Molecular Mycology and Pathogenesis Training Program

Summary

Principal Investigator: Joseph Heitman
Abstract: Although medical advances prolong the lives of many patients with otherwise debilitating or uniformly fatal diseases, such as cancer, AIDS, and organ or stem cell transplants, these medical interventions often compromise host defenses and immunity. Consequently, the incidence of opportunistic fungal infections continues to increase. The development of new antifungal drugs has improved the prognosis for many patients, but they have also fostered the emergence of new and more resistant pathogenic fungi. Thus, it is essential to recruit and train young scientists to develop rigorous independent careers focused on mycological research. The same mandate applies to research on fungal plant pathogens, which continue to reduce the global food supply. Other, non-pathogenic fungi serve as models for eukaryotic systems, and they have fostered profound discoveries and progress in the biomedical sciences and biotechnology. Indeed, progress in genomics and bioinformatics have enhanced the impact of fungal biology and increased the demand for scientists who are capable of applying these methods to model fungi. This application proposes a continuation of the multidisciplinary, tri-institutional Molecular Mycology and Pathogenesis Training Program (MMPTP), which was awarded five years ago. The MMPTP recruits, supports, and trains promising postdoctoral scientists and physicians to develop productive research careers in molecular mycology and pathogenesis. These trainees will become the future experts and leaders in broad areas of fungal research in academia, industry, and government. Candidates for training include recent doctoral graduates in biomedical sciences, physicians who have completed residency training, and scientists from other disciplines who want to apply their expertise to fungi. The participating faculty constitute perhaps the greatest concentration of researchers who study fungi. They share resources, interact regularly, and collaborate frequently. The MMPTP has been highly successful. Over the past five years, we have supported 14 trainees. All nine trainees who completed the program are employed as productive scientists in the USA. One is President of a microbiological diagnostics company, one is a governmental scientist, two are continuing postdoctoral research, and the other five are tenure-tract Assistant Professors at research universities.
Funding Period: 2003-09-01 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. pmc Unisexual and heterosexual meiotic reproduction generate aneuploidy and phenotypic diversity de novo in the yeast Cryptococcus neoformans
    Min Ni
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS Biol 11:e1001653. 2013
  2. pmc Sporangiospore size dimorphism is linked to virulence of Mucor circinelloides
    Charles H Li
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS Pathog 7:e1002086. 2011
  3. pmc Regulatable Ras activity is critical for proper establishment and maintenance of polarity in Aspergillus fumigatus
    Jarrod R Fortwendel
    Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA
    Eukaryot Cell 10:611-5. 2011
  4. pmc Structure, function, and phylogeny of the mating locus in the Rhizopus oryzae complex
    Andrii P Gryganskyi
    Department of Biology, Duke University, Durham, North Carolina, United States of America
    PLoS ONE 5:e15273. 2010
  5. pmc Cryptococcal cell morphology affects host cell interactions and pathogenicity
    Laura H Okagaki
    Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America
    PLoS Pathog 6:e1000953. 2010
  6. pmc The evolution of sex: a perspective from the fungal kingdom
    Soo Chan Lee
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
    Microbiol Mol Biol Rev 74:298-340. 2010
  7. pmc Transcription factors Mat2 and Znf2 operate cellular circuits orchestrating opposite- and same-sex mating in Cryptococcus neoformans
    Xiaorong Lin
    Department of Biology, Texas A and M University, College Station, Texas, United States of America
    PLoS Genet 6:e1000953. 2010
  8. pmc Evolution of the sex-related locus and genomic features shared in microsporidia and fungi
    Soo Chan Lee
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS ONE 5:e10539. 2010
  9. pmc Morphological and genomic characterization of Filobasidiella depauperata: a homothallic sibling species of the pathogenic cryptococcus species complex
    Marianela Rodriguez-Carres
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS ONE 5:e9620. 2010
  10. pmc The chitin synthase genes chsA and chsC are not required for cell wall stress responses in the human pathogen Aspergillus fumigatus
    Luise E Rogg
    Department of Pediatrics, Division of Pediatric Infectious Diseases, Duke University Medical Center, Durham, NC 27710, USA
    Biochem Biophys Res Commun 411:549-54. 2011

Detail Information

Publications43

  1. pmc Unisexual and heterosexual meiotic reproduction generate aneuploidy and phenotypic diversity de novo in the yeast Cryptococcus neoformans
    Min Ni
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS Biol 11:e1001653. 2013
    ....
