The long-term goal of our research is to define the pathogenesis mechanisms of the most common causative agent of human airborne fungal infections, Aspergillus fumigatus. As the incidence of disease caused by A. fumigatus continues to rise and the mortality rate remains near 50%, new insights into the pathophysiology of these infections is needed. Elucidating the mechanisms by which A. fumigatus causes disease has great promise to identify new therapeutic strategies to improve patient outcomes. During the prior funding period we identified hypoxia, low oxygen levels, as a critical component of the infection site microenvironment in models of invasive pulmonary aspergillosis (IPA). Our data suggest that hypoxia contributes to host damage and poor IPA disease outcomes. These observations are consistent with data from many human diseases linking hypoxia with negative therapeutic results. Because we currently do not understand how hypoxia influences the outcome of fungal-host interactions, this is a need to know question given the significant association between hypoxia and poor human disease outcomes. The objective of this renewal proposal is to define molecular mechanisms of A. fumigatus hypoxia adaptation and test novel oxygen mediated therapeutic for improvement of IPA outcomes. Our central hypothesis is that inhibition of the hypoxia transcription factor SrbA mediated genetic network can be achieved to significantly improve IPA outcomes. The central hypothesis and objective of this research will be tested and accomplished by completing three specific aims.
In aim 1, we will define the mechanism by which a new SrbA dependent transcription factor SrbB contributes to a novel hypoxia mediated iron uptake mechanism required for fungal virulence.
In aim 2, we will define a previously unknown role for SrbA mediated fungal carbon catabolite repression in hypoxia adaptation and fungal virulence.
In aim 3, we build on exciting preliminary data suggesting that manipulation of in vivo oxygen lung content through inhibition of the SrbA genetic network improves IPA outcomes. Successful completion of the experiments in this proposal will generate novel insights into mechanisms affecting fungal hypoxia adaptation, new insights into mechanisms of fungal virulence, and development of a new non-invasive therapeutic to improve IPA outcomes. These proposed studies are expected to be part of a continuum of research that will explore and define the tremendous therapeutic opportunities in understanding how fungi adapt to hypoxia.

Public Health Relevance

Human diseases caused by Aspergillus fumigatus are increasingly common and treatment options remain limited. Mortality rates often exceed 50% and new therapeutic interventions are urgently needed to improve patient outcomes. Our goal for this proposal is to test the hypothesis that in vivo oxygen manipulation can thwart fungal virulence and significantly improve disease outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI081838-07
Application #
8901906
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2009-08-15
Project End
2018-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
7
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
Dhingra, Sourabh; Buckey, Jay C; Cramer, Robert A (2018) Hyperbaric Oxygen Reduces Aspergillus fumigatus Proliferation In Vitro and Influences In Vivo Disease Outcomes. Antimicrob Agents Chemother 62:
Ries, Laure Nicolas Annick; Beattie, Sarah; Cramer, Robert A et al. (2018) Overview of carbon and nitrogen catabolite metabolism in the virulence of human pathogenic fungi. Mol Microbiol 107:277-297
Cramer, Robert A; Sheppard, Donald C; Clemons, Karl V (2017) 7th Advances Against Aspergillosis: Basic, diagnostic, clinical and therapeutic studies. Med Mycol 55:1-3
Bultman, Katherine M; Kowalski, Caitlin H; Cramer, Robert A (2017) Aspergillus fumigatus virulence through the lens of transcription factors. Med Mycol 55:24-38
Caffrey-Carr, Alayna K; Hilmer, Kimberly M; Kowalski, Caitlin H et al. (2017) Host-Derived Leukotriene B4 Is Critical for Resistance against Invasive Pulmonary Aspergillosis. Front Immunol 8:1984
Shlezinger, Neta; Irmer, Henriette; Dhingra, Sourabh et al. (2017) Sterilizing immunity in the lung relies on targeting fungal apoptosis-like programmed cell death. Science 357:1037-1041
Thammahong, Arsa; Caffrey-Card, Alayna K; Dhingra, Sourabh et al. (2017) Aspergillus fumigatus Trehalose-Regulatory Subunit Homolog Moonlights To Mediate Cell Wall Homeostasis through Modulation of Chitin Synthase Activity. MBio 8:
Thammahong, Arsa; Puttikamonkul, Srisombat; Perfect, John R et al. (2017) Central Role of the Trehalose Biosynthesis Pathway in the Pathogenesis of Human Fungal Infections: Opportunities and Challenges for Therapeutic Development. Microbiol Mol Biol Rev 81:
Dhingra, Sourabh; Cramer, Robert A (2017) Regulation of Sterol Biosynthesis in the Human Fungal Pathogen Aspergillus fumigatus: Opportunities for Therapeutic Development. Front Microbiol 8:92
Beattie, Sarah R; Mark, Kenneth M K; Thammahong, Arsa et al. (2017) Filamentous fungal carbon catabolite repression supports metabolic plasticity and stress responses essential for disease progression. PLoS Pathog 13:e1006340

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