Host-influenza proteomics leads to metabolic drug repurposing that reduces viral burden while significantly improving survival after lethal infection (TECH2P.917)

Abstract

Abstract A retrospective survey of pediatric patients infected with respiratory pathogens identified increases in glucose metabolism in the lungs of several individuals. After viral infection the host cell mounts an energetic and resource intensive antiviral response, while the virus exploits the host to generate progeny. Using absolute quantification with Host-Influenza Proteomics (HIP) we sought to characterize changes in host cell homeostasis that contribute to these competing processes. Like in the patients, we found gross metabolic changes occurring after influenza infection in primary human respiratory cells as well as dendritic cells. This new metabolic phenotype is distinct from immune activation and involves increases in glycolysis and glutaminolysis, decreased fatty acid β-oxidation concomitant to non-canonical TCA activity. Based on these findings we developed a metabolic drug repurposing screen in human bronchial epithelial cells and high-throughput viral tittering system. We screened over 160 metabolic substrates and small molecules to identify responsive prophylactic and therapeutic pathways (e.g. lipid and glucose metabolism respectively). One compound known to alter glucose sensitivity, NVP-BEZ235, reduced viral titers and significantly increased survival in vivo after lethal influenza challenge. Human PET scans followed by HIP analysis elucidated a unique metabolic signature in influenza-infection exposing targets for therapeutic intervention.