Zinc and covid

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 in ammatory response. Despite the lack of clinical data, certain indications suggest that modulation of zinc status may be bene cial in COVID‐19. In vitro experiments demonstrate that Zn2+ possesses antiviral activity through inhibition of SARS‐CoV RNA polymerase. This effect may underlie therapeutic ef ciency 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‐in ammatory activity by inhibiting NF‐κB signaling and modulation of regulatory

Correspondence to: Dr Alexey A. Tinkov, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119146 Moscow, Russia
E‐mail: tinkov.a.a@gmail.com

Professor Aristidis Tsatsakis, Center of Toxicology Science and Research, Medical School, University of Crete, Voutes, 71409 Heraklion, Greece
E‐mail: tsatsaka@uoc.gr

*Contributed equally
Key words: zinc, coronavirus, SARS‐CoV‐2, pneumonia, immunity

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 de ciency, 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 in ammation, improvement of mucociliary clearance, prevention of ventilator‐induced lung injury, modulation of antiviral and antibacterial immunity. However, further clinical and experimental studies are required.

Contents

1. Introduction

2. Zinc and COVID‐19

3. Zn and respiratory viruses

4. Pneumonia in adults and the elderly

5. Pediatric respiratory infections

6. Zinc and lung in ammation

7. Zinc and S. pneumoniae infection

8. Perspectives and conclusions

1. Introduction

Zinc is an essential metal being involved in a variety of biological processes due to its function as a cofactor, signaling molecule, and structural element. It is involved in the

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE

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

ANATOLY V. SKALNY1,2*, LOTHAR RINK3*, OLGA P. AJSUVAKOVA2,4, MICHAEL ASCHNER1,5, VIKTOR A. GRITSENKO6, SVETLANA I. ALEKSEENKO7,8, ANDREY A. SVISTUNOV1, DEMETRIOS PETRAKIS9, DEMETRIOS A. SPANDIDOS10, JAN AASETH1,11, ARISTIDIS TSATSAKIS1,9 and ALEXEY A. TINKOV1,2,6*

1I.M. Sechenov First Moscow State Medical University (Sechenov University), 119146 Moscow; 2Yaroslavl State University, 150003 Yaroslavl, Russia; 3Institute of Immunology, Medical Faculty,
RWTH Aachen University, D‐52062 Aachen, Germany; 4Federal Research Centre of Biological Systems
and Agro‐technologies of the Russian Academy of Sciences, 460000 Orenburg, Russia; 5Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; 6Institute of Cellular and Intracellular Symbiosis, Russian Academy of Sciences, 460000 Orenburg; 7I.I. Mechnikov North‐Western State Medical University, 191015 St. Petersburg; 8K.A. Rauhfus Children’s City Multidisciplinary Clinical Center
for High Medical Technologies, 191000 St. Petersburg, Russia; 9Center of Toxicology Science and Research, 10Laboratory of Clinical Virology, Medical School, University of Crete, 71409 Heraklion, Greece; 11Research Department, Innlandet Hospital Trust, 3159894 Brumunddal, Norway

Received March 23, 2020; Accepted April 13, 2020 DOI: 10.3892/ijmm.2020.4575

2

SKALNY et al: ZINC AND RESPIRATORY TRACT INFECTIONS: PERSPECTIVES FOR COVID‐19

regulation of carbohydrate and lipid metabolism, as well as the functioning of the reproductive, cardiovascular, and nervous system (1). At the same time, the most critical role of zinc is demonstrated for the immune system. Brie y, zinc regulates proliferation, differentiation, maturation, and functioning of leukocytes and lymphocytes (2). Zinc plays a signaling role involved in the modulation of in ammatory responses (3). It is also a component of nutritional immunity (4). Correspondingly, alteration of zinc status signi cantly affects immune response resulting in increased susceptibility to inflammatory and infectious diseases including acquired immune deficiency syndrome, measles, malaria, tuberculosis, and pneumonia (5). Earlier data demonstrate that populational Zn status is associated with the prevalence of respiratory tract infections in children and adults (6,7).

are exposed to a multitude of chemicals, even in low doses that in the long‐term predispose to chronic diseases and metabolic disturbances (27‐31). Preexisting chronic metabolic diseases including diabetes, cardiovascular diseases (32), and obesity (33) are considered as risk factors for increased COVID‐19 susceptibility and mortality. It is proposed that the elderly are at higher risk of COVID‐19 due to impaired immune function (34).

In view of the high prevalence of zinc de ciency world‐ wide (up to 17%), its impact on population health is considered as a signi cant issue (8). Moreover, certain groups of people, including infants, especially preterm ones, and elderly, are considered to be at high risk of zinc de ciency and its adverse effects (9).

Due to the clearly demonstrated role of zinc in immunity (2), and impaired zinc status in ageing (35), metabolic diseases including diabetes, obesity, and cardiovascular diseases (13), it is speculated that zinc compounds may be used as an adjunct therapy in COVID‐19 treatment (36) for increasing antiviral resistance (37). Of note, zinc was earlier suggested as the potential agent for immune support and prevention of H1N1 in uenza (‘swine u’) (38).

Under zinc deficiency condition, organisms are more susceptible to toxin‐producing bacteria or enteroviral patho‐ gens that activate guanylate and adenylate cyclases, stimulating chloride secretion, causing diarrhea and diminishing absorp‐ tion of nutrients, thus exacerbating an already compromised mineral status. In addition, zinc de ciency may impair the absorption of water and electrolytes, delaying the termination of normally self‐limiting gastrointestinal disease episodes (10). During chronic de ciency, the production of pro‐in amma‐ tory cytokines increases, in uencing the outcome of a large number of in ammatory, metabolic, neurodegenerative and immune diseases (11). Diseases such as rheumatoid arthritis, diabetes (12), atherosclerosis and obesity (13), impaired cogni‐ tive function (14), as well as age‐related macular degeneration (AMD) may be due to zinc deficiency, worsening chronic in ammation and triggering oxidative stress.

In view of lack of clinical data on preventive and/or therapeutic ef ciency of zinc in COVID‐19, as well as primary involvement of the respiratory system, in this review, we will discuss recent clinical data on the role of zinc in protection against bronchopulmonary infections, as well as the existing indications of the direct impact of zinc on nCoV‐2019.

Coronaviridae were considered as the etiological agent in 6‐29% of respiratory infections (15,16), although the severity of the disease varies signi cantly on the particular virus and its virulence (17). The viruses from the Coronaviridae family are zoonotic viruses that can be transmitted from animals to humans. The bat is considered the reservoir for these viruses, but other intermediate animals can also transmit the virus to humans (18). COVID‐19 is a coronavirus disease caused by the novel 2019‐nCoV virus (now called SARS‐CoV‐2) that appeared for the first time in Wuhan, China at the end of 2019 (19). Despite a close relation other two highly pathogenic coronaviruses, MERS‐CoV and SARS‐CoV (20), SARS‐CoV‐2 expanded to the majority of countries (21). On 11 March 2020, WHO characterized COVID‐19 as a pandemic (22). Currently, the prevalence of COVID‐19 exceeds 1,521,200 cases resulting in 92,700 deaths worldwide (23).

2. Zinc and COVID‐19

In view of the global COVID‐19 pandemic, potential protec‐ tive effect of zinc is of particular interest. Zinc is considered as the potential supportive treatment in therapy of COVID‐19 infection due to its immune modulatory effect, as well as direct antiviral effect (36). However, the existing data will be only mechanistically discussed in this review, as direct data on anti‐COVID‐19 effects of zinc are absent to date.

