Degree

Doctor of Philosophy (PhD)

Department

Department of Pathobiological Sciences

Document Type

Dissertation

Abstract

The endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) is an important regulator of innate immune cells. However, its role in pulmonary innate host defenses remains poorly understood. This dissertation elucidates the dual, context-dependent role of IRE1α in host defense against methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. We demonstrate IRE1α’s function as both a detrimental mediator of acute pathology and an essential facilitator of innate immune memory. Our work revealed that acute IRE1α activation during primary MRSA infection is detrimental. In lungs and alveolar macrophages (AMs), IRE1α is activated in response to MRSA infection. Consequently, IRE1α activation triggers a hyperinflammatory cascade, resulting in excessive cytokine production, AM cell death, and impaired bacterial clearance. Genetic ablation of myeloid IRE1α or global pharmacological inhibition of IRE1α significantly improved mice survival, reduced lung injury, and enhanced bacterial clearance in models of both primary and secondary to influenza MRSA pneumonia.

Conversely, we discovered a protective function of IRE1α in the establishment of innate immune memory (trained immunity) against recurrent infection. Pre-exposure to a non-lethal immune stimulus primed mice for enhanced survival against a subsequent lethal MRSA challenge. This protection was contingent upon myeloid IRE1α activation, which drove the expansion of the resident AM population through self-renewal and functionally reprogrammed AMs to be more efficacious. The resulting AMs were efficient at killing bacteria and resolving inflammation. Ablation of myeloid IRE1α reduced the protective training effect, impaired AM reprogramming, and left mice susceptible to recurrent infection.

To summarize, our work demonstrates IRE1α as a key molecular switch in lung innate immunity. IRE1α activation in acute pneumonia is pathological; however, IRE1α activation in a resolved challenge is essential for innate immune memory. Our findings emphasize the potential of IRE1α as a therapeutic target. These results indicate that IRE1α inhibition may be effective in treating hyperinflammation, while controlled IRE1α activation could enhance defensive innate immunity.

Date

12-11-2025

Committee Chair

Abuaita, Basel

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