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 β-amyloid
peptides, a growing body of evidence highlights an interplay between APP, β-amyloid, and innate immunity. Mice
lacking APP are more susceptible to bacterial meningitis, and β-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 β-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.