Methicillin-resistant Staphylococcus aureus (MRSA) infection is the leading cause of hospital-acquired infection worldwide. It causes approximately 14 million infections annually in the United States alone. Increasing antibiotic resistance in this pathogen highlights a compelling need to identify new therapeutic targets to treat MRSA infections. We recently showed that the endoplasmic reticulum (ER) stress sensor, IRE1α, is a key component in innate immune defense against MRSA in macrophages, neutrophils, and in a murine abscess model of infection. We found that IRE1α controls macrophage and neutrophil antimicrobial functions by enhancing production of inflammatory molecules including mitochondrial reactive oxygen species (MitoROS), neutrophil extracellular traps (NETs), and IL-1β, which are essential for resolving MRSA infection in vivo. In the lung, ER stress occurs during infection, air pollutant inhalation and during the development of many pulmonary diseases like Idiopathic Pulmonary Fibrosis and Asthma. However, how IRE1α is involved in progression and resolution of lung diseases is not well understood. Because the lung is a vital organ, macrophages and neutrophils must adequately tune their responses to ensure effective antimicrobial function without excessive tissue damage that could inhibit gas exchange. Therefore, investigation of IRE1α-mediated stress responses during lung infection will lend valuable mechanistic insight into the regulation of pulmonary host defenses. The overarching goal of this proposal is to elucidate the role of IRE1α in pulmonary host defenses during MRSA infection. Our central hypothesis is that infection triggers IRE1α signaling, which enhances lung innate immune effector functions includes bactericidal activity and production of inflammatory mediators. We will accomplish the following Aims to test our hypothesis: (1) Characterize the requirement of IRE1α activation and MitoROS generation to lung macrophage inflammatory responses, and (2) Elucidate whether the IRE1α circuit aids or impedes innate immune defense against pulmonary MRSA infection. Completing this study will establish the ER stress response as an important regulatory network in lung host defense and will lay the groundwork for further studies in the intersection between cellular stress response and lung diseases.