  2. pmc Sporangiospore size dimorphism is linked to virulence of Mucor circinelloides
    Charles H Li
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS Pathog 7:e1002086. 2011
    ..circinelloides species and that plasticity of the sex locus and adaptations in pathogenicity have occurred during speciation of the M. circinelloides complex...
  3. pmc Regulatable Ras activity is critical for proper establishment and maintenance of polarity in Aspergillus fumigatus
    Jarrod R Fortwendel
    Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA
    Eukaryot Cell 10:611-5. 2011
    ..These findings highlight the requirement for balanced Ras activity in the establishment and maintenance of polarized growth in filamentous fungi...
  4. pmc Structure, function, and phylogeny of the mating locus in the Rhizopus oryzae complex
    Andrii P Gryganskyi
    Department of Biology, Duke University, Durham, North Carolina, United States of America
    PLoS ONE 5:e15273. 2010
    ..oryzae produced sterile zygospores. In spite of the reluctance of most strains to mate in vitro, the conserved sex locus structure and evidence for outcrossing suggest that a normal sexual cycle occurs in both species...
  5. pmc Cryptococcal cell morphology affects host cell interactions and pathogenicity
    Laura H Okagaki
    Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota, United States of America
    PLoS Pathog 6:e1000953. 2010
    ..neoformans evades host phagocytosis to allow survival of a subset of the population at early stages of infection. Thus, morphological changes play unique and specialized roles during infection...
  6. pmc The evolution of sex: a perspective from the fungal kingdom
    Soo Chan Lee
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
    Microbiol Mol Biol Rev 74:298-340. 2010
    ....
  7. pmc Transcription factors Mat2 and Znf2 operate cellular circuits orchestrating opposite- and same-sex mating in Cryptococcus neoformans
    Xiaorong Lin
    Department of Biology, Texas A and M University, College Station, Texas, United States of America
    PLoS Genet 6:e1000953. 2010
    ..Further characterization of these elements and their target circuits will reveal genes controlling biological processes central to fungal development and virulence...
  8. pmc Evolution of the sex-related locus and genomic features shared in microsporidia and fungi
    Soo Chan Lee
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS ONE 5:e10539. 2010
    ..Recent phylogenetic studies and gene order analysis suggest that microsporidia share a particularly close evolutionary relationship with the zygomycetes...
  9. pmc Morphological and genomic characterization of Filobasidiella depauperata: a homothallic sibling species of the pathogenic cryptococcus species complex
    Marianela Rodriguez-Carres
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS ONE 5:e9620. 2010
    ..depauperata. We therefore propose that chromosomal rearrangements appear to be a major force driving speciation and sexual divergence in these closely related pathogenic and saprobic species...
  10. pmc The chitin synthase genes chsA and chsC are not required for cell wall stress responses in the human pathogen Aspergillus fumigatus
    Luise E Rogg
    Department of Pediatrics, Division of Pediatric Infectious Diseases, Duke University Medical Center, Durham, NC 27710, USA
    Biochem Biophys Res Commun 411:549-54. 2011
    ..Our findings support the existence of complex post-transcriptional regulatory mechanisms controlling chitin biosynthetic machinery in response to cell wall damage...
  11. pmc Sex in fungi
    Min Ni
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA
    Annu Rev Genet 45:405-30. 2011
    ..As robust and diverse genetic models, fungi provide insights into the molecular nature of sex, sexual specification, and evolution to advance our understanding of sexual reproduction and its impact throughout the eukaryotic tree of life...
  12. pmc Localization and activity of the calcineurin catalytic and regulatory subunit complex at the septum is essential for hyphal elongation and proper septation in Aspergillus fumigatus
    Praveen Rao Juvvadi
    Department of Pediatrics, Division of Pediatric Infectious Diseases, Duke University Medical Center, Durham, NC, USA
    Mol Microbiol 82:1235-59. 2011
    ..These findings confirm a cooperative role for the calcineurin complex in regulating hyphal growth and septation...
