METABOLIC BIOENERGETICS DRIVES ASPERGILLUS FUMIGATUS VIRULENCE

CH Kowalski, AK Caffrey, JJ Obar, RA Cramer

Abstract: 

Purpose:
The ability of microbes to thrive in hypoxic environments is important for virulence. In a murine model of invasive pulmonary aspergillosis (IPA), lesions within the lung experience low oxygen tensions (≤1%). Despite the importance of this response for virulence, molecular mechanisms of hypoxia adaption and its mechanistic link to virulence remain elusive. Here we aim to further elucidate underlying mechanisms through serial passaging of a low virulent A. fumigatus strain through host-mimicking (hypoxic) conditions.
Methods:
We utilized an in vitro microevolution approach to mimic host conditions of low oxygen tension. Strains were collected at early and late stages of serial passaging, and characterized for phenotypes associated with virulence. On going efforts in the laboratory are focused on global gene expression changes in the passaged strains to identify candidate pathways involved in metabolic bioenergetics and virulence.
Results:
Serially passaged strains revealed varied phenotypes from the parental strain in respect to increased sensitivity to redox stress and increased fitness in host-mimicking conditions. In a murine corticosteroid model of IPA, passaged strains exhibited enhanced virulence compared to the parental strain as measured by murine survival. Evidence points to significant alterations in metabolic bioenergetics in these passage strains that confers enhanced in vivo fitness. Within the immunocompetent lung, the passaged strain induced higher levels of inflammatory cytokines early after challenge and appears to be cleared from the lungs more quickly than the parental strain. Further characterization of these underlying mechanisms is in progress.
Conclusion:
Adaptation to hypoxic microenvironments during pulmonary infection is essential for the success of Aspergillus fumigatus. Preliminary data indicates a role for modulation of metabolic bioenergetics in response to chronic low oxygen environments in vitro. These bioenergetic alterations have a role in enhanced fungal virulence in vivo. Variation in the virulence of A. fumigatus strains is proposed to be correlated with their ability to initiate these metabolic alterations.

2016

abstract No: 

67

Full conference title: 

Purpose: The ability of microbes to thrive in hypoxic environments is important for virulence. In a murine model of invasive pulmonary aspergillosis (IPA), lesions within the lung experience low oxygen tensions (≤1%). Despite the importance of this response for virulence, molecular mechanisms of hypoxia adaption and its mechanistic link to virulence remain elusive. Here we aim to further elucidate underlying mechanisms through serial passaging of a low virulent A. fumigatus strain through host-mimicking (hypoxic) conditions. Methods: We utilized an in vitro microevolution approach to mimic host conditions of low oxygen tension. Strains were collected at early and late stages of serial passaging, and characterized for phenotypes associated with virulence. On going efforts in the laboratory are focused on global gene expression changes in the passaged strains to identify candidate pathways involved in metabolic bioenergetics and virulence. Results: Serially passaged strains revealed varied phenotypes from the parental strain in respect to increased sensitivity to redox stress and increased fitness in host-mimicking conditions. In a murine corticosteroid model of IPA, passaged strains exhibited enhanced virulence compared to the parental strain as measured by murine survival. Evidence points to significant alterations in metabolic bioenergetics in these passage strains that confers enhanced in vivo fitness. Within the immunocompetent lung, the passaged strain induced higher levels of inflammatory cytokines early after challenge and appears to be cleared from the lungs more quickly than the parental strain. Further characterization of these underlying mechanisms is in progress. Conclusion: Adaptation to hypoxic microenvironments during pulmonary infection is essential for the success of Aspergillus fumigatus. Preliminary data indicates a role for modulation of metabolic bioenergetics in response to chronic low oxygen environments in vitro. These bioenergetic alterations have a role in enhanced fungal virulence in vivo. Variation in the virulence of A. fumigatus strains is proposed to be correlated with their ability to initiate these metabolic alterations.