NOX2 Activation in COVID-19: Possible Implications for Neurodegenerative Diseases

Abstract

Coronavirus disease 2019 (COVID-19) is a rapidly spreading contagious infectious disease caused by the pathogen severe acute respiratory syndrome coronavirus 2 (SARS COV-2), that primarily affects the respiratory tract as well as the central nervous system (CNS). SARS COV-2 infection occurs through the interaction of the viral protein Spike with the angiotensin II receptor (ACE 2), leading to an increase of angiotensin II and activation of nicotinamide adenine dinucleotide phosphate oxidase2 (NOX2), resulting in the release of both reactive oxygen species (ROS) and inflammatory molecules. The purpose of the review is to explain that SARS CoV-2 infection can determine neuroinflammation that induces NOX2 activation in microglia. To better understand the role of NOX2 in inflammation, an overview of its involvement in neurodegenerative diseases (NDs) such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS) is provided. To write this manuscript, we performed a PubMed search to evaluate the possible relationship of SARS CoV-2 infection in NOX2 activation in microglia, as well as the role of NOX2 in NDs. Several studies highlighted that NOX2 activation in microglia amplifies neuroinflammation. To date, there is no clinical treatment capable of counteracting its activation, however, NOX2 could be a promising pharmaceutical target useful for both the treatment and prevention of NDs and COVID-19 treatment.

Oxidative Stress-Related Mechanisms in SARS-CoV-2 Infections

“…The virus binding to ACE2 receptor initiates its entry to the cell, and after attachment and virion-membrane fusion, ACE2 expression is downregulated [ 57 , 58 ]. The viral protein Spike interaction with ACE2 leads to an excessive production of angiotensin II (Ang II) and activation of NADPH oxidase which subsequently results in enhancing oxidative stress mechanisms (in contrast to what happens during other viral infections) but also releasing inflammatory molecules [ 59 ]. In the course of SARS-CoV-2 infection, angiontensin II availability is increased through the high affinity and resulting binding the virus to ACE2 [ 60 ].…”

“…The virus binding to ACE2 receptor initiates its entry to the cell, and after attachment and virion-membrane fusion, ACE2 expression is downregulated [57,58]. The viral [59]. In the course of SARS-CoV-2 infection, angiontensin II availability is increased through the high affinity and resulting binding the virus to ACE2 [60].…”

Multi-Data Integration Towards a Global Understanding of the Neurological Impact of Human Brain Severe Acute Respiratory Syndrome Coronavirus 2 Infection

“…Furthermore, from our results, several genes appear as correlated to this infection as other works based on exploration of data from patient infected by SARS-CoV-2. From these genes, we note the following: CXCR6 ( Kasela et al, 2021 ), CST9L 4 ( Yan et al, 2020 ), NOXO1 ( Sindona et al, 2021 ), IL28B ( Alothaid et al, 2020 ), FGF23 ( George et al, 2021 ), and finally, the controverted vitamin D receptor VDR ( Ceolin et al, 2021 ).…”

Rationale for Nicotinamide Adenine Dinucleotide (NAD+) Metabolome Disruption as a Pathogenic Mechanism of Post-Acute COVID-19 Syndrome

“… 20 In the context of chronic inflammatory lung conditions, oxidative stress has been shown to activate pro-inflammatory transcription factors, such as NF-kappa B, enhancing the activity of inflammatory pathways associated with the development of these conditions. 20 , 21 Elevated levels of ROS and subsequent oxidative stress are also known to have deleterious effects on neuronal health by initiating intracellular signaling cascades that promote pro-inflammatory gene expression. 21 - 23 …”

“… 20 , 21 Elevated levels of ROS and subsequent oxidative stress are also known to have deleterious effects on neuronal health by initiating intracellular signaling cascades that promote pro-inflammatory gene expression. 21 - 23 …”