Speci cally, Zn2+ cations especially in combination with Zn ionophore pyrithione were shown to inhibit SARS‐coronavirus RNA polymerase (RNA dependent RNA polymerase, RdRp) activity by decreasing its replication (39). These important nd‐ ings demonstrate that Zn2+ may be considered as the particular antiviral agent in COVID‐19 treatment. Of note, recent trials have indicated ef ciency of chloroquine antiviral activity as a treatment of COVID‐19 (40), although the intimate mecha‐ nisms of its antiviral activity require further investigation (41). Earlier ndings demonstrate that chloroquine is a zinc iono‐ phore increasing Zn2+ ux into the cell (42). Moreover, the authors also propose that chloroquine‐mediate zinc in ux may underlie anticancer activity of the compound (42). Similarly, it was hypothesized that increasing intracellular Zn2+ concentra‐ tion by chloroquine may also mediate its antiviral effect against SARS‐CoV‐2. In this view zinc supplementation without chlo‐ roquine might have similar positive effects without adverse side‐effects of chloroquine treatment (43). Hypothetically, such an effect may be also observed using other zinc iono‐ phores like quercetin and epigallocatechin‐gallate (44) with substantially lower toxicity, although clinical trials supported by experimental in vitro studies are required to support this hypothesis.

Another Zn‐related approach to modulation of COVID‐19 may include targeting Zn ions in the structure of viral proteins. Particularly, it has been demonstrated that disul ram‐induced Zn2+ release from papain‐like protease in MERS‐CoV and SARS‐CoV resulting in protein destabilization (45). In view of

COVID‐19 predominantly affects the respiratory system resulting in pneumonia and acute respiratory distress syndrome (24), leading to the requirement of mechanical ventilation (25). In turn, advanced age, acute respiratory distress syndrome (ARDS) and mechanical ventilation are known to be associated with higher COVID‐19 mortality (26). The risk is also increased by modern life in which individuals

the presence of similar critical Zn‐containing sites, Zn‐ejector drugs (e.g., disul ram) may be considered as potential antiviral agents (46) and components of targeted oxidation strategy in anti‐SARS‐CoV‐2 treatment (47).

These ndings along with the existing data on the role of zinc in immunity raised interest to the potential use of zinc in prevention and/or treatment of common cold. A systematic review by Singh and Das (67) published in Cochrane database revealed a significant reduction in common cold duration, as well as the incidence rate ratio of developing common cold (IRR=0.64 (95% CI: 0.47‐0.88), P=0.006) in response to zinc supplementation. The results of meta‐analysis demonstrated that Zn supplementation in the dose >75 mg/day signi cantly reduced duration of common colds (68), with Zn acetate being the most effective form (69).

SARS‐CoV‐2 similarly to SARS‐CoV requires angio‐ tensin‐converting enzyme 2 (ACE2) for entry into target cells (48). Therefore, modulation of ACE2 receptor was considered as the potential therapeutic strategy in COVID‐19 treatment (49). Speth et al (50) demonstrated that zinc expo‐ sure (100 μM) was shown to reduce recombinant human ACE‐2 activity in rat lungs. Although this concentration is close to physiological values of total zinc, the modulating effect of zinc on SARS‐CoV‐2‐ACE2 interaction seem to be only hypothetical (51).

Certain studies also revealed the association between Zn status and respiratory syncytial virus (RSV) infection. Particularly, it has been demonstrated that whole blood zinc was signi cantly lower in children with RSV pneumonia (70). Impaired zinc metabolism in perinatal alcohol exposure is associated with immunosuppression and altered alveolar macrophage activity resulting in increased susceptibility to RSV infection (71). In turn, Zn compounds were shown to inhibit respiratory syncytial virus replication and RSV plaque formation with a more than 1,000‐fold reduction at 10 μm Zn preincubation (72).

Although neither coronavirus HCoV 229E (52) nor HCoV‐OC43 (53) infection caused a signi cant reduction in ciliary beat frequency, HCoV 229E induced ciliary dyskinesia resulting in impaired mucociliary clearance. The latter may not only alter viral particle removal, but also predispose to bacterial co‐infection as observed for in uenza virus (54). In turn, Zn supplementation was shown to improve ciliary length in bronchial epithelium of Zn‐de cient rats (55), as well as increase ciliary beat frequency in vitro (56). Therefore, zinc may hypothetically ameliorate nCoV‐2019‐induced dysfunc‐ tion of mucociliary clearance. Generally, zinc was shown to be essential for respiratory epithelium due to antioxidant and anti‐in ammatory activity (57), as well as regulation of tight junction proteins ZO‐1 and Claudin‐1 (58), thus increasing its barrier functions. In turn, downregulation of tight junction protein complexes e.g., ZO‐1 and Claudin‐1 and reduction in barrier function aggravates viral and bacterial in ammatory processes (59). In addition, loss of TJ perm selectivity in the airways results in an un‐controlled leakage of high molecular weight proteins and water into the airways, which results in the formation of alveolar edema and ARDS (60).

3. Zn and respiratory viruses

Despite limited data on the direct effect of zinc on SARS‐CoV‐2 and COVID‐19, its antiviral effects were demonstrated in other viral diseases. Zinc was shown to have a signi cant impact on viral infections through modulation of viral particle entry, fusion, replication, viral protein translation and further release for a number of viruses including those involved in respiratory system pathology (37,61). Specifically, increasing intracel‐ lular Zn levels through application of Zn ionophores such as pyrithione and hinokitiol signi cantly alters replication of picornavirus, the leading cause of common cold (62). These findings generally correspond to the earlier indications of suppressive effect of zinc on rhinovirus replication originating from the early 1970s (63). In addition, Zn treatment was shown to increase interferon α (IFNα) production by leukocytes (64) and potentiate its antiviral activity in rhinovirus‐infected cells (65). As antiviral activity of IFNα is mediated through JAK1/STAT1 downstream signaling and up‐regulation of antiviral enzymes [e.g., latent ribonuclease (RNaseL) and protein kinase RNA‐activated (PKR)] involved in viral RNA degradation and inhibition of viral RNA translation (66), recent ndings allow to propose that these mechanisms may be stimulated by Zn2+.

It is also notable that zinc de ciency was associated with higher mortality and adverse long‐term outcome in influ‐ enza‐MRSA bacterial superinfection (73), also underlining the importance of considering the risk of bacterial coinfection.

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE

3

Despite the presence of experimental findings on the protective effect of zinc supplementation against respiratory virus infections, clinical and epidemiological data are still to be elaborated and systematized.

4. Pneumonia in adults and the elderly

Zinc is essential for the immune system and elderly people have an increased probability for zinc de ciency (74). Low Zn status was considered as the potential risk factor for pneumonia in elderly. Particularly, subjects with high serum Zn (>70 μg/dl, i.e., approx. 10.8 μmol/l) were characterized by reduced incidence of pneumonia [0.52 (0.36, 0.76), P<0.001], as well as lower disease duration and antibiotic administra‐ tion as compared to low‐Zn (<70 μg/ml) group (75), being also related to all‐cause mortality (76). Serum Zn levels were 15% lower in cases of community‐acquired pneumonia and advanced age, being also associated with pneumonia severity as evaluated by CURB‐65 scores (77). The incidence of severe pneumonia was signi cantly higher in Irani patients with low Zn status, although the mean duration of fever, tachycardia, and tachypnea only tended to be longer, although not signi cant (78). Correspondingly, serum Zn levels were found de cient at the onset of acute respiratory failure with the lowest values observed in septic shock patients. However, no association between serum Zn values and day‐30 mortality or period of stay in intensive care unit was observed (79).

The results of systematic analysis also con rmed the ef ciency of intake of at least 75 mg/day Zn in reduction of pneumonia symptom duration but not severity, with the response being more pronounced in adults than in children (80). At the same time, certain studies failed to reveal any improvement in pneumonia when administered along with standard antibiotic treatment, although the period of supplementation was only 4 days (81).

SKALNY et al: ZINC AND RESPIRATORY TRACT INFECTIONS: PERSPECTIVES FOR COVID‐19

4

In Indian patients high plasma zinc levels were found to be associated with reduced mortality from sepsis as well as lower 48‐h SOFA scores (84). Moreover, persistent low serum Zn levels were associated with increased risk of recurrent sepsis in critically ill patients (85).

