Mitochondrial Calcium Signaling in Alveolar Macrophage-Mediated Defense Against S. pneumoniae

About This Grant

PROJECT SUMMARY Streptococcus pneumoniae infection is the leading cause of community-acquired pneumonia (CAP), resulting in significant morbidity and mortality, particularly among elderly and immunocompromised individuals. Alveolar macrophages (AMs) serve as the first line of defense in the lungs, where they must efficiently clear pathogens while maintaining careful control over inflammatory responses to prevent tissue damage. The molecular mechanisms that enable this delicate balance remain poorly understood. Our research focuses on calcium (Ca2+) signaling through the mitochondrial calcium uniporter (MCU), a highly selective ion channel that controls Ca2+ entry into mitochondrial matrix. We previously discovered that deletion of MCU in bone marrow-derived macrophages severely impairs their ability to kill fungal pathogens while simultaneously triggering excessive inflammation. This dual defect stems from disrupted mitochondrial metabolism and amplified cytosolic Ca2+ signaling mediated by the plasma membrane calcium channel ORAI1. We hypothesize that MCU-mediated mitochondrial Ca2+ (mCa2+) uptake is essential for AM-mediated host defense against S. pneumoniae, and its disruption will impair bacterial clearance while promoting damaging inflammation in the lungs. To test this hypothesis, we will: 1) Define how MCU regulates AM antimicrobial functions and inflammatory responses during S. pneumoniae infection using state-of-the-art Ca2+ imaging, metabolomics, and functional assays; and 2) Determine the impact of myeloid-specific MCU deletion on host defense against pneumococcal pneumonia in vivo using a clinically relevant mouse model. We will employ mice with selective deletion of MCU in myeloid cells (including AMs) and comprehensively assess disease progression through survival studies, bacterial burden quantification, lung histopathology, and molecular analyses of inflammatory mediators. This research will provide fundamental insights into how calcium signaling governs AM function during bacterial pneumonia. Therapeutic targeting of Ca2+ signaling pathways may provide new strategies to enhance bacterial clearance while limiting inflammatory damage during pneumonia.