Introduction
obesity, hyperlipidemia, inflammation, metabolic diseases, infection, respiratory distress, diabetes
OBESITY, VIRUS, SARS-COV-2 INFECTION, HYPERLIPIDEMIA, CORONAVIRUS INFECTION, INFLAMMATION, METABOLIC DISEASES, INFECTION, ELEVATED BLOOD GLUCOSE, CORONAVIRUS, SEVERE ACUTE RESPIRATORY SYNDROME, DIABETES
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-strand RNA virus of the Recent work suggests that COVID-19 progression is dependent on metabolic mechanisms. Elevated blood glucose, obesity, and hyperlipidemia were found to be risk factors for SARS-CoV-2-induced acute respiratory distress, independently from diabetes (Metabolomics of COVID-19 patient sera showed alterations in circulating amino acids, glucose, and lipids, correlated with changes in inflammation and renal function (Alarmingly, evidence from previous coronavirus outbreaks suggests that the metabolic rewiring induced by infection has detrimental and long-term effects post-recovery. MERS infection was associated with long-term immune dysregulation and enhanced susceptibility to metabolic diseases (In this report, we charted the metabolic response of primary lung bronchiole and small airway epithelial cells to SARS-CoV-2 infection validating our results with multiple COVID-19 patient samples. We demonstrate intracellular lipid accumulation driven in part by the inhibition of PPARα-dependent lipid catabolism. Screening pharmacological modulators of the SARS-CoV-2 metabolic landscape showed that fenofibrate, and other PPARα-agonists that induce lipid catabolism, reversed metabolic changes and blocked SARS-CoV-2 replication in vitro. An observational study in 3,233 Israeli patients hospitalized due to COVID-19 was consistent with the in vitro observations, showing lower inflammation and faster recovery in patients taking fibrates, while those taking thiazolidinediones that lead to increased lipid accumulation in certain tissues (Moreover, we performed a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care. These patients demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period and treated with the same standard-of-care. This work demonstrates that pharmacological modulations of PPARα may be an effective treatment for coronavirus infection. The clinical translation of these findings can only be determined following randomized placebo-controlled clinical studies, which are currently ongoing in several international centers.