5. Pediatric respiratory infections

A detailed study by Boudreault et al (82) demonstrated that low plasma Zn predisposes to ventilator‐induced injury in intensive care, being related to the role of metallothionein system in lung protection. These data corroborate the results of the experimental study demonstrating aggravation of ventilation‐induced lung injury in Zn de cient rats (83).

lower respiratory infections including bronchitis, bronchiol‐ itis, pneumonitis. Speci cally, supplementation with 10 mg zinc gluconate in Zn‐de cient children resulted in a nearly twofold reduction of the number of episodes of acute lower respiratory infections as well as the time to recovery (98). In addition, Zn supplementation (30 mg/day) in Thai children signi cantly reduced severity of acute lower respiratory tract infections resulting in faster disease cessation and shorter hospital stay (99). A detailed meta‐analysis demonstrated that Zn supplementation signi cantly decreased the incidence of acute lower respiratory infection de ned according to speci c clinical criteria in children aged <5 years (100).

Altogether, the existing data demonstrate an association between zinc status and pneumonia in adults and elderly, as well as its complications including respiratory failure, ventilator‐induced injury, and sepsis.

In parallel, the impact of Zn supplementation in relation to upper respiratory tract infections was also demonstrated. Particularly, the number of upper respiratory tract infections in Colombian children was reduced by 73% in response to supplementation with 5 mg Zn in a 12‐month randomized clinical trial (101). Certain studies also revealed protective effect of zinc supplementation against both acute upper and lower respiratory diseases in children (102,103).

Initial reports have postulated nearly exceptional suscepti‐ bility of elderly to SARS‐CoV‐2 infection allowing to propose natural resistance to COVID‐19 in children (86). However, detailed analysis of the pediatric COVID‐19 cases (87) and the emerging Russian experience indicate that children may be also severely affected by SARS‐CoV‐2. In view of high incidence of Zn de ciency in infants, the existing data on the association between Zn status and pneumonia in children is also discussed.

6. Zinc and lung in ammation

High incidence of pneumonia in developing countries has been considered as the consequence of zinc de ciency in the population (7). The incidence of low serum zinc in children with severe pneumonia was 80% (88). Correspondingly, a 2‐fold lower level of serum Zn was observed in pediatric acute lower respiratory infection patients (89). Signi cantly lower serum zinc levels were observed in children with pneumonia complicated by sepsis, mechanical ventilation, and cases of lethality (90). Generally, indications of low zinc status in children with pneumonia provide a rationale for preventive Zn supplementation.

In ammation plays the key role in COVID‐19 pathogenesis both at local (pneumonia) and systemic (cytokine storm) levels, and the search for adequate anti‐in ammatory agents is of particular importance (104).

Particularly, Zn supplementation in developing countries reduced pneumonia morbidity by 19% (RR=0.81; 95% CI: 0.73, 0.90), whereas a 15% decrease in pneumonia‐speci c mortality was not significant (91). A recent systematic review and meta‐analysis published in Cochrane database demonstrated that Zn supplementation signi cantly reduced the incidence and prevalence of pneumonia in children by 13 and 41% (92).

Speci cally, Zn de ciency in rats resulted in a signi cant increase in proin ammatory TNFα and VCAM‐1 expression and lung tissue remodeling, being partially reversed by Zn supplementation (105). Zn de ciency also resulted in a signi ‐ cant alteration of lung epithelial cell barrier function through up‐regulation of TNFα, IFNγ, and FasR signaling and cellular apoptosis in vitro (106). Zn de ciency was shown to up‐regu‐ late acute phase response‐related genes through stimulation of JAK‐STAT signaling in lungs under septic conditions (107). Zinc and nitric oxide (NO)‐metallothioneine (MT)‐Zn path‐ ways were shown to mediate lung injury in response to LPS or hyperoxia (108).

In contrast to the demonstrated preventive effects of Zn supplementation, data on the therapeutic effect of zinc in treat‐ ment of childhood pneumonia are con icting (93). Despite the earlier observed reduction of treatment failure risk (94) and case fatality [RR=0.67 (95% CI: 0.24‐0.85)] (95) in children with severe pneumonia, a more recent study demonstrated that Zn supplementation in 2‐24 months old children with radiologically veri ed pneumonia did not result in signi ‐ cant improvement of risk reduction of treatment failure (96). Moreover, Zn supplementation in Zn‐de cient children with pneumonia until achievement of normal serum Zn levels did not improve clinical appearance of the disease (97).

In turn, Zn pretreatment signi cantly reduced LPS‐induced pulmonary endothelial cell damage and increased cell viability in vitro, as well as improved respiratory function as assessed by blood oxygen pressure and saturation (109). It has been demonstrated that Zn pretreatment significantly decreases LPS‐induced neutrophil recruitment to the lungs thus reducing acute lung injury in mice (110).

A number of studies revealed the potential ef ciency of Zn supplementation in prevention of non‐specified acute

It is also notable that zinc de ciency is associated with in ammatory alterations of lung extracellular matrix predis‐ posing to brosis (111). This nding is of particular interest in view of the presence of interstitial pulmonary brosis in COVID‐19 patients (112).

Although the role of zinc in regulation of in ammatory response was discussed in detail in a number of reviews (2,5), certain aspects of the regulatory role of zinc in pneumonia pathogenesis and lung in ammation are still to be elucidated. However, the existing data clearly demonstrate that Zn ions may possess anti‐inflammatory effects in pneumonia thus limiting tissue damage and systemic effects.

Certain studies revealed protective effect of zinc against lung injury in systemic inflammation including sepsis.

Experimental data demonstrate that Zn de ciency increases susceptibility to systemic in ammation and sepsis‐induced organ damage including lungs in a murine model of polymi‐ crobial sepsis (113). In a model of polymicrobial sepsis Zn de ciency resulted in increased NF‐κB p65 mRNA expression and production in lungs resulting in up‐regulation of target genes IL‐1β, TNFα, and ICAM‐1 (114), whereas Zn supple‐ mentation reduced neutrophil in ltration and MPO‐mediated oxidative damage (115,116). Modulation of ERK1/2 and NF‐κB pathways was shown to be critical for protective effect of zinc in lungs under septic conditions (117).

neutrophil in ltration and elevated CXCL1 and IL‐23 produc‐ tion (120).

Correspondingly, patients with sepsis were character‐ ized by low serum Zn levels that may occur due to increased ZIP8 (SLC39A8) mRNA expression. Moreover, serum Zn concentrations inversely correlated with both disease severity and proin ammatory cytokines IL‐6, IL‐8, and TNFα (118). Reciprocal regulation of ZIP8 and NF‐κB expression in response to TNFα or LPS exposure was demonstrated in lung epithelia and alveolar macrophages (119). In addition, ZIP8‐de cient mice were characterized by increased airway

Zn‐mediated respiratory protection was also demonstrated in models of toxic atmospheric pollutant exposure. Particularly, Zn de ciency in agricultural organic dust‐exposed animals aggravated neutrophil migration and proinflammatory cytokine (TNFα, IL‐6, CXCL1) overproduction, as well as increased IL‐23 and CXCL1 expression by macrophages due to NF‐κB activation (121). In turn, Zn supplementation in ciga‐ rette smoke exposed mice signi cantly reduced the number of alveolar macrophages in bronchoalveolar lavage (122).

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE

5

Figure 1. The proposed protective mechanisms of zinc in COVID‐19. 1. Zinc signi cantly 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 in ammatory response resulting in overproduction of proi ammatory cytokines and cytokine storm is known to play a signi cant role in COVID‐19 pathogenesis (103). In turn, zinc possesses anti‐in ammatory activity through inhibition of IKK activity and subsequent NF‐κB signaling resulting in down‐regulation of proin ammatory cytokine production (122,124). Modulation of regulatory T‐cell functions by Zinc may also limit excessive in ammatory response (125,126) as well as the downregulation of proin ammatory 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 bene cial. 6. Zinc status is also associated with risk factors for high COVID‐19 mortality. Speci cally, ageing, immune de ciency, 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 de ciency (149). In turn, Zn supplementation may have bene cial 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.

The observed anti‐inflammatory effects of Zn in lung tissue seem to be mainly mediated by inhibition of NF‐κB signaling through PKA‐induced inhibition of Raf‐1 and IκB kinase β (IKKβ) (123,124) or A20‐dependent inhibi‐ tion (125). Moreover, Zn‐induced modulation of T‐cell activity may also play a significant role in limiting inflammatory response (126,127). Lastly, zinc was shown to normalize the overproduction of proin ammatory cytokines induced by zinc de ciency on the epigenetic level (124,128).

