Date of Award
2026
Document Type
Thesis (Ph.D.)
Department or Program
Microbiology and Immunology
First Advisor
Dr. Joshua Obar
Abstract
Influenza-associated pulmonary aspergillosis (IAPA) is characterized as the development of invasive Aspergillus infection in patients with severe influenza. Unlike classical invasive aspergillosis, which primarily affects immunocompromised hosts, IAPA develops in patients without traditional risk factors. IAPA is associated with high morbidity and mortality and characterized by dysregulated pulmonary inflammation, however the host mechanisms that drive susceptibility remain poorly understood. This dissertation investigates how influenza infection induces a permissive host environment through coordinated disruption of iron homeostasis and innate immune function.
To address this, a murine model of IAPA was developed in which mice were infected with influenza A virus (IAV) followed by secondary Aspergillus fumigatus (Af) challenge. Disease progression was assessed through survival, fungal germination, and markers of lung injury. Myeloid cell function was evaluated using assays of fungal uptake, killing, and reactive oxygen species (ROS) production. Single-cell RNA sequencing of enriched lung myeloid populations was performed to define transcriptional changes associated with IAV-Af coinfection, with a focus on iron-regulatory and immune signaling pathways.
IAV-Af coinfection resulted in increased Af germination, lung injury, and mortality compared to single infections. Despite preserved or elevated inflammatory signaling, monocytes and neutrophils exhibited impaired fungal uptake and killing. Transcriptional analyses revealed dysregulation of iron homeostasis, including reduced ferritin expression and altered iron-handling pathways, alongside suppression of interferon and phagocytic signaling programs in IAPA. Elevated bioavailable iron promoted fungal growth and was associated with reduced antimicrobial effector function.
These findings demonstrate that IAPA susceptibility arises from a failure of coordinated immune–metabolic regulation. Influenza-driven disruption of iron homeostasis reshapes the lung microenvironment and impairs myeloid cell function, creating conditions that favor fungal outgrowth. This work establishes iron dysregulation as a central driver of susceptibility and provides a mechanistic framework for the development of targeted host-directed therapies in IAPA.
Recommended Citation
Grau, Madeleine S., "INFLUENZA-INDUCED IMMUNE METABOLIC REPROGRAMMING DRIVES SUSCEPTIBILITY TO SECONDARY PULMONARY ASPERGILLOSIS" (2026). Dartmouth College Ph.D Dissertations. 469.
https://digitalcommons.dartmouth.edu/dissertations/469
