Author ORCID Identifier

https://orcid.org/0000-0003-2473-3981

Date of Award

Spring 6-15-2025

Document Type

Thesis (Ph.D.)

Department or Program

Microbiology and Immunology

First Advisor

Joshua J Obar

Abstract

The genus Aspergillus comprises over 250 species of fungi. Within this genus, only a handful of species cause disease in humans. One species is Aspergillus fumigatus (A.f.), an environmentally ubiquitous, saprophytic fungal pathogen. Lung infections due to A.f. range from invasive infection to allergic forms of the disease. Allergic bronchopulmonary aspergillosis (ABPA) is one of the most severe forms and presents as a hypersensitivity that often results in off-target damage to the surrounding airways. Patients with ABPA are sensitized to fungal antigens and this is commonly seen in cystic fibrosis and genetic predispositions. Recent data from our lab shown how viruses which specifically infect fungi, called mycoviruses, impact various forms of A.f. disease in a murine lung model of infection. By utilizing virally infected and cured strains of A.f., we have studied differences in the host response against these fungal spores. In this work, I show how tissue-resident alveolar macrophages (AlvMϕs) recognize the genome of the mycovirus in a MAVS-dependent manner. This leads to interferon (IFN) production, which our lab has shown to be required for anti-fungal immunity. Furthermore, I have evidence suggesting that mycoviruses are capable of being released into the extracellular environment by exploiting the production of fungal extracellular vesicles. These viruses can go on to stimulate host IFN production from AlvMϕs in a manner that is dependent on the presence of TGFβ and MAVS. I describe how in a low-dose ABPA model that mycovirusinfected strains of A.f. lead to decreased systemic IgE antibody levels in mice. These data suggest a potential role for mycoviral infection in boosting acute IFN signaling, thereby dampening allergic disease. Finally, we have begun looking at how the cytokine TGFβ reprograms metabolic pathways in AlvMϕs using a fetal liver-derived macrophage cell model. These metabolic changes allow for IFN production following TLR2 stimulation. This unconventional IFN pathway has broad implications in host immunity against various bacterial and fungal species.

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