key: cord-0970477-zmkvs7e7 authors: Skalny, Anatoly V.; Rossi Lima, Thania Rios; Ke, Tao; Zhou, Ji-Chang; Bornhorst, Julia; Alekseenko, Svetlana I.; Aaseth, Jan; Anesti, Ourania; Sarigiannis, Dimosthenis A.; Tsatsakis, Aristides; Aschner, Michael; Tinkov, Alexey A. title: Toxic metal exposure as a possible risk factor for COVID-19 and other respiratory infectious diseases date: 2020-10-16 journal: Food Chem Toxicol DOI: 10.1016/j.fct.2020.111809 sha: eb663a201b03ea9a53ccc02c71156e8180145695 doc_id: 970477 cord_uid: zmkvs7e7 Multiple medical, lifestyle, and environmental conditions, including smoking and particulate pollution, have been considered as risk factors for COronaVIrus Disease 2019 (COVID-19) susceptibility and severity. Taking into account the high level of toxic metals in both particulate matter (PM2.5) and tobacco smoke, the objective of this review is to discuss recent data on the role of heavy metal exposure in development of respiratory dysfunction, immunotoxicity, and severity of viral diseases in epidemiological and experimental studies, as to demonstrate the potential crossroads between heavy metal exposure and COVID-19 severity risk. The existing data demonstrate that As, Cd, Hg, and Pb exposure is associated with respiratory dysfunction and respiratory diseases (COPD, bronchitis). These observations corroborate laboratory findings on the role of heavy metal exposure in impaired mucociliary clearance, reduced barrier function, airway inflammation, oxidative stress, and apoptosis. The association between heavy metal exposure and severity of viral diseases, including influenza and respiratory syncytial virus has been also demonstrated. The latter may be considered a consequence of adverse effects of metal exposure on adaptive immunity. Therefore, reduction of toxic metal exposure may be considered as a potential tool for reducing susceptibility and severity of viral diseases affecting the respiratory system, including COVID-19. COronaVIrus Disease 2019 is an infectious disease caused by coronavirus SARS-CoV-2 that first occurred in October and caused a massive outbreak in December 2019 (Frutos et al., 2020) . During the last 10 months COVID-19 affected more than 30 million people worldwide, and is considered as a cause of more than 950,000 deaths (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). The virus predominantly affects the respiratory system, causing COVID-19 pneumonia , although other systems are also involved especially in severe cases due to vascular dysfunction (Varga et al., 2020) and cytokine storm (Shimabukuro-Vornhagen et al., 2018) resulting in systemic inflammation (Yuki et al., 2020) . These features are tightly linked to COVID-19-associated immune dysregulation characterized by lymphopenia with a concomitant decline in T helper, T suppressor, and regulatory T cells, and leukocytosis, increased neutrophil-to-lymphocyte-ratio (Qin et al., 2020) , as well as lymphocyte and NK-cell dysfunction (Vabret et al., 2020) . The key symptoms include fever, cough, fatigue, expectoration, and dyspnea, as well as less common gastrointestinal symptoms including diarrhea, nausea and vomiting . Moreover, clinical course of the disease is highly variable, being characterized by high number of asymptomatic and mild cases, but frequently progressing to pneumonia, acute J o u r n a l P r e -p r o o f Particularly, an increase in PM 2.5 , PM 10 , NO 2 and O 3 concentrations in 120 cities in China has been associated with newly confirmed COVID-19 cases . In addition, it has been demonstrated that every 1 μg/m 3 increase in PM 2.5 level results in an 8% increase in COVID-19 mortality rate . However, despite the presence of rather convincing data on the role of environmental pollution as a risk factor for susceptibility, these conclusions should be viewed with caution due to lack of qualitative and quantitative analysis of particulate matter (Contini, Costabile, 2020) . It has been also proposed that heavy metals may significantly mediate health hazards of particulate matter (Chen, Lippmann, 2009 ). Another potential external factor associated with COVID-19 severity is smoking, although the existing data are highly contradictory. A recent analysis revealed a nearly twofold higher risk of severe COVID-19 (odds ratio (OR) = 1.98; 95% confidence interval (95%CI): 1.29-3.05) . However, sensitivity analysis demonstrated that the study by Guan et al. (2020) originating from Wuhan was considered as the main source of heterogeneity, and its exclusion resulted in insignificant association between smoking and COVID-19 severity. Other studies also met with contradictions, indicating both lack of an association (Lippi, Henry, 