SARS-CoV-2 and Other Respiratory Viruses: What Does Oxidative Stress Have to Do with It?

Figure 1

The process of reactive oxygen species formation in SARS-CoV-2 infection. The virus is able to enter the cell through the ACE2 receptor, and the serine protease TMPRSS2 is located on the membrane of some cell types. This leads to the recognition of the pathogen by a PRR, the recruitment of immune cells, and an increase in proinflammatory cytokines, thus leading to the production of reactive oxygen species and oxidative stress, representing an important immune response of the host cell. In parallel to these processes, regulation of the renin-angiotensin system (RAS) is also demonstrated, which, in this case, contributes to the increased inflammatory response and the production of ROS. NADPH oxidase (NOX), the main enzyme expressed by granulocytes and macrophages, induces the production of ROS, starting with reactive oxygen species formed from two oxygen molecules and an unpaired electron, superoxide anion (O₂^-). From there, the decreased proficiency of electron chain transport leads to the generation of other ROS in sequence, such as H₂O₂ and OH^-. In response to the peroxidation of polyunsaturated fatty acids and tissue damage generated by oxidative stress, expression of the nuclear factor Nrf2 occurs along with the sMAF proteins, leading to the expression of antioxidant response elements (AREs) and consequently the production of antioxidant enzymes, such as superoxide dismutases (SODs), in response to exacerbated O₂^- production. Glutathione peroxidases (GPXs) and catalase (CAT) act mainly by converting ROS into molecular water. Under homeostatic conditions, KEAP1 represses Nrf2 activity by marking Nrf2 for rapid degradation through the ubiquitin-proteasome system, thus preventing Nrf2 from reaching the cell nucleus and transcribing antioxidant response genes.