Date of Award

Summer 8-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Steve Templeton

Second Advisor

Kyu Hong Cho

Third Advisor

Scott Glen Canfield

Abstract

Invasive aspergillosis (IA), caused by Aspergillus fumigatus, is a life-threatening infection in immunocompromised individuals, necessitating novel host-directed therapies. Macrophages are pivotal in antifungal defense, yet their function can be dysregulated; the influence of the adipokine adiponectin (APN) on this process is not fully understood. This thesis investigated the role of APN signaling in alveolar macrophage (AM) and bone marrow-derived macrophage (BMDM) responses to A. fumigatus and assessed the therapeutic potential of the APN receptor agonist, AdipoRon. Initial studies revealed that genetic deficiency in APN or its receptors renders AMs intrinsically pro-inflammatory and significantly impaired fungicidal activity against A. fumigatus. Subsequent pharmacological activation of APN receptors in these deficient AMs using AdipoRon effectively rescued these defects. AdipoRon treatment enhanced fungal killing, a benefit attributed to the promotion of LC3-associated phagocytosis (LAP), and concurrently dampened inflammatory responses. Extending these findings, investigations in BMDMs demonstrated that APN deficiency similarly led to a hyper-inflammatory state and impaired fungal clearance. Furthermore, APN deficiency critically altered macrophage cell fate decisions during A. fumigatus infection, promoting detrimental necrotic cell death. AdipoRon treatment of APN-deficient BMDMs not only attenuated inflammation and improved fungal killing but also favorably modulated cell death pathways, inducing a shift from necrosis towards apoptosis. Collectively, this thesis establishes APN signaling as a critical homeostatic regulator of macrophage antifungal immunity, profoundly influencing inflammatory responses, pathogen elimination mechanisms like LAP, and cell fate decisions. The findings underscore the therapeutic potential of AdipoRon to restore macrophage protective functions and mitigate immunopathology in IA, providing a strong rationale for exploring APN pathway modulation as a host-directed strategy, especially in conditions of APN dysregulation.

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