2020) and a direct association between smoking and COVID-19 severity (Vardavas, Nikitara, 2020) . Finally, a systematic review and meta-analysis dated from June 2020 has been demonstrated that current smokers have higher odds for adverse outcome of COVID-19 than non-current smokers, but lower risk in comparison to former smokers . Despite significant contradiction in epidemiological data, smoking induced up-regulation of ACE2 receptor (Brake et al., 2020) in addition to lung inflammation, impaired barrier functions, mucus overproduction, and mucociliary clearance (Berlin et al., 2020) that could be mechanistically linked to higher risk of COVID-19. Hazardous effects of tobacco smoke could be attributed to the presence of more than 5,000 chemicals, with heavy metals such as cadmium and lead being among the 98 most toxic agents (Talhout et al., 2011) . Taken into account a high level of toxic metals in both particulate matter and tobacco smoke, it is reasonable to propose that metal toxicity may in part underlie the association between PM exposure and COVID-19 severity, although this hypothesis has yet to be confirmed. Cadmium (Cd) was shown to underlie a significant part of adverse effects of tobacco smoke exposure through induction of oxidative stress and impaired macrophage functions (Sarigiannis and Salifoglou, 2016; Ganguly et al., 2018) . Particularly, it has been demonstrated that urinary Cd levels were associated with lower forced expiratory J o u r n a l P r e -p r o o f al., 2019). In addition, CdCl 2 is also capable of decreasing barrier function of bronchial epithelial cells through altered expression of tight junction proteins zonula occludens-1 (ZO-1) and occluding (Cao et al., 2015) . One of the potential mechanisms of lung damage in response to Cd exposure may include antagonistic relationships between the latter and zinc (Zn) ions Knoell et al., 2020) that is involved in respiratory protection (Skalny et al., 2020) . In an experimental study, oral Cd pretreatment was accompanied by significantly increased titers of respiratory syncytial virus (RSV) in lung tissues and severe lung damage due to aggravation of inflammation, oxidative stress, and mitochondrial dysfunction (Go et al., 2018) . Correspondingly, Cd exposure potentiated inflammatory lung damage in a murine model of H1N1 infection (Chandler et al., 2019) . In addition, Cd exposure promoted influenza virus replication in MCDK cells in a dose-dependent manner (Checconi et al., 2013) . Several epidemiological (Krueger, Wade, 2016) and laboratory (Seth et al., 2003) studies also indicated the association between Cd exposure and non-airborne viral diseases, that may be generally attributable to immunotoxic effect of Cd and its negative impact on antiviral immunity (Fig. 3) . Cd toxicity is associated with altered hematopoietic stem and progenitor cells differentiation causing a shift to myelopoiesis from lymphopoiesis . In addition, Cd affects T cell subsets characterized by reduction of T-helper (CD4+) cells and induction of cytotoxic T cells (CD8+), being indicative of metal immunotoxicity, and resulting in down-regulation of interferon-γ (IFN-γ) and interleukin-2 (IL-2) production (Pathak, Khandelwal, 2008) . Developmental Cd exposure was shown to affect immune system maturation through alteration of DN1 and DN2 thymocyte ratio, also resulting in reduced natural killer (NK)-cell and granulocyte content in spleen accompanied by increased CD4+ and CD8+ T cells, as well as CD45R/B220+ B cells count (Holásková et al., 2012) . More recently, a study conducted in male Sprague-Dawley rats demonstrated that subchronic exposure to Cd (32 ppm cadmium chloride in drinking water for 10 weeks) led to a slight increase in the relative weight of the spleen and in the regulatory T cells number. Cd-exposed animals also showed a significant increase in the production of IFN-γ and IL-10, suggesting an impact on immune cell function and cellularity, which may stimulate inflammatory responses (Turley et al. 2019) . Generally, these findings are indirectly in agreement with the observation on the inverse association between Cd exposure and T lymphocyte (Zeng et al., 2020) and memory T cell levels in children (Nygaard et al., 2017) . The immunotoxic effect of Cd exposure is also associated with development of aberrant inflammatory response due to altered cytokine expression profile (Hossein-Khannazer et al., 2020) . Earlier data have demonstrated that adult female zebrafish exposed to 1 mg L−1 Cd for 24 or 96 hours led to an increase in the levels of tumor necrosis factorα (TNF-α) in the brain, liver and ovary, as well as increase in mRNA levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB) in