6

7. Zinc and S. pneumoniae infection

course of the disease, it appears that adequate Zn status may possess protective effect as adjuvant therapy of COVID‐19 through reducing lung in ammation, improvement of muco‐ ciliary clearance, prevention of ventilator‐induced lung injury, modulation of antibacterial and antiviral immunity especially in elderly (Fig. 1). Further clinical and experimental studies are strongly required to elucidate the potential role of Zn de ciency in COVID‐19 susceptibility, as well as effects of Zn supplementation, and the underlying mechanisms.

Acknowledgements

Not applicable.

Funding

The study was partially supported by the Russian Ministry of Science and Higher Education, Project no. 0856‐2020‐0008. MA was supported by NIH grants nos. NIEHS R0110563, R01ES07331 and NIEHS R01ES020852.

Availability of data and materials

Not applicable.

Authors’ contributions

Conceptualization: AVS, LR, MA, JA, AT, AAT; validation, research, resources, data reviewing, and writing: AVS, LR, OPA, MA, VAG, SIA, AAS, DP, DAS, JA, AT, AAT; gure preparation and edition: AAT; review and editing: AVS, LR, MA, JA, AT, AAT. All authors read and approved the nal manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

DAS is the Editor‐in‐Chief for the journal, but had no personal involvement in the reviewing process, or any influence in terms of adjudicating on the nal decision, for this article. The other authors declare that they have no competing interests.

References

8. Perspectives and conclusions

SKALNY et al: ZINC AND RESPIRATORY TRACT INFECTIONS: PERSPECTIVES FOR COVID‐19

Although COVID‐19 is characterized by viral pneumonia caused by SARS‐CoV‐2 virus, bacterial co‐infection may represent a signi cant issue due its high incidence in H1N1 in uenza‐associated pneumonia (129). Speci cally, human coronavirus NL63 was associated with increased adherence of S. pneumoniae to epithelial cells (130). In turn, Streptococcus pneumoniae infection is considered as the most common cause of pneumonia.

Zinc is an essential component of antibacterial immunity (5). Particularly, Zn de ciency was associated with reduced killing activity of phagocytes in pneumococcal infection (131). In turn, Zn supplementation ameliorated the association between naso‐ pharyngeal S. pneumoniae carriage and acute lower respiratory infection in children (132). Zn de ciency also predisposed to impaired immune response to Pneumococcal surface protein A, increased nasal S. pneumoniae colonization, and severe pneu‐ mococcal infection in mice (133) resulting in shorter survival time after infection (134). Correspondingly, patients with better immune response to 23‐valent pneumococcal polysaccharide vaccine were characterized by signi cantly higher serum Zn levels (135). However, no effect (136) or serotype‐specific effect (137) of Zn on antibody production in response to poly‐ valent pneumococcal vaccine was observed. Zn may also exert toxic effect on S. pneumoniae reducing its growth through interference with Mn(II) homeostasis and development of cytoplasmic manganese de ciency (138). The latter, in turn, increases bacterial susceptibility to oxygen‐dependent killing by neutrophils (139).

A number of studies demonstrated antibacterial effect of zinc oxide nanoparticles (140). Particularly, ZnO was shown to inhibit both growth and biofilm formation by S. pneumoniae (141). Similar effect was observed for other bacterial agents involved in etiology of pneumonia, including K. pneumoniae (142), methicillin‐resistant S. aureus (143), and P. aeruginosa (144). However, the potential antibacterial application of ZnO‐(NPs) may be limited due to their toxicity to human lung cells (145), as well as impairment of phagocytic activity of macrophages in bronchi and lungs (146).

When considering the relationship between S. pneumoniae and zinc, one should also note essentiality of Zn ions for bacteria. Specifically, adequate Zn uptake is required for normal bacterial growth and morphology, as well as coloniza‐ tion and virulence (147). Pneumococcal bio lm formation was also shown to be dependent on Zn bioavailability (148).

The obtained data demonstrate that adequate zinc status of the individual increases immune reactivity. Correspondingly, inadequate zinc supply may predispose to infectious diseases of upper and lower respiratory tract. Although the therapeutic effects of Zn are considered as inconsistent, the existing evidence‐based data indicate ef ciency of Zn supplementation and improvement of Zn status in prevention of pneumonia and its complications due to anti‐in ammatory effect of zinc.

1. Prasad AS: Discovery of Zinc for Human Health and Biomarkers of Zinc Deficiency. In: Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals. Collins JF (ed). Academic Press, Cambridge, pp241‐260, 2017.

Certain indirect indications of the potential antiviral effect of Zn against nCoV‐2019 exist, although their biomedical relevance is yet to be studied. In view of recent data on clinical

4. Haase H and Rink L: Multiple impacts of zinc on immune function. Metallomics 6: 1175‐1180, 2014.

2. Wessels I, Maywald M and Rink L: Zinc as a gatekeeper of immune function. Nutrients 9: 1286, 2017.

3. Maywald M, Wessels I and Rink L: Zinc signals and immunity. Int J Mol Sci 18: 2222, 2017.

5. Gammoh NZ and Rink L: Zinc in infection and in ammation. Nutrients 9: 624, 2017.

6. Aftanas LI, Bonitenko EYu, Varenik VI, Grabeklis AR, Kiselev MF, Lakarova EV, Nechiporenko SP, Nikolaev VA, Skalny AV and Skalnaya MG: Element status of population of Central Federal Region. In: Element status of population of Russia. Part II. Skalny AV and Kiselev MF (eds.) ELBI‐SPb, Saint Petersburg, p430, 2011.

29. Fountoucidou P, Veskoukis AS, Kerasioti E, Docea AO, Taitzoglou IA, Liesivuori J, Tsatsakis A and Kouretas D: A mixture of routinely encountered xenobiotics induces both redox adaptations and perturbations in blood and tissues of rats after a long‐term low‐dose exposure regimen: The time and dose issue. Toxicol Lett 317: 24‐44, 2019.

7. Walker CLF, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, O’Brien KL, Campbell H and Black RE: Global burden of childhood pneumonia and diarrhoea. Lancet 381: 1405‐1416, 2013.

30. Tsatsakis AM, Kouretas D, Tzatzarakis MN, Stivaktakis P, Tsarouhas K, Golokhvast KS, Rakitskii VN, Tutelyan VA, Hernandez AF, Rezaee R, et al: Simulating real‐life exposures to uncover possible risks to human health: A proposed consensus for a novel methodological approach. Hum Exp Toxicol 36: 554‐564, 2017.

8. Bailey RL, West KP Jr and Black RE: The epidemiology of global micronutrient de ciencies. Ann Nutr Metab 66 (Suppl 2): 22‐33, 2015.

9. Yasuda H and Tsutsui T: Infants and elderlies are susceptible to zinc de ciency. Sci Rep 6: 21850, 2016.

31. Tsatsakis A, Tyshko NV, Docea AO, Shestakova SI, Sidorova YS, Petrov NA, Zlatian O, Mach M, Hartung T and Tutelyan VA: The effect of chronic vitamin deficiency and long term very low dose exposure to 6 pesticides mixture on neurological outcomes ‐ A real‐life risk simulation approach. Toxicol Lett 315: 96‐106, 2019.

10. Wapnir RA: Zinc de ciency, malnutrition and the gastrointestinal tract. J Nutr 130 (Suppl): 1388S‐1392S, 2000.

11. Bonaventura P, Benedetti G, Albarède F and Miossec P: Zinc and its role in immunity and in ammation. Autoimmun Rev 14: 277‐285, 2015.

32. Wu C, Chen X, Cai Y, Zhou X, Xu S, Huang H, Wu C, Chen X, Cai Y, Zhou X, et al: Risk factors associated with acute respi‐ ratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan. JAMA Intern Med: Mar 13, 2020 (Epub ahead of print).

12. Chabosseau P and Rutter GA: Zinc and diabetes. Arch Biochem Biophys 611: 79‐85, 2016.

13. Olechnowicz J, Tinkov A, Skalny A and Suliburska J: Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism. J Physiol Sci 68: 19‐31, 2018.

