Angiopoietin-like 4 as a Biomarker and Therapy Target for Acute Lung Damage in Influenza and Secondary Bacterial Infection.

Influenza infections and associated secondary bacterial infections threaten the lives of millions of people every year. However, designing effective vaccines and treatment options has proven difficult because the influenza virus evolves rapidly. Therefore, it may be beneficial to identify host proteins that are associated with influenza infection. One effective therapeutic option is to accelerate lung repair and recovery following influenza infection. However, although many individual aspects of these host-pathogen interactions during the course of influenza infection have been studied, there is little information on the host’s response during the repair stage of the infection. In our preliminary study, we identified the host protein angiopoietin-like 4 (ANGPTL4) as a potential biomarker of acute lung damage and a therapy target to facilitate lung repair. We demonstrated that ANGPTL4 expression was increased during influenza infection and that treatment with neutralizing antibodies against ANGPTL4 significantly improved lung recovery. However, the role of ANGPTL4 and its underlying mechanism remain unclear. In this proposal, we will first identify the stimuli and the cell types responsible for the increased expression of ANGPTL4 by performing in situ hybridization, dual immunofluorescence and in vitro culture. Next, using in vivo imaging, multiple analyte detection and laser capture microdissection coupled to microarrays we will investigate the in vivo effects of ANGPTL4 during influenza infection. Finally, we will examine the expression of ANGPTL4 and the effect of anti-ANGPTL4 during both influenza virus infections and influenza virus-bacterial super-infection. To underscore the biological relevance of ANGPTL4, we will examine its expression in clinical samples of pneumococcal infection and in lung resections from various inflammatory and infectious diseases. Our study will represent the first demonstration of the novel role of ANGPTL4 in influenza lung infection and will therefore advance our understanding of influenza pathogenesis and promote the development of new diagnostic and therapeutic strategies.