  13. pmc Calcineurin plays key roles in the dimorphic transition and virulence of the human pathogenic zygomycete Mucor circinelloides
    Soo Chan Lee
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS Pathog 9:e1003625. 2013
    ..Our results demonstrate that the calcineurin pathway orchestrates the yeast-hyphal and spore size dimorphic transitions that contribute to virulence of this common zygomycete fungal pathogen...
  14. pmc Phosphorylation of Calcineurin at a novel serine-proline rich region orchestrates hyphal growth and virulence in Aspergillus fumigatus
    Praveen R Juvvadi
    Department of Pediatrics, Division of Pediatric Infectious Diseases, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS Pathog 9:e1003564. 2013
    ..These findings suggest the possibility of harnessing this unique SPRR for innovative antifungal drug design to combat invasive aspergillosis. ..
  15. pmc Temporal analysis of the magnaporthe oryzae proteome during conidial germination and cyclic AMP (cAMP)-mediated appressorium formation
    William L Franck
    Center for Integrated Fungal Research, North Carolina State University, Raleigh, North Carolina 27606, USA
    Mol Cell Proteomics 12:2249-65. 2013
    ..Collectively, the data presented here provide the first comprehensive view of the M. oryzae proteome during early infection-related development and highlight biological processes important for pathogenicity. ..
  16. pmc Heat shock protein 90 is required for conidiation and cell wall integrity in Aspergillus fumigatus
    Frederic Lamoth
    Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
    Eukaryot Cell 11:1324-32. 2012
    ..Targeting Hsp90 with fungal-specific inhibitors to cripple stress response compensatory pathways represents an attractive new antifungal strategy...
  17. pmc Plasma membrane localization is required for RasA-mediated polarized morphogenesis and virulence of Aspergillus fumigatus
    Jarrod R Fortwendel
    Department of Microbiology and Immunology, University of South Alabama, Mobile, Alabama, USA
    Eukaryot Cell 11:966-77. 2012
    ..Our results demonstrate that plasma membrane-associated RasA is critical for polarized morphogenesis, cell wall stability, and virulence in A. fumigatus...
  18. pmc Function of Cryptococcus neoformans KAR7 (SEC66) in karyogamy during unisexual and opposite-sex mating
    Soo Chan Lee
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA
    Eukaryot Cell 11:783-94. 2012
    ..neoformans mating, which demonstrates a different evolutionary trajectory for the KAR genes in C. neoformans compared to those in S. cerevisiae...
  19. pmc Transcriptional regulation of chitin synthases by calcineurin controls paradoxical growth of Aspergillus fumigatus in response to caspofungin
    Jarrod R Fortwendel
    Departments of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA
    Antimicrob Agents Chemother 54:1555-63. 2010
    ..Taken together, our data suggest a mechanistic role for A. fumigatus calcineurin signaling in the chitin biosynthetic response observed during paradoxical growth in the presence of high-dose caspofungin treatment...
  20. pmc Diploids in the Cryptococcus neoformans serotype A population homozygous for the alpha mating type originate via unisexual mating
    Xiaorong Lin
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS Pathog 5:e1000283. 2009
    ..Our findings underscore the importance of same-sex mating in shaping the current population structure of this important human pathogenic fungus, with implications for mechanisms of selfing and inbreeding in other microbial pathogens...
  21. pmc Phylogeny and phenotypic characterization of pathogenic Cryptococcus species and closely related saprobic taxa in the Tremellales
    Keisha Findley
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA
    Eukaryot Cell 8:353-61. 2009
    ....
  22. ncbi Excess costs of hospital care associated with neonatal candidemia
    P Brian Smith
    Department of Pediatrics, 3179 Duke University Medical Center, Durham NC, 27710, USA
    Pediatr Infect Dis J 26:197-200. 2007
    ..Candida is an increasingly important nosocomial pathogen within intensive care nurseries. The purpose of this study was to determine the attributable cost of candidemia in neonates...
  23. pmc Cryptococcus neoformans mates on pigeon guano: implications for the realized ecological niche and globalization
    Kirsten Nielsen
    Department of Molecular Genetics and Microbiology, Research Drive, Duke University Medical Center, Durham, NC 27710, USA
    Eukaryot Cell 6:949-59. 2007
    ..gattii. Based on these studies, we hypothesize that an ancestral Cryptococcus strain gained the ability to sexually reproduce in pigeon guano and then swept the globe...
