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 #
2R01AI081838-06A1
Application #
8759323
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2009-08-15
Project End
2018-07-31
Budget Start
2014-08-02
Budget End
2015-07-31
Support Year
6
Fiscal Year
2014
Total Cost
$405,000
Indirect Cost
$155,000
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Blosser, Sara J; Merriman, Brittney; Grahl, Nora et al. (2014) Two C4-sterol methyl oxidases (Erg25) catalyse ergosterol intermediate demethylation and impact environmental stress adaptation in Aspergillus fumigatus. Microbiology 160:2492-506
Chung, Dawoon; Barker, Bridget M; Carey, Charles C et al. (2014) ChIP-seq and in vivo transcriptome analyses of the Aspergillus fumigatus SREBP SrbA reveals a new regulator of the fungal hypoxia response and virulence. PLoS Pathog 10:e1004487
Chung, Dawoon; Thammahong, Arsa; Shepardson, Kelly M et al. (2014) Endoplasmic reticulum localized PerA is required for cell wall integrity, azole drug resistance, and virulence in Aspergillus fumigatus. Mol Microbiol 92:1279-98
Shepardson, Kelly M; Jhingran, Anupam; Caffrey, Alayna et al. (2014) Myeloid derived hypoxia inducible factor 1-alpha is required for protection against pulmonary Aspergillus fumigatus infection. PLoS Pathog 10:e1004378
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Jimenez-Lopez, Claudia; Collette, John R; Brothers, Kimberly M et al. (2013) Candida albicans induces arginine biosynthetic genes in response to host-derived reactive oxygen species. Eukaryot Cell 12:91-100
Marakalala, Mohlopheni J; Vautier, Simon; Potrykus, Joanna et al. (2013) Differential adaptation of Candida albicans in vivo modulates immune recognition by dectin-1. PLoS Pathog 9:e1003315
Shepardson, Kelly M; Cramer, Robert A (2013) Fungal cell wall dynamics and infection site microenvironments: signal integration and infection outcome. Curr Opin Microbiol 16:385-90
Grahl, Nora; Dinamarco, Taisa Magnani; Willger, Sven D et al. (2012) Aspergillus fumigatus mitochondrial electron transport chain mediates oxidative stress homeostasis, hypoxia responses and fungal pathogenesis. Mol Microbiol 84:383-99

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