In vivo Hypoxia and a Fungal Alcohol Dehydrogenase Influence the Pathogenesis of Invasive Pulmonary Aspergillosis

PLoS Pathogens

Srisombat Puttikamonkul¹  Robert A. Cramer¹  Nora Grahl¹  Lisa Y. Ngo²  Tobias M. Hohl²  Jeffrey M. Macdonald³  Michael P. Gamcsik³ 

[1] Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana, United States of America;Infectious Disease Sciences, Vaccine and Infectious Disease Division, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America;Joint Department of Biomedical Engineering, University of North Carolina, Chapel Hill, and North Carolina State University, Raleigh, North Carolina, United States of America

关键词: Mouse models;    Aspergillus fumigatus;    Ethanol;    Fungal pathogens;    Hypoxia;    Fermentation;    Medical hypoxia;    Inflammation;   

DOI  :  10.1371/journal.ppat.1002145

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Currently, our knowledge of how pathogenic fungi grow in mammalian host environments is limited. Using a chemotherapeutic murine model of invasive pulmonary aspergillosis (IPA) and 1H-NMR metabolomics, we detected ethanol in the lungs of mice infected with Aspergillus fumigatus. This result suggests that A. fumigatus is exposed to oxygen depleted microenvironments during infection. To test this hypothesis, we utilized a chemical hypoxia detection agent, pimonidazole hydrochloride, in three immunologically distinct murine models of IPA (chemotherapeutic, X-CGD, and corticosteroid). In all three IPA murine models, hypoxia was observed during the course of infection. We next tested the hypothesis that production of ethanol in vivo by the fungus is involved in hypoxia adaptation and fungal pathogenesis. Ethanol deficient A. fumigatus strains showed no growth defects in hypoxia and were able to cause wild type levels of mortality in all 3 murine models. However, lung immunohistopathology and flow cytometry analyses revealed an increase in the inflammatory response in mice infected with an alcohol dehydrogenase null mutant strain that corresponded with a reduction in fungal burden. Consequently, in this study we present the first in vivo observations that hypoxic microenvironments occur during a pulmonary invasive fungal infection and observe that a fungal alcohol dehydrogenase influences fungal pathogenesis in the lung. Thus, environmental conditions encountered by invading pathogenic fungi may result in substantial fungal metabolism changes that influence subsequent host immune responses.

【 授权许可】

CC BY