  24. pmc Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA
    Robyn M Perrin
    Department of Plant Pathology, University of Wisconsin Madison, Madison, Wisconsin, United States of America
    PLoS Pathog 3:e50. 2007
    ..Our findings suggest that LaeA is a novel target for comprehensive modification of chemical diversity and pathogenicity...
  25. pmc Phosphatidylinositol transfer proteins and functional specification of lipid signaling pools
    Vytas A Bankaitis
    Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599 7090, USA
    Adv Enzyme Regul 47:27-40. 2007
  26. pmc Virulence attributes and hyphal growth of C. neoformans are quantitative traits and the MATalpha allele enhances filamentation
    Xiaorong Lin
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS Genet 2:e187. 2006
    ..Further characterization of these QTL regions will reveal additional quantitative trait genes controlling biological processes central to fungal development and pathogenicity...
  27. ncbi Neonatal Candida meningitis: significance of cerebrospinal fluid parameters and blood cultures
    M Cohen-Wolkowiez
    Department of Pediatrics, Duke University, Durham, NC 27705, USA
    J Perinatol 27:97-100. 2007
    ..The purpose of this study was to examine the frequency of normal cerebrospinal fluid (CSF) parameters in Candida meningitis and the proportion of candidemia associated with Candida meningitis...
  28. ncbi Phylogenomic analysis of non-ribosomal peptide synthetases in the genus Aspergillus
    Robert A Cramer
    Duke University Medical Center, Department of Molecular Genetics and Microbiology, Durham, NC 27710, USA
    Gene 383:24-32. 2006
    ..Further analysis of these genes and their peptide products may identify important roles for secondary metabolites produced by NRPS in Aspergillus physiology, ecology, and fungal pathogenicity...
  29. pmc Transcription factor Nrg1 mediates capsule formation, stress response, and pathogenesis in Cryptococcus neoformans
    Kari L Cramer
    Department of Medicine and Molecular Genetics Microbiology, Duke University Medical Center 3355, Durham, North Carolina 27710, USA
    Eukaryot Cell 5:1147-56. 2006
    ..Consistent with prior studies in hypocapsular mutants, the nrg1 mutant strain is attenuated in an animal model of disseminated cryptococcal disease...
  30. pmc Eca1, a sarcoplasmic/endoplasmic reticulum Ca2+-ATPase, is involved in stress tolerance and virulence in Cryptococcus neoformans
    Weihua Fan
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
    Infect Immun 75:3394-405. 2007
    ..Eca1 is likely involved in maintaining ER function, thus contributing to stress tolerance and virulence acting in parallel with Ca2+-calcineurin signaling...
  31. pmc Calcineurin inhibition or mutation enhances cell wall inhibitors against Aspergillus fumigatus
    William J Steinbach
    Division of Pediatric Infectious Diseases, Duke University Medical Center, Durham, NC 27710, USA
    Antimicrob Agents Chemother 51:2979-81. 2007
    ..Quantification of 1,3-beta-d-glucan revealed decreased amounts in the calcineurin A (DeltacnaA) mutant. Calcineurin can be an excellent adjunct therapeutic target in combination with other cell wall inhibitors against A. fumigatus...
  32. pmc Quantification of 1,3-beta-D-glucan levels in children: preliminary data for diagnostic use of the beta-glucan assay in a pediatric setting
    P Brian Smith
    Department of Pediatrics, Division of Pediatric Infectious Diseases, Duke University Medical Center, Durham, North Carolina 27710, USA
    Clin Vaccine Immunol 14:924-5. 2007
    ..We found higher 1,3-beta-D-glucan levels in children than those previously reported in adults...
  33. pmc The Cryptococcus neoformans Rho-GDP dissociation inhibitor mediates intracellular survival and virulence
    Michael S Price
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
    Infect Immun 76:5729-37. 2008
    ..This reduction in virulence of the rdi1Delta mutant occurs in the absence of major growth defects in rich medium and with classical virulence-associated phenotypes...
