Metabolic dysfunction and immunometabolism in COVID-19 pathophysiology and therapeutics

Abstract

The COVID-19 pandemic has emerged as a public health crisis and has placed a significant burden on healthcare systems. Patients with underlying metabolic dysfunction, such as type 2 diabetes mellitus and obesity, are at a higher risk for COVID-19 complications, including multi-organ dysfunction, secondary to a deranged immune response, and cellular energy deprivation. These patients are at a baseline state of chronic inflammation associated with increased susceptibility to the severe immune manifestations of COVID-19, which are triggered by the cellular hypoxic environment and cytokine storm. The altered metabolic profile and energy generation of immune cells affect their activation, exacerbating the imbalanced immune response. Key immunometabolic interactions may inform the development of an efficacious treatment for COVID-19. Novel therapeutic approaches with repurposed drugs, such as PPAR agonists, or newly developed molecules such as the antagomirs, which block microRNA function, have shown promising results. Those treatments, alone or in combination, target both immune and metabolic pathways and are ideal for septic COVID-19 patients with an underlying metabolic condition.

Fig. 1. Pathophysiologic changes in patients with COVID-19 and metabolic dysfunction and potential therapeutic agents.

This graph depicts the mechanisms by which SARS-CoV-2 infection leads to hyperimmune response and sepsis in patients with metabolic dysfunction as well as potential therapeutic molcules with their targets. Diffuse tissue hypoxia and viral replication in the pulmonary epithelium along with TLR activation result in immune cell activation, cytokine release and immunomodulation. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, IL interleukin, TLR toll-like receptor, HIF hypoxia-inducible factor, PPAR peroxisome proliferator-activated receptor.