Working Hypothesis for Glucose Metabolism and SARS-CoV-2 Replication: Interplay Between the Hexosamine Pathway and Interferon RF5 Triggering Hyperinflammation. Role of BCG Vaccine?

Abstract 
Respiratory epithelial cells, dendritic cells (DCs) and macrophages (1) secrete low levels of the antiviral factor interferons (IFNs) (2) and high levels of proinflammatory cytokines such as tumor necrosis factor alpha (TNFα), IL-6, and IL-1β, IP-10, MCP-3, characterizing the pathophysiologic features of severe acute respiratory syndrome (ARDS) induced by SARS-CoV-2 infection (3). Researchers hypothesized that after COVID-19 infects human cells, the virus utilizes an excess of glucose for a fast viral replication from the hexosamine biosynthetic pathway (HBP) hijacking substrates from the metabolic environment. This process induces overexpression of interferon IRF5, leading to a massive inflammatory gene overexpression, endoplasmic reticulum (ER) stress, and cytokine dysregulation profile. This deleterious cytokine overproduction is referred to as the cytokine storm (Figure 1). It leads to an increased risk of vascular hyperpermeability, multiorgan failure, and hyperinflammation (4, 5). Little is known about the molecular immunometabolic mechanism that triggers the uncontrolled surge in cytokine secretion and the cellular regulation of the hyperinflammatory cascade intertwined with the COVID-19 viral replication.