33. Huang R, Zhu L, Xue L, Liu L, Yan X, Wang J, Zhang B, Xu T, Ji F, et al: Clinical ndings of patients with coronavirus disease 2019 in Jiangsu province, China: A retrospective, multi‐center study. SSRN, 2020. https://ssrn.com/abstract=3548785. Accessed Febryary 28, 2020.

14. Kozlowski H, Luczkowski M, Remelli M and Valensin D: Copper, zinc and iron in neurodegenerative diseases (Alzheimer’s, Parkinson’s and prion diseases). Coord Chem Rev 256: 2129‐2141, 2012.

15. Berry M, Gamieldien J and Fielding BC: Identi cation of new respiratory viruses in the new millennium. Viruses 7: 996‐1019, 2015.

34. Jiang F, Deng L, Zhang L, Cai Y, Cheung CW and Xia Z: Review of the clinical characteristics of coronavirus disease 2019 (COVID‐19). J Gen Intern Med: Mar 4, 2020 (Epub ahead of print).

16. Peiris JSM: Coronaviruses. In: Clinical Virology. Richman DD, Whitley RJ and Hayden FG (eds). 4th edition. ASM Press, Washington, pp1244‐1265, 2016.

35. Haase H and Rink L: The immune system and the impact of zinc during aging. Immun Ageing 6: 9, 2009.

17. Docea AO, Tsatsakis A, Albulescu D, Cristea O, Zlatian O, Vinceti M, Moschos SA, Tsoukalas D, Goumenou M, Drakoulis N, et al: A new threat from an old enemy: Re‐emergence of coronavirus (Review). Int J Mol Med 45: 1631‐1643, 2020.

36. Zhang L and Liu Y: Potential interventions for novel coronavirus in China: A systematic review. J Med Virol 92: 479‐490, 2020.

18. Goumenou M, Spandidos DA and Tsatsakis A: [Editorial] Possibility of transmission through dogs being a contributing factor to the extreme Covid 19 outbreak in North Italy. Mol Med Rep 21: 2293‐2295, 2020.

37. Read SA, Obeid S, Ahlenstiel C and Ahlenstiel G: The role of zinc in antiviral immunity. Adv Nutr 10: 696‐710, 2019.

19. Lai CC, Shih TP, Ko WC, Tang HJ and Hsueh PR: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and coronavirus disease‐2019 (COVID‐19): The epidemic and the challenges. Int J Antimicrob Agents 55: 105924, 2020.

39. te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ and van Hemert MJ: Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog 6: e1001176, 2010.

20. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, Li Y, Hu Z, Zhong W and Wang M: Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS‐CoV‐2 infection in vitro. Cell Discov 6: 16, 2020.

40. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W and Xiao G: Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019‐nCoV) in vitro. Cell Res 30: 269‐271, 2020.

21. Khachfe HH, Chahrour M, Sammouri J, Salhab H, Makki B and Fares MY: An epidemiological study on COVID‐19: A rapidly spreading disease. Cureus 12: e7313, 2020.

41. Liu J, Zheng X, Tong Q, Li W, Wang B, Sutter K, Trilling M, Lu M, Dittmer U and Yang D: Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS‐CoV, MERS‐CoV, and 2019‐nCoV. J Med Virol 92: 491‐494, 2020.

22. World Health Organization (WHO): Coronavirus disease 2019. Events as they happen. WHO, Geneva, 2020. https://www.who.int/ emergencies/diseases/novel‐coronavirus‐2019/events‐as‐they‐happen. Updated April 9, 2020.

42. Xue J, Moyer A, Peng B, Wu J, Hannafon BN and Ding WQ: Chloroquine is a zinc ionophore. PLoS One 9: e109180, 2014. 43. Guastalegname M and Vallone A: Could chloroquine/hydroxy‐

23. World Health Organization (WHO): Coronavirus disease (COVID‐2019). Situation report ‐ 81. WHO, Geneva, 2020. https://www.who.int/docs/default‐source/coronaviruse/situation‐ reports/20200410‐sitrep‐81‐covid‐19.pdf. Accessed April 10, 2020.

chloroquine be harmful in Coronavirus disease 2019 (COVID‐19)

24. Rothan HA and Byrareddy SN: The epidemiology and pathogenesis of coronavirus disease (COVID‐19) outbreak. J Autoimmun 109: 102433, 2020.

treatment? Clin Infect Dis: Mar 24, 2020 (Epub ahead of print). 44. Dabbagh‐Bazarbachi H, Clergeaud G, Quesada IM, Ortiz M, O’Sullivan CK and Fernández‐Larrea JB: Zinc ionophore activity of quercetin and epigallocatechin‐gallate: From Hepa 1‐6 cells to a liposome model. J Agric Food Chem 62: 8085‐8093,

25. Ñamendys‐Silva SA: Respiratory support for patients with COVID‐19 infection. Lancet Respir Med 8: e18, 2020.

2014.
45. Lin MH, Moses DC, Hsieh CH, Cheng SC, Chen YH, Sun CY

26. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, et al: Clinical course and outcomes of critically ill patients with SARS‐CoV‐2 pneumonia in Wuhan, China: a single‐centered, retrospective, observational study. Lancet Respir Med: Feb 24, 2020 (Epub ahead of print).

and Chou CY: Disul ram can inhibit MERS and SARS coro‐ navirus papain‐like proteases via different modes. Antiviral Res 150: 155‐163, 2018.

27. Docea AO, Goumenou M, Calina D, Arsene AL, Dragoi CM, Gofita E, Pisoschi CG, Zlatian O, Stivaktakis PD, Nikolouzakis TK, et al: Adverse and hormetic effects in rats exposed for 12 months to low dose mixture of 13 chemicals: RLRS part III. Toxicol Lett 310: 70‐91, 2019.

46. Sargsyan K, Chen T, Grauffel C and Lim C: Identifying COVID‐19 drug‐sites susceptible to clinically safe Zn‐ejector drugs using evolutionary/physical principles. OSF Preprints, 2020. https://osf.io/snuqf/. Accessed February 13, 2020.

28. Hernández AF, Docea AO, Goumenou M, Sarigiannis D, Aschner M and Tsatsakis A: Application of novel technologies and mechanistic data for risk assessment under the real‐life risk simu‐ lation (RLRS) approach. Food Chem Toxicol 137: 111123, 2020.

48. Hoffmann M, Kleine‐Weber H, Krüger N, Mueller MA, Drosten C and Pöhlmann S: The novel coronavirus 2019 (2019‐nCoV) uses the SARS‐coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. bioRxiv (In Press).

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE

7

38. Sandstead HH and Prasad AS: Zinc intake and resistance to H1N1 in uenza. Am J Public Health 100: 970‐971, 2010.

47. Xu L, Tong J, Wu Y, Zhao S and Lin BL: Targeted oxidation strategy (TOS) for potential inhibition of Coronaviruses by disulfiram ‐ a 70‐year old anti‐alcoholism drug. ChemRxiv (In Press).

8

SKALNY et al: ZINC AND RESPIRATORY TRACT INFECTIONS: PERSPECTIVES FOR COVID‐19

49. Zhang H, Penninger JM, Li Y, Zhong N and Slutsky AS: Angiotensin‐converting enzyme 2 (ACE2) as a SARS‐CoV‐2 receptor: Molecular mechanisms and potential therapeutic target. Intensive Care Med 46: 586‐590, 2020.

74. Haase H, Mocchegiani E and Rink L: Correlation between zinc status and immune function in the elderly. Biogerontology 7: 421‐428, 2006.

50. Speth R, Carrera E, Jean‐Baptiste M, Joachim A and Linares A: Concentration‐dependent effects of zinc on angiotensin‐converting enzyme‐2 activity (1067.4). FASEB J 28 (Suppl 1): 1067.4, 2014.

75. Barnett JB, Hamer DH and Meydani SN: Low zinc status: A new risk factor for pneumonia in the elderly? Nutr Rev 68: 30‐37, 2010.

51. Chilvers MA, McKean M, Rutman A, Myint BS, Silverman M and O’Callaghan C: The effects of coronavirus on human nasal ciliated respiratory epithelium. Eur Respir J 18: 965‐970, 2001.

