Hypoxia Adapatation and Fungal Virulence of Aspergillus fumigatus

Summary

Principal Investigator: ROBERT ANDREW CRAMER
Abstract: Invasive aspergillosis (IA) is caused by the mould Aspergillus fumigatus and is an understudied disease of growing significance that causes over 3,500 deaths in the United States annually. The spectrum of patients susceptible to A. fumigatus infections is also dramatically increasing with the development of new medical technologies. Currently, our understanding of the mechanisms utilized by this common mould to cause disease is limited. Though it is likely that A. fumigatus encounters significant environmental stress during IA, how the fungus adapts to micro-environments found in vivo at sites of infection is not fully understood. We have discovered that A. fumigatus encounters significant hypoxia during infection. Importantly, we have discovered that adaptation to hypoxia is genetically regulated in this mould and required for fungal virulence. Thus, the long-term objective of this proposal is to define the molecular mechanisms utilized by this fungus to adapt to hypoxia and cause disease in immunocompromised patients. This may lead to development of novel therapeutic interventions for IA. This proposal has three specific aims designed to define the molecular mechanism of hypoxia adaptation as mediated by a sterol-regulatory element binding protein (SREBP), SrbA, that mediates hypoxia adaptation and fungal virulence in A. fumigatus. In aim 1, we will define where and when SrbA is activated in A. fumigatus establishing the first part of a model of SrbA mediated hypoxia adaptation in A. fumigatus. In aim 2, we will identify and characterize the key players that interact with SrbA and likely regulate its activity adding the second regulatory layer to our model. In aim 3, the key downstream effectors of SrbA that mediate adaptation to hypoxia by A. fumigatus will be identified and characterized. Completion of these 3 aims will offer much needed insights into the mechanisms of a novel virulence attribute of A. fumigatus and lay the foundation for a model of SREBP signaling in a pathogenic mould for the first time. Investigations in these specific aims will also provide additional targets for future studies to elucidate mechanisms of hypoxia adaptation that may be applicable to a broad-spectrum of pathogenic moulds. PUBLIC HEALTH RELEVANCE: Lethal infections by common moulds are becoming increasingly common with advances in medical technologies. Treatment options for these infections are very limited, and new therapeutic interventions are urgently needed. This proposal seeks to discover new therapeutic options to treat invasive aspergillosis caused by the filamentous mould Aspergillus fumigatus.
Funding Period: -------------------- - --------------------
more information: NIH RePORT

Top Publications

  1. pmc Regulation of hypoxia adaptation: an overlooked virulence attribute of pathogenic fungi?
    Nora Grahl
    Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana, USA
    Med Mycol 48:1-15. 2010
  2. pmc Differential adaptation of Candida albicans in vivo modulates immune recognition by dectin-1
    Mohlopheni J Marakalala
    Division of Immunology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town, South Africa
    PLoS Pathog 9:e1003315. 2013
  3. pmc Fungal cell wall dynamics and infection site microenvironments: signal integration and infection outcome
    Kelly M Shepardson
    Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
    Curr Opin Microbiol 16:385-90. 2013
  4. pmc Hypoxia enhances innate immune activation to Aspergillus fumigatus through cell wall modulation
    Kelly M Shepardson
    Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MT 59717, USA
    Microbes Infect 15:259-69. 2013
  5. pmc Candida albicans induces arginine biosynthetic genes in response to host-derived reactive oxygen species
    Claudia Jimenez-Lopez
    Department of Microbiology and Molecular Genetics, University of Texas Health Science Center at Houston, Houston, Texas, USA
    Eukaryot Cell 12:91-100. 2013
  6. pmc Coordination of hypoxia adaptation and iron homeostasis in human pathogenic fungi
    DaWoon Chung
    Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth Hanover, NH, USA
    Front Microbiol 3:381. 2012
  7. pmc Dsc orthologs are required for hypoxia adaptation, triazole drug responses, and fungal virulence in Aspergillus fumigatus
    Sven D Willger
    Department of Immunology and Infectious Disease, Montana State University, Bozeman, Montana, USA
    Eukaryot Cell 11:1557-67. 2012
  8. pmc Endoplasmic reticulum localized PerA is required for cell wall integrity, azole drug resistance, and virulence in Aspergillus fumigatus
    DaWoon Chung
    Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
    Mol Microbiol 92:1279-98. 2014
  9. pmc TmpL, a transmembrane protein required for intracellular redox homeostasis and virulence in a plant and an animal fungal pathogen
    Kwang Hyung Kim
    Virginia Bioinformatics Institute and Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
    PLoS Pathog 5:e1000653. 2009
  10. pmc HacA-independent functions of the ER stress sensor IreA synergize with the canonical UPR to influence virulence traits in Aspergillus fumigatus
    Xizhi Feng
    Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
    PLoS Pathog 7:e1002330. 2011

