Simultaneously targeting hyperinflammation and hyperglycemia following respiratory viral infection

Abstract

Abstract Individuals with hyperglycemia are at great risk of developing exaggerated pulmonary inflammation following infection with respiratory viruses including SARS-CoV-2. Conversely, SARS-CoV-2 infection has been linked to the development of new onset of hyperglycemia and diabetes. Despite global vaccination efforts, SARS-CoV-2 infection continues to be a great public health challenge, and corticosteroids targeting hyper-inflammation remain the mainstay treatment for severe COVID-19. However, steroidal medicine arises the risk of hyperglycemia, limiting its usage. Here, we showed that a second-generation thiazolidines drug MSDC-0602K (MSDC), a mitochondrial pyruvate carrier inhibitor, simultaneously decreased excessive pulmonary inflammation and hyperglycemia in normal and obese hosts during influenza infection, as such, reducing host morbidity and mortality. scRNA-seq analysis revealed that MSDC treatment reduced lung macrophage inflammation, and myeloid-specific ablation of MPC2 led to dampened lung inflammation. Further, MSDC inhibited human lung macrophage inflammatory responses following SARS-CoV-2 infection, and dampened inflammation in lung autopsies of COVID-19 patients. Mechanistically, MSDC treatment destabilized HIF-1a protein, a transcription factor promoting inflammatory responses of lung macrophages, by repressing cellular Acetyl-CoA levels and HIF-1a acetylation. Our results suggest that MSDC has the great potential to treat severe COVID-19 or other respiratory viral infection, particularly in patients with underlying metabolic conditions, by simultaneously repressing hyper-cytokinemia and hyperglycemia. Supported by NIH AG069264, NIH AI150599