Author ORCID Identifier
https://orcid.org/0000-0002-8548-5080
Date of Award
3-2025
Document Type
Thesis (Ph.D.)
Department or Program
Microbiology and Immunology
First Advisor
Robert A. Cramer
Second Advisor
Joshua J. Obar
Third Advisor
Christopher J. Shoemaker
Abstract
Aspergillus fumigatus is a ubiquitous mold found in the environment. However, this mold can also cause a life-threatening infection termed invasive pulmonary aspergillosis (IPA). IPA is caused by defects in innate immune cell function which lead to an inability of the host to clear inhaled conidia, resulting in unchecked fungal growth in the lung. The ability of myeloid cells to produce reactive oxygen species (ROS) is critical for immunity against A. fumigatus. While the importance of host-generated ROS is clear, what determines conidial viability against ROS insult is largely unknown. In this dissertation, we provide insight into the factors that contribute to viability and death of A. fumigatus conidia during ROS and leukocyte stress. We identify a role for A. fumigatus cytochrome c in susceptibility to conidial cell death induced by exogenous ROS and leukocytes. Additionally, we identify the A. fumigatus p-21 activated kinase pakA as a mediator of susceptibility to conidial cell death from ROS and leukocytes. Using comparative phosphoproteomics, we identify that phosphorylation of substrates associated with autophagy and peroxisome function are pakA-dependent during H2O2 exposure. The data provided in this dissertation give insight into the nature of how fungi control viability in response to ROS at a critical point of immunity that determines infection outcomes.
Original Citation
- James MR, Aufiero MA, Vesely EM, Dhingra S, Liu K-W, Hohl TM, Cramer RA: Aspergillus fumigatus cytochrome c impacts conidial survival during sterilizing immunity. mSphere 2023, 8:e0030523
- James MR, Doss KE, Cramer RA: New developments in Aspergillus fumigatus and host reactive oxygen species responses. Curr Opin Microbiol 2024, 80:102521.
Recommended Citation
James, Matthew Robert, "Determinants of reactive oxygen species-induced conidial cell death in Aspergillus fumigatus" (2025). Dartmouth College Ph.D Dissertations. 358.
https://digitalcommons.dartmouth.edu/dissertations/358