the liver and ovary in the first evaluation time (Zheng et al. 2016 ). On the other hand, zebrafish embryos exposed for 15 weeks to 5 μg/L Cd presented a decrease of nitric oxide (NO) and iNOS levels in the liver and spleen, accompanied by decreased transcriptional levels of IL-6, IL-10, IL-1β and TNF-α in liver. These findings indicate an immunosuppressive activity of Cd that was followed by a compensatory effect observed due to an increase in the mRNA levels of these cytokines in the spleen . In vitro, exposure to various concentrations of Cd caused decreased viability of RAW 264.7 cell line, murine macrophage-derived cell. Increase in the production of reactive oxygen and nitrogen species was observed in response to activating stimulus by Salmonella enterica Serovar Enteritidis via pattern-recognition receptors (PRRs). When exposed to CdCl 2 , proinflammatory cytokines IL-1 and chemokine (C-X-C motif) ligand 1 (CXCL1) were highly upregulated whereas IL-6 and IL-10 were suppressed, indicating an important effect of cadmium on the macrophage functions modulation in innate immune response to infection (Riemschneider et al. 2015) . Cd exposure may also sustain systemic inflammatory reaction through modulation of gut microbiota and subsequent increase in LPS levels (Tinkov et al., 2018) . Although respiratory dysfunction is known to be the characteristic feature of acute mercury (Hg) vapor inhalation (Smiechowicz et al., 2017) , data on the relationship between environmental Hg pollution and pulmonary function are rather insufficient. Previous studies revealed a significant inverse association between hair Hg and respiratory function in subjects from artisanal and small-scale gold mining areas (Pateda et al., 2018) . High serum Hg levels (third tertile) were associated with increased odds of obstructive lung disease (OR= 3.62; 95%CI: 1.29-10.18) in a dusty area . The results of a follow-up analysis involving 4,350 Korean children demonstrated that blood Hg is associated with higher odds of asthma and bronchi hyperresponsiveness (Kim et al., 2015) . However, further data show contradictory results, underlining the importance of investigation of the association between prenatal and lifetime Hg exposure and asthma (Heinrich et al., 2017) . Serum mercury as well as lead levels were found to be higher in children with recurrent wheezing (Razi et al., 2011) . Blood Hg levels were also associated with increased exhaled nitric oxide levels, being considered as a marker of airway inflammation (Min, Min, 2013) . It is also notable that high maternal toenail Hg content was associated with increased risk of lower respiratory infections, but not upper respiratory tract infections in infants (Emeny et al., 2019) . Both methylmercury (CH 3 Hg) (Yu et al., 2015) and HgCl 2 (Park, Park, 2007) were shown to be cytotoxic for A549 cells through induction of oxidative stress and apoptosis. The latter may occur due to Hg-induced modulation of Bax, p53, and Bcl2 expression (Ali et al., 2018) . Similar effect was observed in alveolar type II epithelial cell exposed to mercury (Lu et al., 2010) . Correspondingly, both Hg and Cd exposure were shown to induce oxidative stress accompanied by heat shock protein 70 (Hsp70) expression, although Cd was relatively more toxic as compared to Hg (Han et al., 2007) . ER stress may be also considered as the potential mechanism of lung toxicity of Hg (Jagannathan et al., 2017) . It is also notable that inhalation of elementary mercury vapor significantly upregulated proinflammatory cytokine expression in lung tissue (Liu et al., 2003) . Although direct data on the impact of Hg on airway epithelium permeability are insufficient, it has been demonstrated that Hg exposure affects expression of tight junction proteins in colonic epithelial cells (Vazquez et al., 2014) . Morphological analysis demonstrated that Hg exposure may induce inflammatory response characterized by inflammatory cells infiltration and altered extracellular matrix (Naidoo et al., 2019) through proinflammatory effect of the metal (Fig. 2) Several epidemiological and experimental studies have demonstrated the association between Hg exposure and airborne viral infections. The association between mercury exposure and measles antibodies was found to be significant only in children with low folate and high methylmalonic acid (MMA) values, whereas in other children the relationship was found to be inverse (Gallagher et al., 2011) . Similarly, associations between Hg and rubeola antibody levels were affected by folate, MMA, and homocysteine levels (Gallagher et al., 2013) . Experimental studies have clearly demonstrated that Hg exposure may modulate