Targeting host metabolism in respiratory viral infections

Targeting host metabolism in respiratory viral infections: can we exploit viral metabolic reprogramming with drug interventions to ameliorate disease symptoms and severity or even prevent the virus from taking hold?

Influenza (Flu) and respiratory syncytia virus (RSV) infections are major causes of mortality worldwide and pose increased risks to children. Effective Flu vaccines remain elusive and therapy relies on early detection and treatment with viral targeting drugs of variable efficacy, while none exist for RSV. One way to circumvent some of these issues is to target the host. Despite growing evidence, from our lab and others, to support a role for targeting metabolism in respiratory viral pathogenesis little is known about it. Several brief clinical reports alerted radiologists that following Flu vaccination subjects receiving PET/CT scans are prone to positive hypermetabolic lesions in draining lymph nodes near the injection site. We performed a retrospective study of PET scans from immune compromised pediatric subjects undergoing chemotherapy and found subjects with respiratory viral infections had hypermetabolic regions in their lungs. We collected upper airway cells from children with community acquired viral respiratory infections and found they had significant increases in glycolysis and mitochondrial respiration and the respiratory metabolome. We confirmed these findings in vitro using pediatric human bronchial epithelial cells and murine dendritic cells (DC). Interestingly, during infection these cells acquired a similar metabolic phenotype through shared and distinct molecular mechanisms and some of which were differentially modulated by Dactolisib treatment. These differences in response to infection allows DC to retain metabolic control and plasticity that is lost when epithelial cells are infected. Even so, DC immune functions were limited with metabolic restrictions. Given we previously demonstrated oral treatment the metabolic drug Dactolisib increases survival in life threatening influenza infections, which has since been proven effective in elderly adults, this line of therapy needs further delineation as do other metabolic targets in viral infection.    

Learning Objectives:

• Respiratory viruses reprogram host metabolism
• Innate immune cells are resistant to metabolic rewiring by viruses
• Re-purposed metabolic drugs have the potential to prevent respiratory viral infection