Targeting Angiopoietin-like 4 (ANGPTL4) in Severe Community Acquired Pneumonia

PROJECT SUMMARY Community-acquired pneumonia (CAP) is a common cause of morbidity and mortality in hospitalized patients but therapeutics are limited. In response, identification of modifiable pathways to alter host response and improve outcomes in patients with severe CAP has been highlighted as a NHLBI research priority. Our research group has identified angiopoietin-like 4 (ANGPTL4) as a potential mediator in adverse outcomes in CAP from viral and bacterial pathogens. We have generated preliminary data in a discovery proteomic analysis of 5000 different plasma proteins. We found that ANGPTL4 was one of the top proteins associated with fewer ventilator free days and worse hospital mortality in severe CAP due to COVID-19. Next, in a multi-center cohort, we replicated these findings in COVID-19 that higher ANGPTL4 concentrations were associated with worse clinical outcomes, and obtained preliminary evidence that ANGPTL4 is also associated with outcomes in severe CAP due to bacteria3. We also have generated data that genetically targeting Angptl4 is protective in mice with severe influenza, a finding that is supported by pre-clinical data that inhibition of ANGPTL4 signaling through a monoclonal antibody is protective in viral pneumonia. In addition, independent research groups have also found that ANGPTL4 is associated with clinical outcomes in severe CAP. Together, these findings support our hypothesis that ANGPTL4 expression is a significant determinant of outcomes from CAP, independent of pathogen type, and that modulation can lead to improved clinical outcomes. To further examine this hypothesis, we will use complementary clinical and pre-clinical studies in the following aims. In Aim 1, we will determine the relationship between plasma ANGPTL4 levels and outcomes in a hospitalized population with varying severity at enrollment (acute care and ICU) and pathogen type (viral and bacterial). In Aim 2, we will infer causal relationships between ANGPTL4 concentrations and risk for pulmonary and extra- pulmonary organ dysfunction using a non-overlapping 2-sample Mendelian randomization genetic approach. In Aim 3, we will evaluate the role of ANGPTL4 in pre-clinical models of viral and bacterial pneumonia and determine the relative contributions of the proteolytically processed cANGPTL4 and nANGPTL4 peptides. The outstanding qualifications of our team in the fields of sepsis, community acquired pneumonia, molecular epidemiology, and pre-clinical models uniquely position us to deliver an integrated molecular view of host response in CAP that is not only responsive to the challenges in severe CAP care identified by global leaders, but could fundamentally alter paradigms of patient care in severe CAP. The long-term goals are to delineate the role of ANGPTL4 in severe CAP through understanding which clinical outcomes are most closely linked with ANGPTL4 levels through epidemiological and genetic causal inference analyses and to understand the cell of origin and relative contributions of different cleavage products of ANGPTL4 through pre-clinical studies.