Plasma surfactant proteins and lipid mediators in the airway associate with different stages of viral infection and resolution in a sub-lethal mouse Influenza A model

Abstract Viral quantification serves as a valid biomarker for detecting Influenza A infection however viral burden is not closely associated with disease severity or clinical outcomes. Biomarkers reflecting the status of the host immune response are needed to monitor and/or predict disease outcomes in a hospitalized setting. Here, we utilized a sub-lethal mouse model of Influenza A infection to explore plasma and airway cytokines, plasma surfactant proteins (SP-D, SP-A and CC16), and airway bioactive lipid mediators as potential biomarkers of lung leakage and host response, respectively. This study aimed to assess the pharmacodynamic response of these biomarkers after treatment with an efficacious dose of an anti-HA stalk-binding antibody and to assess association of these biomarkers with disease severity metrics. Plasma SP-D and IP-10 correlated with lung viral titers while SP-A and CC16 tracked more closely with changes in bronchial albumin levels and body weight. Bioactive lipid precursors Arachidonic Acid (AA), Docosahexaenoicacid (DHA) and Eicosapentaenoic acid (EPA), reported to have both pro- and anti-inflammatory properties, increase in the lung with infection. 17-HDHA, a DHA metabolite reported to be pro-resolving, was induced later during disease resolution. With anti-HA antibody treatment, all plasma surfactant proteins and precursor lipids in the airway were reduced and 17-HDHA production was accelerated. In summary, plasma SP-D may serve as an early biomarker of host response and/or potentially indicate a decline in lung epithelium integrity. Plasma SP-A, CC16, and pro-inflammatory lipid mediators such as AA may reflect the ongoing host response and may therefore be more closely associated with disease outcomes.