76. Meydani SN, Barnett JB, Dallal GE, Fine BC, Jacques PF, Leka LS and Hamer DH: Serum zinc and pneumonia in nursing home elderly. Am J Clin Nutr 86: 1167‐1173, 2007.

52. Maret W: Analyzing free zinc(II) ion concentrations in cell biology with uorescent chelating molecules. Metallomics 7: 202‐211, 2015.

77. Bhat MH, Rather AB, Dhobi GN, Koul AN, Bhat FA and Hussain A: Zinc levels in community acquired pneumonia in hospitalized patients; a case control study. Egypt J Chest Dis Tuberc 65: 485‐489, 2016.

53. Essaidi‐Laziosi M, Brito F, Benaoudia S, Royston L, Cagno V, Fernandes‐Rocha M, Piuz I, Zdobnov E, Huang S, Constant S, et al: Propagation of respiratory viruses in human airway epithelia reveals persistent virus‐specific signatures. J Allergy Clin Immunol 141: 2074‐2084, 2018.

78. Saleh P, Sadeghpour A, Mirza‐Aghazadeh‐Attari M, Hatampour M, Naghavi‐Behzad M and Tabrizi A: Relationship between plasma levels of zinc and clinical course of pneumonia. Tanaffos 16: 40‐45, 2017.

54. Pittet LA, Hall‐Stoodley L, Rutkowski MR and Harmsen AG: In uenza virus infection decreases tracheal mucociliary velocity and clearance of Streptococcus pneumoniae. Am J Respir Cell Mol Biol 42: 450‐460, 2010.

79. Linko R, Karlsson S, Pettilä V, Varpula T, Okkonen M, Lund V, Ala‐Kokko T and Ruokonen E; FINNALI Study Group: Serum zinc in critically ill adult patients with acute respiratory failure. Acta Anaesthesiol Scand 55: 615‐621, 2011.

55. Darma A, Ranuh RG, Merbawani W, Setyoningrum RA, Hidajat B, Hidayati SN, Andaryanto A and Sudarmo SM: Zinc supplementation effect on the bronchial cilia length, the number of cilia, and the number of intact bronchial cell in zinc de ciency rats. Indones Biomed J 12: 78‐84, 2020.

80. Saigal P and Hanekom D: Does zinc improve symptoms of viral upper respiratory tract infection? EBP 23: 37‐39, 2020.

56. Woodworth BA, Zhang S, Tamashiro E, Bhargave G, Palmer JN and Cohen NA: Zinc increases ciliary beat frequency in a calcium‐dependent manner. Am J Rhinol Allergy 24: 6‐10, 2010.

82.Boudreault F, Pinilla‐Vera M, Englert JA, Kho AT, Isabelle C, Arciniegas AJ, Barragan‐Bradford D, Quintana C, Amador‐Munoz D, Guan J, et al; MICU Registry: Zinc de ciency primes the lung for ventilator‐induced injury. JCI Insight 2: e86507, 2017.

57. Truong‐Tran AQ, Carter J, Ruffin R and Zalewski PD: New insights into the role of zinc in the respiratory epithelium. Immunol Cell Biol 79: 170‐177, 2001.

83. Chen X, Bian J and Ge Y: Zinc‐de cient diet aggravates venti‐ lation‐induced lung injury in rats. J Biomed Res 26: 59‐65, 2012. 84. Visalakshy J, Surendran S, Pillai MPG, Rajendran A and Sherif AA: Could plasma zinc be a predictor for mortality and severity in sepsis syndrome? Int J Res Med Sci 5: 3929‐3934,

58. Roscioli E, Jersmann HP, Lester S, Badiei A, Fon A, Zalewski P and Hodge S: Zinc de ciency as a codeterminant for airway epithelial barrier dysfunction in an ex vivo model of COPD. Int J Chron Obstruct Pulmon Dis 12: 3503‐3510, 2017.

2017.
85. Hoeger J, Simon TP, Beeker T, Marx G, Haase H and Schuerholz T:

59. Wittekindt OH: Tight junctions in pulmonary epithelia during lung in ammation. P ugers Arch 469: 135‐147, 2017.

Persistent low serum zinc is associated with recurrent sepsis in critically ill patients ‐ A pilot study. PLoS One 12: e0176069, 2017.

60. Günzel D and Yu AS: Claudins and the modulation of tight junction permeability. Physiol Rev 93: 525‐569, 2013.

86. Lee PI, Hu YL, Chen PY, Huang YC and Hsueh PR: Are children less susceptible to COVID‐19? J Microbiol Immunol Infect: Feb 25, 2020 (Epub ahead of print).

61. Ishida T: Review on the role of Zn2+ ions in viral pathogenesis and the effect of Zn2+ ions for host cell‐virus growth inhibition. Am J Biomed Sci Res: 2, AJBSR.MS.ID.000566, 2019.

87. DongY,MoX,HuY,QiX,JiangF,JiangZandTongS: Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics (In Press).

62. Krenn BM, Gaudernak E, Holzer B, Lanke K, Van Kuppeveld FJM and Seipelt J: Antiviral activity of the zinc ionophores pyrithione and hinokitiol against picornavirus infections. J Virol 83: 58‐64, 2009.

88. Kumar N, Jayaprakash S and Kavitha D: Low serum zinc level ‐ a possible marker of severe pneumonia. JMSCR 5: 21554‐21570, 2017.

63. Korant BD, Kauer JC and Butterworth BE: Zinc ions inhibit replication of rhinoviruses. Nature 248: 588‐590, 1974.

89. Islam SN, Kamal MM, Rahmatullah R, Sadi SKS and Ahsan M: Serum zinc levels in children with acute respiratory infections: Association with sociodemography and nutritional status. Clin Nutr Exp 22: 11‐18, 2018.

64. Cakman I, Kirchner H and Rink L: Zinc supplementation recon‐ stitutes the production of interferon‐α by leukocytes from elderly persons. J Interferon Cytokine Res 17: 469‐472, 1997.

65. Berg K, Bolt G, Andersen H and Owen TC: Zinc potentiates the antiviral action of human IFN‐α tenfold. J Interferon Cytokine Res 21: 471‐474, 2001.

90. Saleh NY and Abo El Fotoh WMM: Low serum zinc level: The relationship with severe pneumonia and survival in critically ill children. Int J Clin Pract 72: e13211, 2018.

66. Lin FC and Young HA: Interferons: Success in anti‐viral immu‐ notherapy. Cytokine Growth Factor Rev 25: 369‐376, 2014.

91. Yakoob MY, Theodoratou E, Jabeen A, Imdad A, Eisele TP, Ferguson J, Jhass A, Rudan I, Campbell H, Black RE, et al: Preventive zinc supplementation in developing countries: Impact on mortality and morbidity due to diarrhea, pneumonia and malaria. BMC Public Health 11 (Suppl 3): S23, 2011.

67. Singh M and Das RR: Zinc for the common cold. Cochrane Database Syst Rev 2013: CD001364, 2013.

68. Hemilä H: Zinc lozenges and the common cold: A meta‐analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage. JRSM Open 8: 2054270417694291, 2017.

92. Lassi ZS, Moin A and Bhutta ZA: Zinc supplementation for the prevention of pneumonia in children aged 2 months to 59 months. Cochrane Database Syst Rev 12: CD005978, 2016.

69. Hemilä H: Zinc lozenges may shorten the duration of colds: A systematic review. Open Respir Med J 5: 51‐58, 2011.

93. Das RR, Singh M and Sha q N: Short‐term therapeutic role of zinc in children <5 years of age hospitalised for severe acute lower respiratory tract infection. Paediatr Respir Rev 13: 184‐191, 2012.

70. Che Z and Sun J: Investigation on relationship between whole blood zinc and Fe elements with children pneumonia caused by respiratory syncytial virus. Int J Lab Med 37: 2401‐2402, 2016.

71. Johnson JK, Harris FL, Ping XD, Gauthier TW and Brown LAS: Role of zinc insufficiency in fetal alveolar macrophage dysfunction and RSV exacerbation associated with fetal ethanol exposure. Alcohol 80: 5‐16, 2019.

