HIF-1, the Warburg Effect, and Macrophage/Microglia Polarization Potential Role in COVID-19 Pathogenesis

Abstract

Despite the international scientific community's commitment to improve clinical knowledge about coronavirus disease 2019 (COVID-19), knowledge regarding molecular details remains limited. In this review, we discuss hypoxia's potential role in the pathogenesis of the maladaptive immune reaction against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The state of infection, with serious respiratory dysfunction, causes tissues to become hypoxic due to a discrepancy between cellular O₂ uptake and consumption similar to that seen within tumor tissue during the progression of numerous solid cancers. In this context, the heterogeneous clinical behavior and the multiorgan deterioration of COVID-19 are discussed as a function of the upregulated expression of the hypoxia-inducible factor-1 (HIF-1) and of the metabolic reprogramming associated with HIF-1 and with a proinflammatory innate immune response activation, independent of the increase in the viral load of SARS-CoV-2. Possible pharmacological strategies targeting O₂ aimed to improve prognosis are suggested.

Figure 1

Severe SARS-CoV-2 syndrome as a result of hypoxia and HIF-1 signaling pathway activation. ARDS: acute respiratory distress syndrome; CCL: chemokine (C-C motif) ligand; CRS: cytokine release syndrome; DIC: disseminated intravascular coagulation; HIF-1: hypoxia-inducible factor; IL: interleukin; iNOS: inducible NO synthase; pVHL: von Hippel-Lindau tumor suppressor; SARS-CoV-2: severe acute respiratory syndrome coronavirus; TNF: tumor necrosis factor.