Zinc and respiratory tract infections: Perspectives for COVID‑19 (Review)

Anatoly V Skalny, Lothar Rink, Olga P Ajsuvakova, Michael Aschner, Viktor A Gritsenko, Svetlana I Alekseenko, Andrey A Svistunov, Demetrios Petrakis, Demetrios A Spandidos, Jan Aaseth, Aristidis Tsatsakis, Alexey A Tinkov, Anatoly V Skalny, Lothar Rink, Olga P Ajsuvakova, Michael Aschner, Viktor A Gritsenko, Svetlana I Alekseenko, Andrey A Svistunov, Demetrios Petrakis, Demetrios A Spandidos, Jan Aaseth, Aristidis Tsatsakis, Alexey A Tinkov

Abstract

In view of the emerging COVID‑19 pandemic caused by SARS‑CoV‑2 virus, the search for potential protective and therapeutic antiviral strategies is of particular and urgent interest. Zinc is known to modulate antiviral and antibacterial immunity and regulate inflammatory response. Despite the lack of clinical data, certain indications suggest that modulation of zinc status may be beneficial in COVID‑19. In vitro experiments demonstrate that Zn2+ possesses antiviral activity through inhibition of SARS‑CoV RNA polymerase. This effect may underlie therapeutic efficiency of chloroquine known to act as zinc ionophore. Indirect evidence also indicates that Zn2+ may decrease the activity of angiotensin‑converting enzyme 2 (ACE2), known to be the receptor for SARS‑CoV‑2. Improved antiviral immunity by zinc may also occur through up‑regulation of interferon α production and increasing its antiviral activity. Zinc possesses anti‑inflammatory activity by inhibiting NF‑κB signaling and modulation of regulatory T‑cell functions that may limit the cytokine storm in COVID‑19. Improved Zn status may also reduce the risk of bacterial co‑infection by improving mucociliary clearance and barrier function of the respiratory epithelium, as well as direct antibacterial effects against S. pneumoniae. Zinc status is also tightly associated with risk factors for severe COVID‑19 including ageing, immune deficiency, obesity, diabetes, and atherosclerosis, since these are known risk groups for zinc deficiency. Therefore, Zn may possess protective effect as preventive and adjuvant therapy of COVID‑19 through reducing inflammation, improvement of mucociliary clearance, prevention of ventilator‑induced lung injury, modulation of antiviral and antibacterial immunity. However, further clinical and experimental studies are required.

Figures

Figure 1
Figure 1
The proposed protective mechanisms of zinc in COVID-19. 1. Zinc significantly improves cilia morphology (54) and increases ciliary beat frequency (55) thus improving mucociliary clearance and removal of bacteria and virus-containing particles. By up-regulating tight junction proteins ZO-1 and claudin-1 (57) and increasing antioxidant activity of respiratory epithelia (56) zinc also increases barrier function of the latter. In turn, coronavirus infection was shown to impair mucociliary clearance (50) predisposing the lung for further viral and bacterial aggression. 2. Zinc may also possess antiviral activity through inhibition of RdRp and blocking further replication of viral RNA as demonstrated for SARS-CoV (38). Indirect evidence also indicates that Zn2+ may decrease activity of ACE2 (49), known to be the receptor for SARS-CoV-2 (47). 3. Modulation of antiviral immunity by zinc may also limit SARS-CoV-2 infection at least through up-regulation of IFNα production (63) and increasing its antiviral activity (64). The latter may be mediated through IFNα-induced JAK1/STAT1 signaling and up-regulation of antiviral proteins (RNaseL and PKR) known to degrade viral RNA and inhibit its translation (65). 4. Excessive inflammatory response resulting in overproduction of proiflammatory cytokines and cytokine storm is known to play a significant role in COVID-19 pathogenesis (103). In turn, zinc possesses anti-inflammatory activity through inhibition of IKK activity and subsequent NF-κB signaling resulting in down-regulation of proinflammatory cytokine production (122,124). Modulation of regulatory T-cell functions by Zinc may also limit excessive inflammatory response (125,126) as well as the downregulation of proinflammatory cytokine production (127,123). 5. Given a high risk of bacterial co-infection in viral pneumonia (128), Zn-induced inhibition of S. pneumoniae growth through modulation of bacterial Mn(II) homeostasis (137) may also be beneficial. 6. Zinc status is also associated with risk factors for high COVID-19 mortality. Specifically, ageing, immune deficiency, as well as metabolic diseases such as obesity, diabetes, and atherosclerosis, are known to be both risk factors for high disease mortality (31,32) and zinc deficiency (149). In turn, Zn supplementation may have beneficial effect in modulation of at least some of these risk factors. ACE2, angiotensin-converting enzyme 2; IFN, interferon; IKK, IκB kinase; NF-κB, nuclear factor-κB; ARDS, acute respiratory distress syndrome.

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