94. Basnet S, Shrestha PS, Sharma A, Mathisen M, Prasai R, Bhandari N, Adhikari RK, Sommerfelt H, Valentiner‐Branth P and Strand TA; Zinc Severe Pneumonia Study Group: A randomized controlled trial of zinc as adjuvant therapy for severe pneumonia in young children. Pediatrics 129: 701‐708, 2012.

72. Suara RO and Crowe JE Jr: Effect of zinc salts on respiratory syncytial virus replication. Antimicrob Agents Chemother 48: 783‐790, 2004.

95. Srinivasan MG, Ndeezi G, Mboijana CK, Kiguli S, Bimenya GS, Nankabirwa V and Tumwine JK: Zinc adjunct therapy reduces case fatality in severe childhood pneumonia: A randomized double blind placebo‐controlled trial. BMC Med 10: 14, 2012.

73. Kaynar AM, Andreas A, Maloy A, Austin W, Pitt BR, Gopal R and Alcorn JF: Zinc de ciency worsens the long‐term outcome and exacerbates in ammation in a murine model of in uenza‐MRSA superinfection. Am J Respir Crit Care Med 199: A4130, 2019.

81. Shara S and Allami A: Ef cacy of zinc sulphate on in‐hospital outcome of community‐acquired pneumonia in people aged 50 years and over. Int J Tuberc Lung Dis 20: 685‐688, 2016.

96. Bagri NK, Bagri N, Jana M, Gupta AK, Wadhwa N, Lodha R, Kabra SK, Chandran A, Aneja S, Chaturvedi MK, et al: Ef cacy of oral zinc supplementation in radiologically confirmed pneumonia: Secondary analysis of a randomized controlled trial. J Trop Pediatr 64: 110‐117, 2018.

116. Ganatra HA, Varisco BM, Harmon K, Lahni P, Opoka A and Wong HR: Zinc supplementation leads to immune modulation and improved survival in a juvenile model of murine sepsis. Innate Immun 23: 67‐76, 2017.

97. Yuan X, Qian SY, Li Z and Zhang ZZ: Effect of zinc supple‐ mentation on infants with severe pneumonia. World J Pediatr 12: 166‐169, 2016.

117. Slinko S, Piraino G, Hake PW, Ledford JR, O’Connor M, Lahni P, Solan PD, Wong HR and Zingarelli B: Combined zinc supplementation with proinsulin C‐peptide treatment decreases the in ammatory response and mortality in murine polymi‐ crobial sepsis. Shock 41: 292‐300, 2014.

98. Shah UH, Abu‐Shaheen AK, Malik MA, Alam S, Riaz M and Al‐Tannir MA: The ef cacy of zinc supplementation in young children with acute lower respiratory infections: A randomized double‐blind controlled trial. Clin Nutr 32: 193‐199, 2013.

118. Besecker BY, Exline MC, Holly eld J, Phillips G, Disilvestro RA, Wewers MD and Knoell DL: A comparison of zinc metabolism, in ammation, and disease severity in critically ill infected and noninfected adults early after intensive care unit admission. Am J Clin Nutr 93: 1356‐1364, 2011.

99. Rerksuppaphol S and Rerksuppaphol L: A randomized controlled trial of zinc supplementation in the treatment of acute respiratory tract infection in Thai children. Pediatr Rep 11: 7954, 2019.

119.Liu MJ, Bao S, Gálvez‐Peralta M, Pyle CJ, Rudawsky AC, Pavlovicz RE, Killilea DW, Li C, Nebert DW, Wewers MD, et al: ZIP8 regulates host defense through zinc‐mediated inhibition of NF‐κB. Cell Rep 3: 386‐400, 2013.

100. Roth DE, Richard SA and Black RE: Zinc supplementation for the prevention of acute lower respiratory infection in children in developing countries: Meta‐analysis and meta‐regression of randomized trials. Int J Epidemiol 39: 795‐808, 2010.

120.Hall SC, Smith DR, Kata asz DM, Bailey KL and Knoell DL: Novel role of zinc homeostasis in IL‐23 regulation and host defense following bacterial infection. J Immunol 202 (Suppl 1): 62.6, 2019.

101.Martinez‐Estevez NS, Alvarez‐Guevara AN and Rodriguez‐Martinez CE: Effects of zinc supplementation in the prevention of respiratory tract infections and diarrheal disease in Colombian children: A 12‐month randomised controlled trial. Allergol Immunopathol (Madr) 44: 368‐375, 2016.

121.Knoell DL, Smith DA, Sapkota M, Heires AJ, Hanson CK, Smith LM, Poole JA, Wyatt TA and Romberger DJ: Insuf cient zinc intake enhances lung in ammation in response to agri‐ cultural organic dust exposure. J Nutr Biochem 70: 56‐64, 2019.

102. Aggarwal R, Sentz J and Miller MA: Role of zinc administration in prevention of childhood diarrhea and respiratory illnesses: A meta‐analysis. Pediatrics 119: 1120‐1130, 2007.

122. Lang CJ, Hansen M, Roscioli E, Jones J, Murgia C, Leigh Ackland M, Zalewski P, Anderson G and Ruf n R: Dietary zinc mediates in ammation and protects against wasting and metabolic derangement caused by sustained cigarette smoke exposure in mice. Biometals 24: 23‐39, 2011.

103.Khera D, Singh S, Purohit P, Sharma P and Singh K: Prevalence of Zinc de ciency and effect of Zinc supplemen‐ tation on prevention of acute respiratory infections: A non randomized open label study. SSRN, 2018. https://ssrn.com/ abstract=3273670. Accessed October 26, 2018.

123. von Bülow V, Dubben S, Engelhardt G, Hebel S, Plümäkers B, Heine H, Rink L and Haase H: Zinc‐dependent suppression of TNF‐α production is mediated by protein kinase A‐induced inhibition of Raf‐1, IκB kinase β, and NF‐κB. J Immunol 179: 4180‐4186, 2007.

104.Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS and Manson JJ; HLH Across Speciality Collaboration, UK: COVID‐19: Consider cytokine storm syndromes and immuno‐ suppression. Lancet 395: 1033‐1034, 2020.

105. Biaggio VS, Pérez Chaca MV, Valdéz SR, Gómez NN and Gimenez MS: Alteration in the expression of inflammatory parameters as a result of oxidative stress produced by moderate zinc de ciency in rat lung. Exp Lung Res 36: 31‐44, 2010.

124. Wessels I, Haase H, Engelhardt G, Rink L and Uciechowski P: Zinc deficiency induces production of the proinflammatory cytokines IL‐1β and TNFα in promyeloid cells via epigenetic and redox‐dependent mechanisms. J Nutr Biochem 24: 289‐297, 2013.

106.Bao S and Knoell DL: Zinc modulates cytokine‐induced lung epithelial cell barrier permeability. Am J Physiol Lung Cell Mol Physiol 291: L1132‐L1141, 2006.

125. Prasad AS, Bao B, Beck FW and Sarkar FH: Zinc‐suppressed in ammatory cytokines by induction of A20‐mediated inhi‐ bition of nuclear factor‐κB. Nutrition 27: 816‐823, 2011.

107. Liu MJ, Bao S, Napolitano JR, Burris DL, Yu L, Tridandapani S and Knoell DL: Zinc regulates the acute phase response and serum amyloid A production in response to sepsis through JAK‐STAT3 signaling. PLoS One 9: e94934, 2014.

126.Wellinghausen N, Martin M and Rink L: Zinc inhibits interleukin‐1‐dependent T cell stimulation. Eur J Immunol 27: 2529‐2535, 1997.

108.St Croix CM, Leelavaninchkul K, Watkins SC, Kagan VE and Pitt BR: Nitric oxide and zinc homeostasis in acute lung injury. Proc Am Thorac Soc 2: 236‐242, 2005.

127.Rosenkranz E, Metz CH, Maywald M, Hilgers RD, Weßels I, Senff T, Haase H, Jäger M, Ott M, Aspinall R, et al: Zinc supplementation induces regulatory T cells by inhibition of Sirt‐1 deacetylase in mixed lymphocyte cultures. Mol Nutr Food Res 60: 661‐671, 2016.

