Potential protective mechanisms of green tea polyphenol EGCG against COVID-19

Abstract

Background: The world is in the midst of the COVID-19 pandemic. In this comprehensive review, we discuss the potential protective effects of (-)-epigallocatechin-3-gallate (EGCG), a major constituent of green tea, against COVID-19.

Scope and approach: Information from literature of clinical symptoms and molecular pathology of COVID-19 as well as relevant publications in which EGCG shows potential protective activities against COVID-19 is integrated and evaluated.

Key findings and conclusions: EGCG, via activating Nrf2, can suppress ACE2 (a cellular receptor for SARS-CoV-2) and TMPRSS2, which mediate cell entry of the virus. Through inhibition of SARS-CoV-2 main protease, EGCG may inhibit viral reproduction. EGCG via its broad antioxidant activity may protect against SARS-CoV-2 evoked mitochondrial ROS (which promote SARS-CoV-2 replication) and against ROS burst inflicted by neutrophil extracellular traps. By suppressing ER-resident GRP78 activity and expression, EGCG can potentially inhibit SARS-CoV-2 life cycle. EGCG also shows protective effects against 1) cytokine storm-associated acute lung injury/acute respiratory distress syndrome, 2) thrombosis via suppressing tissue factors and activating platelets, 3) sepsis by inactivating redox-sensitive HMGB1, and 4) lung fibrosis through augmenting Nrf2 and suppressing NF-κB. These activities remain to be further substantiated in animals and humans. The possible concerted actions of EGCG suggest the importance of further studies on the prevention and treatment of COVID-19 in humans. These results also call for epidemiological studies on potential preventive effects of green tea drinking on COVID-19.

Keywords: COVID-19; EGCG; Prevention; SARS-CoV-2; Tea; Treatment.

Fig. 1

Chemical structure of major green tea catechins.

Fig. 2

Cytokine storm development after SARS-CoV-2 infection. SARS-CoV-2 induces a maladaptive and uncontrolled generalized immune response. Immune cells like T-lymphocytes, macrophages and dendritic cells secrete immense amounts of cytokines and chemokines. Neutrophils and neutrophil extracellular traps (NETs) further fuel the hyper-inflammation that again stimulates NETs, causing a feedback snowballing effect and eventually leading to ARDS. Modified from (Kalyanaraman, 2020) and (Coperchini et al., 2020).

Fig. 3

Proposed mechanism by which COVID-19 is aggravated in diabetic conditions. The main feature of diabetes, hyperglycemia, promotes the replication of SARS-CoV-2 and the development of neutrophil extracellular traps (NETs). Hyperglycemia also strongly upregulates receptor for advanced glycation end products (RAGE) and increases the RAGE ligands — high mobility group box 1 (HMGB1). SARS-CoV-2 also strongly stimulates the formation of NETs and synthesis of HMGB1. Upon activation by its receptor (HMGB1), the RAGE signaling and NETs both induce cytokine storm, sepsis and thrombosis.

Fig. 4

Proposed multiple-target actions by EGCG to prevent or alleviate COVID-19. EGCG via its direct antioxidant activity and induction of Nrf2 prevents or suppresses oxidative stress and inflammation. Through its downregulation of angiotensin-converting enzyme 2 (ACE2) via Nrf2 and direct inhibition of main protease (M^pro), EGCG inhibits the infection and replication of SARS-CoV-2. These activities in combination with direct inhibition of key enzymes or proteins, contribute to the prevention or alleviation of cytokine storm, ER stress, sepsis, thrombosis and lung fibrosis that are caused by SARS-CoV-2 infection.