Defining a role for PARP1 in driving RSV induced pulmonary pathology

Abstract The mechanisms underlying how Respiratory Syncytial Virus (RSV) subverts dendritic cell (DC) immune function to enhance pathology are not well defined, but we have recently shown RSV alters DC metabolism. Analysis of Reverse Phase Protein Array (RPPA) data, which identifies phosphorylated cytoplasmic proteins (>400 in the analysis), revealed one of the most differentially activated signaling molecules, PARP1, had increased activation (phosphorylation) in RSV infected DC. PARP1 is a DNA damage enzyme that, in an NAD+ depleting manner, polymerizes deposition of poly-ADP-ribosylation (PAR) units in cellular proteins, possibly altering their physiological properties. Our data shows genomic ablation of PARP1 negates the capacity of RSV to manipulate DC metabolism at the early stage of infection. Enzymatic inhibition or genomic ablation of PARP1 resulted in increased key innate immune cytokine expression including type I interferon and IL-12, which together promote a more appropriate anti-viral environment. PARP1 −/−mice and PARP1 inhibitor treated mice were protected against RSV induced immunopathology including airway inflammation and mucus hypersecretion as indicated by PAS staining of lung tissue. Assessment of isolated airway epithelial cells demonstrated genomic depletion of PARP1 did not alter RSV induced innate cytokines, suggesting predominately an immune cell effect upon RSV infection. Together, these data highlight PARP1 may be a logical target for therapeutic intervention during RSV infections to diminish the immunopathology and reduce disease severity. Supported by grants from NIH (R35 HL150682, R01 AI138348)