Nosocomial pneumonia elicited lung tau impairs learning - PROJECT SUMMARY/ABSTRACT Critical illness and severe injury often lead to widespread cognitive impairment, known as post-intensive care syndrome and chronic critical illness. These sequelae, characterized by single or multiple organ system dysfunction with varying clinical presentations, commonly involve brain dysfunction during and after critical illness. Symptoms can manifest as acute delirium or persistent cognitive decline, potentially resulting in irreversible brain damage. While factors such as relative brain hypoxia, anesthetics, sedatives, cytokine storms, mechanical ventilation, and hospitalization have been examined as contributors, the role of peripheral tau variants generated after lung infections on cognitive health remains unknown. Further, cognitive impairment is more frequent and severe in patients with pneumonia, creating a comorbidity spiral. Thus, it is crucial to assess the role of lung infection-elicited cytotoxic peripheral tau variants in this public health crisis. Our recent work has shown that lung endothelium expresses at least four tau isoforms; endothelial cells release these cytotoxic tau variants into the cell media or bloodstream in response to bacterial infection. Tau, named for the “microtubule-associated protein tau”, is thought to physiologically bind and stabilize microtubule complexes, which are important for maintaining cell morphology and structure. For many decades, cytopathic tau variants are known to be associated with several neuropathological diseases, though emerging evidence now indicates their involvement in peripheral organ pathology, including the lung and heart. Importantly, the endothelial tau released after the cells are exposed to virulent Pseudomonas aeruginosa bacterial strains are hyperphosphorylated, are cytotoxic and neurotoxic, and can cause neuronal tau aggregation in vitro. Considering the importance of pneumonia-cognitive impairment comorbidity, along with our recent discovery that bacterial infection causes hyperphosphorylation of lung endothelial tau variants—conferring cyto- and neurotoxicity—we propose the novel concept that infection triggers the production of endothelial cytotoxic small-tau and/or big-tau variants that impair neural information processing, ultimately leading to prolonged learning deficits In this project, we aim to systematically study Pseudomonas aeruginosa-triggered endothelial tau variant phosphorylation, their release, and how phosphorylation modulates their cyto- and neurotoxicity. We will identify key tau phosphorylation sites and investigate the underlying mechanism by which these cytotoxic endothelial tau variants cause neural dysfunction. This project expands our understanding of tau-related pathology beyond neurodegenerative contexts by investigating these variants in respiratory infections. Findings will provide insights into shared pathogenic mechanisms between peripheral and brain tau variants.