Scientific Experts

  • D S Askew
  • Hubertus Haas
  • ROBERT ANDREW CRAMER
  • Bridget M Barker
  • Nora Grahl
  • Kelly M Shepardson
  • DaWoon Chung
  • Sara J Blosser
  • Sven D Willger
  • Srisombat Puttikamonkul
  • Mohlopheni J Marakalala
  • Claudia Jimenez-Lopez
  • Tobias M Hohl
  • Lisa Y Ngo
  • Vishukumar Aimanianda
  • Jean Paul Latge
  • Sara J Wezensky
  • Michael Blatzer
  • Xizhi Feng
  • Haiyan Li
  • Kwang Hyung Kim
  • Arsa Thammahong
  • Michael C Lorenz
  • Simon Vautier
  • Hector M Mora-Montes
  • Alistair J P Brown
  • Gordon D Brown
  • Carol A Munro
  • Yoichiro Iwakura
  • Robert Wheeler
  • John R Collette
  • Alex Hopke
  • Robert T Wheeler
  • Graeme I Murray
  • Kimberly M Brothers
  • Joanna Potrykus
  • Neil A R Gow
  • Ann Kerrigan
  • Mihai G Netea
  • Louise A Walker
  • Donna M MacCallum
  • Taisa Magnani Dinamarco
  • Margaret M Lehmann
  • E Jean Cornish
  • Gustavo H Goldman
  • Brittany A Fleming
  • AurĂ©lien Mazurie
  • Long Jason Lu
  • William C Nierman
  • Margaret V Powers-Fletcher
  • Karthik Krishnan
  • Daryl L Richie
  • Jeffrey M MacDonald
  • Judith C Rhodes
  • Lukas Hartl
  • Simon L Newman
  • Michael P Gamcsik
  • Minlu Zhang
  • LAURA WOOLLETT
  • Jeremey D Bell
  • Nicola Beckmann
  • Kelly D Craven
  • Elizabeth J Cornish
  • Kevin K Fuller
  • Christopher B Lawrence
  • Biswarup Mukhopadhyay
  • Yangrae Cho
  • Sang Wook Park