109. Krones CJ, Klosterhalfen B, Butz N, Hoelzl F, Junge K, Stumpf M, Peiper C, Klinge U and Schumpelick V: Effect of zinc pretreatment on pulmonary endothelial cells in vitro and pulmonary function in a porcine model of endotoxemia. J Surg Res 123: 251‐256, 2005.

128.Kahmann L, Uciechowski P, Warmuth S, Plümäkers B, Gressner AM, Malavolta M, Mocchegiani E and Rink L: Zinc supplementation in the elderly reduces spontaneous in ammatory cytokine release and restores T cell functions. Rejuvenation Res 11: 227‐237, 2008.

110. Wessels I, Pupke JT, von Trotha KT, Gombert A, Himmelsbach A, Fischer HJ, Jacobs MJ, Rink L and Grommes J: Zinc supple‐ mentation ameliorates lung injury by reducing neutrophil recruitment and activity. Thorax 75: 253‐261, 2020.

129.Kim H: Outbreak of novel coronavirus (COVID‐19): What is the role of radiologists? Eur Radiol: Feb 18, 2020 (Epub ahead of print).

111.Biaggio VS, Salvetti NR, Pérez Chaca MV, Valdez SR, Ortega HH, Gimenez MS and Gomez NN: Alterations of the extracellular matrix of lung during zinc de ciency. Br J Nutr 108: 62‐70, 2012.

130. Golda A, Malek N, Dudek B, Zeglen S, Wojarski J, Ochman M, Kucewicz E, Zembala M, Potempa J and Pyrc K: Infection with human coronavirus NL63 enhances streptococcal adherence to epithelial cells. J Gen Virol 92: 1358‐1368, 2011.

112.Luo W, Yu H, Gou J, Li X, Sun Y, Li J and Liu L: Clinical pathology of critical patient with novel Coronavirus pneumonia (COVID‐19). Preprints 2020: 2020020407, 2020.

131. Eijkelkamp BA, Morey JR, Neville SL, Tan A, Pederick VG, Cole N, Singh PP, Ong CY, Gonzalez de Vega R, Clases D, et al: Dietary zinc and the control of Streptococcus pneumoniae infection. PLoS Pathog 15: e1007957, 2019.

113.Knoell DL, Julian MW, Bao S, Besecker B, Macre JE, Leikauf GD, DiSilvestro RA and Crouser ED: Zinc de ciency increases organ damage and mortality in a murine model of polymicrobial sepsis. Crit Care Med 37: 1380‐1388, 2009.

132.Coles CL, Sherchand JB, Khatry SK, Katz J, Leclerq SC, Mullany LC and Tielsch JM: Zinc modifies the association between nasopharyngeal Streptococcus pneumoniae carriage and risk of acute lower respiratory infection among young children in rural Nepal. J Nutr 138: 2462‐2467, 2008.

114. Bao S, Liu MJ, Lee B, Besecker B, Lai JP, Guttridge DC and Knoell DL: Zinc modulates the innate immune response in vivo to polymicrobial sepsis through regulation of NF‐kappaB. Am J Physiol Lung Cell Mol Physiol 298: L744‐L754, 2010.

133.Strand TA, Hollingshead SK, Julshamn K, Briles DE, Blomberg B and Sommerfelt H: Effects of zinc de ciency and pneumococcal surface protein A immunization on zinc status and the risk of severe infection in mice. Infect Immun 71: 2009‐2013, 2003.

115. Nowak JE, Harmon K, Caldwell CC and Wong HR: Prophylactic zinc supplementation reduces bacterial load and improves survival in a murine model of sepsis. Pediatr Crit Care Med 13: e323‐e329, 2012.

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE

9

10

SKALNY et al: ZINC AND RESPIRATORY TRACT INFECTIONS: PERSPECTIVES FOR COVID‐19

134.Strand TA, Briles DE, Gjessing HK, Maage A, Bhan MK and Sommerfelt H: Pneumococcal pulmonary infection, septicaemia and survival in young zinc‐depleted mice. Br J Nutr 86: 301‐306, 2001.

143.Kadiyala U, Turali‐Emre ES, Bahng JH, Kotov NA and VanEpps JS: Unexpected insights into antibacterial activity of zinc oxide nanoparticles against methicillin resistant Staphylococcus aureus (MRSA). Nanoscale 10: 4927‐4939, 2018.

135.Hamza SA, Mousa SM, Taha SE, Adel LA, Samaha HE and Hussein DA: Immune response of 23‐valent pneumococcal poly‐ saccharide vaccinated elderly and its relation to frailty indices, nutritional status, and serum zinc levels. Geriatr Gerontol Int 12: 223‐229, 2012.

144. Ann LC, Mahmud S, Bakhori SKM, Sirelkhatim A, Mohamad D, Hasan H, Seeni A and Rahman RA: Antibacterial responses of zinc oxide structures against Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyogenes. Ceram Int 40: 2993‐3001, 2014.

136. Mansouri F, Vaziri S, Janbakhsh A, Sayad B, Najafi F, Karimivafa SM, Kashef M and Azizi M: The effect of zinc on the Immune responses of pneumococcal vaccination in elderly. Int J Med Microbiol 10: 67‐73, 2016.

145.Sahu D, Kannan GM, Vijayaraghavan R, Anand T and Khanum F: Nanosized zinc oxide induces toxicity in human lung cells. ISRN Toxicol 2013: 316075, 2013.

137. Osendarp SJ, Prabhakar H, Fuchs GJ, van Raaij JM, Mahmud H, Tofail F, Santosham M and Black RE: Immunization with the heptavalent pneumococcal conjugate vaccine in Bangladeshi infants and effects of zinc supplementation. Vaccine 25: 3347‐3354, 2007.

146. Lin CD, Kou YY, Liao CY, Li CH, Huang SP, Cheng YW, Liao WC, Chen HX, Wu PL, Kang JJ, et al: Zinc oxide nanopar‐ ticles impair bacterial clearance by macrophages. Nanomedicine (Lond) 9: 1327‐1339, 2014.

138. Jacobsen FE, Kazmierczak KM, Lisher JP, Winkler ME and Giedroc DP: Interplay between manganese and zinc homeo‐ stasis in the human pathogen Streptococcus pneumoniae. Metallomics 3: 38‐41, 2011.

147. Bayle L, Chimalapati S, Schoehn G, Brown J, Vernet T and Durmort C: Zinc uptake by Streptococcus pneumoniae depends on both AdcA and AdcAII and is essential for normal bacterial morphology and virulence. Mol Microbiol 82: 904‐916, 2011.

139. McDevitt CA, Ogunniyi AD, Valkov E, Lawrence MC, Kobe B, McEwan AG and Paton JC: A molecular mechanism for bacterial susceptibility to zinc. PLoS Pathog 7: e1002357, 2011.

148. Brown LR, Caulkins RC, Schartel TE, Rosch JW, Honsa ES, Schultz‐Cherry S, Meliopoulos VA, Cherry S and Thornton JA: Increased zinc availability enhances initial aggregation and biofilm formation of Streptococcus pneumoniae. Front Cell Infect Microbiol 7: 233, 2017.

140. Pasquet J, Chevalier Y, Pelletier J, Couval E, Bouvier D and Bolzinger MA: The contribution of zinc ions to the antimi‐ crobial activity of zinc oxide. Colloids Surf A Physicochem Eng Asp 457: 263‐274, 2014.

149. Skalnaya MG and Skalny AV: Essential trace elements in human health: a physician’s view. Publishing House of Tomsk State University, Tomsk, 2018.

141. Bhattacharyya P, Agarwal B, Goswami M, Maiti D, Baruah S and Tribedi P: Zinc oxide nanoparticle inhibits the bio lm formation of Streptococcus pneumoniae. Antonie van Leeuwenhoek 111: 89‐99, 2018.

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License.

 

142.Reddy LS, Nisha MM, Joice M and Shilpa PN: Antimicrobial activity of zinc oxide (ZnO) nanoparticle against Klebsiella pneumoniae. Pharm Biol 52: 1388‐1397, 2014.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: