**Abstract**

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in the late 2019 and spread rapidly throughout the world, becoming a pandemic in March 2020. It became obvious early that the prognosis of this illness is highly variable, ranging from few mild symptoms to severe complications and death, indicating that aside from the pathogen virulence, host factors contribute significantly to the overall outcome. Like SARS-CoV and Human Coronavirus NL63 (HCoV-NL63-NL63), SARS-CoV-2 enters host cells via several receptors among which angiotensin converting enzyme-2 (ACE-2) are the most studied. As this protein is widely expressed in the lungs, blood vessels, brain, kidney, testes and ovaries, the effects of this virus are widespread, affecting many body tissues and organs. Viral attachment to ACE-2 downregulates this protein, disrupting angiotensin II (ANG II) hydrolysis that in return contributes to the unchecked accumulation of this peptide. ANG II toxicity is the result of excessive activation of ANG II type 1 receptors (AT-1Rs) and N-methyl-D-aspartate NMDA receptors (NMDARs). Overstimulation of these proteins, along with the loss of angiotensin (1–7) (ANG 1–7), upregulates reactive oxygen species (ROS), inflicting end-organ damage (hit 1). However, a preexistent redox impairment may be necessary for the development of SARS-CoV-2 critical illness (hit 2). Here we propose a two-hit paradigm in which COVID-19 critical illness develops primarily in individuals with preexistent antioxidant dysfunction. Several observational studies are in line with the two hit model as they have associated poor COVID-19 prognosis with the hereditary antioxidant defects. Moreover, the SARS-CoV-2 interactome reveals that viral antigen NSP5 directly inhibits the synthesis of glutathione peroxidase (GPX), an antioxidant enzyme that along with glucose-6-phosphate dehydrogenase (G6PD) protect the body from oxidative damage. Indeed, individuals with G6PD deficiency have less favorable COVID-19 outcomes compared to the general population.

**Keywords:** Sars-CoV-2, antiviral psychotropic drugs, glucose-6-phosphate dehydrogenase, glutathione peroxidase, endocytic pathway, calmodulin
