham Award, Medical Mycological Society of the Americas, for continuous, outstanding, meritorious contributions to medical mycology (2018)
  • ASM Award for Basic Research, American Society for Microbiology, for discoveries fundamental in advancing understanding of the microbial world (2019)
  • Edward Novitski Prize, Genetics Society of America, honoring work on human fungal pathogens and identifying molecular targets of widely-used immunosuppressive drugs, a seminal contribution to discovery of TOR, which regulates cell growth in response to nutrients (2019)
  • Fellow and Co-Director, Canadian Institute for Advanced Research program, Fungal Kingdom:  Threats & Opportunities (2019-2026)
  • Elected, American Academy of Arts and Sciences (2020)
  • Elected, National Academy of Sciences (2021)
  • Distinguished Mycologist Award, Mycological Society of America (2021)
  • Elected, German National Academy of Sciences – Leopoldina (2021)

Distinguished Lectures

  • 2001      Plenary Lecture, Asilomar Fungal Genetics meeting
  • 2007      Plenary Lecture, International Yeast meeting, Melbourne, Australia
  • 2007      Keynote Lecture, Drexel University College of Medicine, Graduate program in Microbiology and Immunology research symposium
  • 2009      Division F Lecture, American Society of Microbiology General Meeting
  • 2009      Keynote Lecture, Third FEBS Human Fungal Pathogens Course, La Colle sur Loup, France
  • 2010      Foundation Lecture, British Society for Medical Mycology, Exeter, UK
  • 2010      Plenary Lecture, 9th International Mycological Congress, Edinburgh, Scotland
  • 2011      Keynote Lecture, 14th Annual Bay Area Microbial Pathogenesis Symposium, UCSF
  • 2011      Keynote Lecture, 8th International Conference on Cryptococcus and Cryptococcosis, Charleston, SC
  • 2011      Karling Lecture, Mycological Society of America, Fairbanks, Alaska
  • 2011      Keynote Lecture, Molecular Biology of Fungi 10 meeting, Marburg, Germany
  • 2012      Plenary Lecture, 13th International Congress on Yeasts, Madison, Wisconsin
  • 2013      Plenary Lecture, Asilomar Fungal Genetics meeting
  • 2013      Plenary Lecture, Korean Microbiology Society meeting
  • 2014      Plenary Lecture, 12th European Conference on Fungal Genetics, Seville, Spain
  • 2014      Keynote Lecture, 12th International Conference on Molecular Epidemiology and Evolutionary Genetics of Infectious Diseases (MEEGID), Bangkok, Thailand
  • 2014      Plenary Lecture, Max Planck Institute for Evolutionary Biology, Plön, Germany, Matt Meselson Seminar Series on the Evolution of Sex; Evolution of Sexual Reproduction
  • 2015      Plenary Speaker, ISHAM international meeting, Melbourne, Australia
  • 2017      Max Delbrück Lecture, German Genetics Society Meeting, Bochum, Germany
  • 2019      Gene E. Michaels Honorary Mycology Lecture, University of Georgia, Athens, GA

Talks