Reaction Cycles of Halogen Species in the Immune Defense: Implications for Human Health and Diseases and the Pathology and Treatment of COVID-19

Abstract

There is no vaccine or specific antiviral treatment for COVID-19, which is causing a global pandemic. One current focus is drug repurposing research, but those drugs have limited therapeutic efficacies and known adverse effects. The pathology of COVID-19 is essentially unknown. Without this understanding, it is challenging to discover a successful treatment to be approved for clinical use. This paper addresses several key biological processes of reactive oxygen, halogen and nitrogen species (ROS, RHS and RNS) that play crucial physiological roles in organisms from plants to humans. These include why superoxide dismutases, the enzymes to catalyze the formation of H2O2, are required for protecting ROS-induced injury in cell metabolism, why the amount of ROS/RNS produced by ionizing radiation at clinically relevant doses is ~1000 fold lower than the endogenous ROS/RNS level routinely produced in the cell and why a low level of endogenous RHS plays a crucial role in phagocytosis for immune defense. Herein we propose a plausible amplification mechanism in immune defense: ozone-depleting-like halogen cyclic reactions enhancing RHS effects are responsible for all the mentioned physiological functions, which are activated by H2O2 and deactivated by NO signaling molecule. Our results show that the reaction cycles can be repeated thousands of times and amplify the RHS pathogen-killing (defense) effects by 100,000 fold in phagocytosis, resembling the cyclic ozone-depleting reactions in the stratosphere. It is unraveled that H2O2 is a required protective signaling molecule (angel) in the defense system for human health and its dysfunction can cause many diseases or conditions such as autoimmune disorders, aging and cancer. We also identify a class of potent drugs for effective treatment of invading pathogens such as HIV and SARS-CoV-2 (COVID-19), cancer and other diseases, and provide a molecular mechanism of action of the drugs or candidates.

Exploring Molecular Insights of Cereal Peptidic Antioxidants in Metabolic Syndrome Prevention

“…Examples of antioxidants are vitamins A, C, E, carotenoids (including beta-carotene and astaxanthins), and polyphenols (such as flavonoids, isoflavones, anthocyanins, chlorogenic, and catechins) [ 7 , 8 , 9 ]. Examples of prooxidants, particularly the reactive species, include reactive oxygen species (ROS) [ 6 , 10 ], reactive sulfur species (RSS) [ 11 ], reactive electrophile species (RES) [ 12 ], reactive carbonyl species (RCS) [ 13 , 14 ], reactive nitrogen species (RNS) [ 15 , 16 , 17 ], and reactive halogen species (RHS) [ 10 , 15 , 18 ]. ROS, RHS, and RNS are toxic oxidants that cause damage to DNA, RNA, lipids, and phagocytosed pathogen proteins, especially during inflammation [ 10 ].…”

“…Examples of prooxidants, particularly the reactive species, include reactive oxygen species (ROS) [ 6 , 10 ], reactive sulfur species (RSS) [ 11 ], reactive electrophile species (RES) [ 12 ], reactive carbonyl species (RCS) [ 13 , 14 ], reactive nitrogen species (RNS) [ 15 , 16 , 17 ], and reactive halogen species (RHS) [ 10 , 15 , 18 ]. ROS, RHS, and RNS are toxic oxidants that cause damage to DNA, RNA, lipids, and phagocytosed pathogen proteins, especially during inflammation [ 10 ]. According to Yang et al [ 19 ], ROS, RHS, and RNS cause apoptosis by directly oxidizing protein, lipid, and DNA signaling pathways, which increases the risk of CVD, specifically atherosclerosis.…”

“…However, there is evidence that, when RNS is produced in excess, it disrupts protein synthesis in the body, which harms mitochondrial metabolism dynamics and mitophagy in the nervous system [ 17 ]. RHS, especially those with chlorine, bromine, and iodine (thus, HOX with X=Cl, Br or I) induce injuries to DNA, RNA, lipids, and proteins cells [ 10 , 15 ]. They render the immune system’s defense useless when they are released into the body in high quantities by reversing the action of phagocytes (including neutrophils, monocytes, macrophages, mast cells, dendritic cells, osteoclasts, and eosinophils) that capture pathogens, and, thus, instigate disease or infection pathogenesis [ 10 ].…”

“…RHS, especially those with chlorine, bromine, and iodine (thus, HOX with X=Cl, Br or I) induce injuries to DNA, RNA, lipids, and proteins cells [ 10 , 15 ]. They render the immune system’s defense useless when they are released into the body in high quantities by reversing the action of phagocytes (including neutrophils, monocytes, macrophages, mast cells, dendritic cells, osteoclasts, and eosinophils) that capture pathogens, and, thus, instigate disease or infection pathogenesis [ 10 ]. When RHS interreact with extracellular myeloperoxidase (MPO) produced by neutrophils to provide immune system defenses against pathogens, it results in tissue damage, cellular damage, and inflammatory reactions that facilitate the occurrence of a variety of diseases, particularly CVD (atherosclerosis), obesity, T2DM, and, ultimately, metabolic syndrome (MetS) [ 10 , 18 ].…”

Drug Repurposing for COVID-19 using Graph Neural Network with Genetic, Mechanistic, and Epidemiological Validation

“…The emergence of SARS-CoV-2 (2019 novel coronavirus, COVID-19) has created a global pandemic. As of today (August 27, 2020), there have been over 24 million COVID-19 cases worldwide, but no vaccine or highly effective antiviral treatment for COVID-19 patients is available yet (1). While many millions more will likely be infected, some pessimistic estimation is that it may take at least one year for an approved effective vaccine to be in place (2).…”