Saturday, May 4, 2024
5/4/2024
PROJECT SUMMARY Neutrophil activation in response to infection is a double-edged sword that can either kill invading pathogens and/or inflict tissue damage. Thus, neutrophils inextricably define whether the innate immune response to infection is beneficial or deleterious to the host. The interdependence of neutrophil degranulation and release of extracellular traps (NETs) has emerged as an important player in acute and chronic inflammation. This new R21 proposal is based on the unexpected discovery that the amyloid precursor protein (APP) regulates neutrophil degranulation and NETosis during Pseudomonas aeruginosa infection in the lung. While APP is known to drive the pathology of Alzheimer's disease via production of neurotoxic ß-amyloid peptides, a growing body of evidence highlights an interplay between APP, ß-amyloid, and innate immunity. Mice lacking APP are more susceptible to bacterial meningitis, and ß-amyloid is an antimicrobial peptide. Preliminary data are presented to support the premise that App knockout mice show increased mortality and lung injury compared to wild type controls in response to P. aeruginosa infection. Surprisingly, P. aeruginosa-infected App knockout mice also exhibit increased neutrophil influx compared to wild type controls. In addition, in vitro studies demonstrate that isolated bone marrow-derived neutrophils from App knockout mice display increased degranulation and NETosis. Together, these published and preliminary data support a conceptually innovative and technically feasible approach for two Specific Aims that will test the HYPOTHESIS that APP modulates neutrophil degranulation and NETosis to limit lung injury during P. aeruginosa infection. Aim 1 will elucidate the protective role of APP during P. aeruginosa-induced lung injury. Aim 2 will test the utility of APP and ß-amyloid peptides as predictors of outcome in critically ill patients. Our discovery that APP protects the host during P. aeruginosa lung infection is a highly significant conceptual advance with broad impact across the fields of lung biology and neurobiology. P. aeruginosa is the most frequent Gram-negative pathogen causing pneumonia in patients with chronic lung disease (e.g., chronic obstructive pulmonary disease and cystic fibrosis), and is prevalent in critically ill patients with respiratory failure in the intensive care unit. In the most severe cases, pneumonia progresses to acute lung injury, sepsis, and multi-organ failure. Importantly, survivors often suffer long-term sequelae such as post-intensive care syndrome (PICS) and neurocognitive dysfunction that reduce overall quality of life. Thus, our proposed studies may reveal potentially transformative links between a pathogen-mediated dysfunctional APP response in neutrophils and organ dysfunction and neurocognitive sequelae.
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