  34. pmc Trans-Golgi network and endosome dynamics connect ceramide homeostasis with regulation of the unfolded protein response and TOR signaling in yeast
    Carl J Mousley
    Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599 7090, USA
    Mol Biol Cell 19:4785-803. 2008
    ..These results provide new insight into Sec14 function, and they emphasize the TGN/endosomal system as a central hub for homeostatic regulation in eukaryotes...
  35. pmc Isolates of Cryptococcus neoformans from infected animals reveal genetic exchange in unisexual, alpha mating type populations
    Tien Bui
    Discipline of Microbiology, School of Molecular and Microbial Biosciences, University of Sydney, New South Wales, Australia
    Eukaryot Cell 7:1771-80. 2008
    ....
  36. pmc Calcineurin target CrzA regulates conidial germination, hyphal growth, and pathogenesis of Aspergillus fumigatus
    Robert A Cramer
    Duke University Medical Center, Box 3499, Pediatric Infectious Diseases, Durham, NC 27710, USA
    Eukaryot Cell 7:1085-97. 2008
    ..In addition, the importance of CrzA to the production of disease is critical, and thus CrzA is an attractive fungus-specific antifungal target for the treatment of invasive aspergillosis...
  37. pmc Impact of mating type, serotype, and ploidy on the virulence of Cryptococcus neoformans
    Xiaorong Lin
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
    Infect Immun 76:2923-38. 2008
    ..This study provides insights into the impact of ploidy, mating type, and serotype on virulence and the impact of hybridization on the fitness and virulence of a eukaryotic microbial pathogen...
  38. ncbi Functional anatomy of phospholipid binding and regulation of phosphoinositide homeostasis by proteins of the sec14 superfamily
    Gabriel Schaaf
    Department of Cell and Developmental Biology, School of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7090, USA
    Mol Cell 29:191-206. 2008
    ..Collectively, these findings outline functional mechanisms for the Sec14 superfamily and reveal additional layers of complexity for regulating phosphoinositide homeostasis in eukaryotes...
  39. pmc alpha AD alpha hybrids of Cryptococcus neoformans: evidence of same-sex mating in nature and hybrid fitness
    Xiaorong Lin
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA
    PLoS Genet 3:1975-90. 2007
    ..These findings provide insights on the origins, genetic mechanisms, and fitness impact of unisexual hybridization in the Cryptococcus population...
  40. pmc Many globally isolated AD hybrid strains of Cryptococcus neoformans originated in Africa
    Anastasia P Litvintseva
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS Pathog 3:e114. 2007
    ....
  41. pmc Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production
    Robert A Cramer
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
    Eukaryot Cell 5:972-80. 2006
    ..This result suggests that gliotoxin is not required for virulence in an immunosuppressed host with an invasive pulmonary infection...

Research Grants12

  1. UNIVERSITY OF SOUTHERN CALIFORNIA CLINICAL TRIALS UNIT
    Fred R Sattler; Fiscal Year: 2013
    ..g. East LA) that will often be applicable for the care of patients in developing countries. ADMINISTRATIVE COMPONENT: ..
  2. Cryptococcus neoformans Gene Knockout Resource
    Hiten D Madhani; Fiscal Year: 2013
    ....
  3. Eunice Kennedy Shriver NICHD Cooperative Multicenter Neonatal Research Network
    Ronald Goldberg; Fiscal Year: 2013
    ....
  4. Chemical-genetic functional annotation of the genome of a meningitis pathogen
    Hiten D Madhani; Fiscal Year: 2013
    ..In addition, this work is anticipated to define chemical modulators of essential virulence pathways, which are expected to be powerful tools for studies of pathogen biology and future therapeutic development. ..
  5. Development of Monoclonal Antibody (Mab) Biologics against Neonatal Candidiasis
    Jose L Lopez-Ribot; Fiscal Year: 2013
    ....
  6. Antifungal drug target prioritization using Cryptococcus neoformans
    Alexander Idnurm; Fiscal Year: 2013
    ..The discovery of these essential genes represents new avenues for the development of antifungal agents. ..
  7. Pheromones and Titan Cell Production in Cryptococcus neoformans
    Kirsten Nielsen; Fiscal Year: 2013
    ..This proposal studies morphological changes in response to the host environment. Once we know how C. neoformans is able to grow and survive in the host, we can develop treatment strategies that block this process. ..