Epigenetic modifications associated with genes implicated in cytokine storm: The potential biotherapeutic effects of vitamins and minerals in COVID‐19

Abstract

Cytokine storm is a phrase used to refer to an abrupt upsurge in the circulating levels of various pro-inflammatory cytokines, causing increased stimulation and activity of immune cells during disease conditions. The binding of pattern recognition receptors to pathogen-associated molecular patterns during COVID-19 infection recruits response machinery involving the activation of transcription factors and proteins required for a robust immune response by host cells. These immune responses could be influenced by epigenetic modifications as evidenced by significant variations in COVID-19 pathophysiology and response to therapy observed among patients across the globe. Considering that circulating levels of interleukin 1, tumor necrosis factorα, and interleukin 6 are significantly elevated during cytokine storm in COVID-19 patients, genetic and epigenetic variations in the expression and function of these proteins could enhance our understanding of the disease pathogenesis. Treatment options that repress the transcription of specific cytokine genes during COVID-19 infection could serve as possible targets to counteract cytokine storm in COVID-19.Therefore, the present article reviews the roles of cytokines and associated genes in the COVID-19 cytokine storm, identifies epigenetic modifications associated with the disease progression, and possible ameliorative effects of some vitamins and minerals obtained as epigenetic modifiers for the control of cytokine storm and disease severity in COVID-19 patients. Practical applicationsCOVID-19 causes mortality and morbidity that adversely affect global economies.Despite a global vaccination campaign, side effects associated with vaccination, misconceptions, and a number of other factors have affected the expected successes.

The critical impacts of cytokine storms in respiratory disorders

“…These pro-inflammatory cytokines attract more inflammatory cells and immune cells, hence causing activation of adaptive immune response with the recruitment of CD4 + and CD8 + T cells, which results in persistent inflammatory response that activates emergency granulopoiesis, macrophage activation, and erythro-phagocytosis which damages pulmonary tissue architecture. Erythro-phagocytosis results in anemia, capillary leakage, and activation of the intrinsic pathway of coagulation which results in the formation of emboli in the blood vascular system [ 46 ]. Furthermore, in CS natural regulatory systems like Tregs which produce IL-10 and TNF-β are down-regulated by excessive production of pro-inflammatory cytokines.…”

The epigenetic legacy of ICU feeding and its consequences

“…Whether such telomere-shortening may predispose to long-term developmental impairments should be further investigated. Vitamins have been proposed as epigenetic modifiers, to enhance immunity and reduce inflammatory responses, in COVID-19 patients [98]. Importantly, effects of early-PN versus late-PN on clinical outcome and epigenetic changes in the (P) EPaNIC study could not be explained by differences in vitamin administration as vitamins were equally supplemented to both groups when EN was insufficient [7][8][9][10]85,86].…”

Involvement of epigenetics in affecting host immunity during SARS-CoV-2 infection

“…The elevated levels of different pro-inflammatory cytokines like IL-1β, IL8, TNF-α, IFN-γ, IL-12, IL-18, IL-33, IL-6, IL-4, monocyte chemoattractant protein ( MCP1 ), macrophage inflammatory protein 1-α ( MIP1A ) and granulocyte-colony stimulating factor ( G-CSF ) cause an excessive influx of various immune cells to the site of infection, leading to lungs damage and multi-organ failure [142] , [143] , [144] . The cytokine storm is a familiar principal mechanism of acute respiratory distress syndrome ( ARDS ), which is the chief cause of death upon SARS-CoV-2 infection [145] . Generally, ARDS makes immunocompromised, chronically ill, and older patients more susceptible to hyperinflammation [146] .…”

“…Besides vitamins, many minerals also play a crucial role in regulating the epigenome of specific genes involved in SARS-CoV-2 pathogenesis. Minerals such as magnesium (Mg), iron (Fe), potassium (K) and zinc (Zn) have been known for a long to have anti-inflammatory, anti-viral and antioxidant activities, and their deficiency causes demethylation of IL-6 promoter and cellular damage by activation of immune cells [145] . Recent clinical studies observed that low plasma levels of minerals like Zn correlated with increased virulence and complications in SARS-CoV-2 infection in patients [179] , [180] .…”

“…Zn is a crucial element involved as a co-factor in many epigenetic, immunomodulatory and antioxidant pathways. Therefore the disease severity in COVID-19 patients having low plasma Zn concentrations could be due to the reduced activity of Zn-dependent histone-modifying enzymes [145] . It has also been predicted that the decreased plasma level of Zn and Mg could be due to excessive consumption of these minerals by the metal-binding pro-inflammatory cytokines that are released in large amounts during infection [182] .…”