Detail Information

Publications19

  1. pmc Regulation of hypoxia adaptation: an overlooked virulence attribute of pathogenic fungi?
    Nora Grahl
    Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana, USA
    Med Mycol 48:1-15. 2010
    ..In this review, we focus on known oxygen sensing mechanisms that non-pathogenic and pathogenic fungi utilize to adapt to hypoxic microenvironments and their possible relation to fungal virulence...
  2. pmc Differential adaptation of Candida albicans in vivo modulates immune recognition by dectin-1
    Mohlopheni J Marakalala
    Division of Immunology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town, South Africa
    PLoS Pathog 9:e1003315. 2013
    ..albicans and the immune system and have significant implications for our understanding of susceptibility and treatment of human infections with this pathogen...
  3. pmc Fungal cell wall dynamics and infection site microenvironments: signal integration and infection outcome
    Kelly M Shepardson
    Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
    Curr Opin Microbiol 16:385-90. 2013
    ..A challenge moving forward is to further understand these mechanisms and harness them for therapeutic benefit. ..
  4. pmc Hypoxia enhances innate immune activation to Aspergillus fumigatus through cell wall modulation
    Kelly M Shepardson
    Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MT 59717, USA
    Microbes Infect 15:259-69. 2013
    ....
  5. pmc Candida albicans induces arginine biosynthetic genes in response to host-derived reactive oxygen species
    Claudia Jimenez-Lopez
    Department of Microbiology and Molecular Genetics, University of Texas Health Science Center at Houston, Houston, Texas, USA
    Eukaryot Cell 12:91-100. 2013
    ..In summary, phagocytosis induces this single amino acid biosynthetic pathway in an ROS-dependent manner...
  6. pmc Coordination of hypoxia adaptation and iron homeostasis in human pathogenic fungi
    DaWoon Chung
    Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth Hanover, NH, USA
    Front Microbiol 3:381. 2012
    ..Thus, both oxygen and iron availability are intimately tied with fungal virulence and responses to existing therapeutics and further elucidation of their interrelationship should have significant clinical implications...
  7. pmc Dsc orthologs are required for hypoxia adaptation, triazole drug responses, and fungal virulence in Aspergillus fumigatus
    Sven D Willger
    Department of Immunology and Infectious Disease, Montana State University, Bozeman, Montana, USA
    Eukaryot Cell 11:1557-67. 2012
    ..fumigatus that mediate hypoxia adaptation, fungal virulence, and triazole drug susceptibility and that are likely linked to regulation of SrbA function...
  8. pmc Endoplasmic reticulum localized PerA is required for cell wall integrity, azole drug resistance, and virulence in Aspergillus fumigatus
    DaWoon Chung
    Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
    Mol Microbiol 92:1279-98. 2014
    ..fumigatus is a promising research direction to uncover a new fungal specific antifungal drug target. ..
  9. pmc TmpL, a transmembrane protein required for intracellular redox homeostasis and virulence in a plant and an animal fungal pathogen
    Kwang Hyung Kim
    Virginia Bioinformatics Institute and Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
    PLoS Pathog 5:e1000653. 2009
    ..Our results strongly suggest that dysregulation of oxidative stress homeostasis in the absence of TmpL is the underpinning cause of the developmental and virulence defects observed in these studies...
  10. pmc HacA-independent functions of the ER stress sensor IreA synergize with the canonical UPR to influence virulence traits in Aspergillus fumigatus
    Xizhi Feng
    Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
    PLoS Pathog 7:e1002330. 2011
    ..Together, these findings demonstrate that IreA has both HacA-dependent and HacA-independent functions that contribute to the expression of traits that are essential for virulence in A. fumigatus...
  11. pmc Implications of hypoxic microenvironments during invasive aspergillosis
    Sara J Wezensky
    Department of Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717, USA
    Med Mycol 49:S120-4. 2011
    ..We focus on three areas where hypoxia may play a role in determining the outcome of infection: fungal virulence, host immune responses, and efficacy of current antifungal drug treatments...
  12. pmc The small GTPase RacA mediates intracellular reactive oxygen species production, polarized growth, and virulence in the human fungal pathogen Aspergillus fumigatus
    Haiyan Li
    Plant Biology Division, The Samuel Roberts Noble Foundation Inc, Ardmore, OK 73401, USA
    Eukaryot Cell 10:174-86. 2011
    ..These results demonstrate that in vitro growth phenotypes do not always correlate with in vivo virulence and raise intriguing questions about the role of RacA in Aspergillus virulence...
  13. pmc Immune responses against Aspergillus fumigatus: what have we learned?
    Robert A Cramer
    Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana, USA
    Curr Opin Infect Dis 24:315-22. 2011
    ..This review covers the molecular and cellular events that mediate innate and CD4 T-cell responses to A. fumigatus and fungal attributes that counter hostile microenvironments and, in turn, affect host responses...
  14. pmc In vivo hypoxia and a fungal alcohol dehydrogenase influence the pathogenesis of invasive pulmonary aspergillosis
    Nora Grahl
    Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana, United States of America
    PLoS Pathog 7:e1002145. 2011
    ..Thus, environmental conditions encountered by invading pathogenic fungi may result in substantial fungal metabolism changes that influence subsequent host immune responses...
  15. pmc Aspergillus fumigatus mitochondrial electron transport chain mediates oxidative stress homeostasis, hypoxia responses and fungal pathogenesis
    Nora Grahl
    Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MT, USA
    Mol Microbiol 84:383-99. 2012
    ..Thus, our results demonstrate a previously unidentified role for fungal mitochondrial respiration in the pathogenesis of aspergillosis, and lay the foundation for future research into its role in hypoxia signalling and adaptation...
  16. pmc Transcriptomic and proteomic analyses of the Aspergillus fumigatus hypoxia response using an oxygen-controlled fermenter
    Bridget M Barker
    Department of Immunology and Infectious Disease, Montana State University, Bozeman, MT, USA
    BMC Genomics 13:62. 2012
    ....
  17. pmc SREBP-dependent triazole susceptibility in Aspergillus fumigatus is mediated through direct transcriptional regulation of erg11A (cyp51A)
    Sara J Blosser
    Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana, USA
    Antimicrob Agents Chemother 56:248-57. 2012
    ..Taken together, our results demonstrate a critical role for SrbA-mediated regulation of ergosterol biosynthesis and triazole drug interactions in A. fumigatus that may have clinical importance...
  18. pmc SREBP coordinates iron and ergosterol homeostasis to mediate triazole drug and hypoxia responses in the human fungal pathogen Aspergillus fumigatus
    Michael Blatzer
    Division of Molecular Biology Biocenter, Innsbruck Medical University, Innsbruck, Austria
    PLoS Genet 7:e1002374. 2011
    ..These results support a role for SREBP-mediated iron regulation in fungal virulence, and they lay a foundation for further exploration of SREBP's role in iron homeostasis in other eukaryotes...