(163c) Unraveling the Multifaceted Roles of Zinc Homeostasis in Host Defense: A Systems Biology Perspective

The role of zinc homeostasis in pathogenesis and particularly host defense against infection, has garnered increasing attention due to its multifaceted involvement in cellular processes. This investigation helps further establish the importance of zinc's fundamental role in maintaining human health through the lens of systems biology. Zinc serves as a crucial cofactor for numerous enzymes and transcription factors involved in immune regulation, oxidative stress, epithelial barrier function, and cell viability within tissue microenvironments. Dysregulation of zinc homeostasis is associated with pathological conditions, including infection, chronic obstructive pulmonary disease (COPD), and lung cancer amongst others. Systematic approaches that integrate “omics” technologies, computational modeling, and network analyses offer a more comprehensive framework to elucidate the complex interplay between zinc dynamics, cellular function, and tissue preservation during stress. Here we hypothesized that altered zinc mobilization via ZIP8, a zinc transporter that is vital for proper immune function, will result in significant dysregulation in multiple signal transduction pathways (such as mTOR, Pi3k/Akt signaling, etc.) causing impairment of metabolic and immune responses associated with host defense. To test our hypothesis, we compared a ZIP8 knockout mouse model to wild type control mice before and after bacterial pneumonia. Using combined systems biology approaches we were able to reveal novel mechanistic insight into disease pathology as well as potential therapeutic targets to reduce the incidence of morbidity and mortality associated with pneumococcal pneumonia, a leading cause of pneumonia world-wide. The overarching goal moving forward is to develop strategies that consider dietary zinc status and related genetic susceptibilities that foster patient-specific, personalized interventions aimed at restoring zinc homeostasis in order to decrease the severity and extent of bacterial pneumonia.