manifestation of airborne viral infections. In particular, pretreatment with inorganic Hg significantly aggravated coxsackievirus B3 (CVB3) infection-induced myocarditis characterized by sever macrophage infiltration and proinflammatory cytokine overproduction, whereas posttreatment did not possess similar effect in mice (Nyland et al., 2012; . It is also notable that coxsackievirus B3 (CB3) infection in mice is accompanied by a twofold increase in brain Hg content, whereas Se levels were found to be elevated only by 36% (Ilbäck et al., 2005) . Taken together with a later observed decrease in intestinal, serum, and hepatic Hg levels (Ilbäck et al., 2008) , these findings are indicative of redistribution of Hg into brain providing an additional link between viral diseases and neurotoxicity. The observations on positive association between body Hg burden and parenterally-transmitted HIV infection (Emokpae, Mbonu, 2018) also support indirectly the impact of Hg on antiviral immunity. In view of the role of bats as carriers for SARS-CoV-2 (Docea et al., 2020) , it is also noteworthy that high Hg levels in bats are associated with impaired immunity and higher susceptibility to infectious agents (Becker et al., 2017) . It is notable that the role of environmental, including heavy metals, and/or pollution may play a significant role in increased susceptibility of host organisms to viral zoonotic infections was also earlier proposed by Rotshild (2015) . The observed interference between Hg toxicity and viral infections may be mediated by immunotoxic effect of the metal (Gardner, Nyland, 2016) (Fig. 3) . Particularly, it has been demonstrated that ethylmercury (thiomersal) and methylmercury, but not HgCl 2 possessed cytotoxic effect in a human T cell line (Jurkat) (Guzzi et al., 2012) . Notably, Weigand et al. (2015) showed that exposure of T and B cell lines (EL4 T cells and WEHI-231 B cells) to low doses of mercury (II) chloride (HgCl 2 ) during 12 or 96 hours induced, in the absence of antigenic stimulation, increased levels of signaling molecules, such as ERK1/2, PKCα and p38MAPK, indicating inappropriate activation of these cells. MeHg exposure in Steller sea lion was shown to alter T and B cell proliferation due to aberrant expression of regulatory cytokines including INF-γ, IL-6, IL-10, and TNF-α (Levin et al., 2020). Increased susceptibility to fungal infections was also associated with reduced number of splenic CD3+CD4+ lymphocytes, as well as Th1 and Th17 cells (Batista-Duharte et al., 2018) . In utero exposure of BALB/c mice to HgCl2 by subcutaneous injection was able to induce a significant upregulation of arginase, IFN-γ, STAT1, vitronectin, and TNF Superfamily Member 1 (TNFSF18) in male offspring. These changes, being more pronounced in males, may modulate the baseline immune response and thus reflect risks in adulthood health . At the same time, another study demonstrated that MeHg exposure may result in suppression of interferon-γ (IFN-γ) production in peripheral blood mononuclear cells (De Vos et al., 2007) . In a more recent study, male C57BL/6 mice exposed subcutaneously to 25 mg/kg/day of methylmercury chloride presented, after seven days, increased expression of TNF-α -related genes in samples of different tissues, including liver, kidney and brain. The same study which included mouse neural cell line (C17.2 cells) also clarified that NF-κB may participate as a transcription factor in the TNF-α induction (Iwai-Shimada et al. 2016) , being indicative of the impact of Hg exposure on systemic inflammation (Maqbool et al., 2017) . In addition, Hg-induced inflammation is tightly interrelated with autoimmunity (Pollard et al., 2019) that may also impair physiological immune and inflammatory reactions. Several studies have demonstrated an inverse association between environmental lead exposure levels and impaired respiratory function. Specifically, blood lead Pb levels were shown in Polish schoolchildren to have a negative effect on lung vital capacity (VC) and FVC (Little et al., 2017) . Living in an e-waste emission area resulted in a significant increase in blood Pb levels that were inversely associated with FEV1 in children . It has been also demonstrated that Pb exposure assessed by urinary metal levels is associated with reduced lung function (FEV1) especially as a result of interaction between Pb exposure and antioxidant (NQO1, NAD(P)H quinone dehydrogenase) gene polymorphisms (Wei et al., 2020) . Moreover, of all heavy metals studied (Hg, Cd, Pb) only blood Pb levels were inversely and adversely associated with pulmonary function assessed by FEV1 and FVC (Pan et al., 2020) . Pb exposure is known to play a causal role in respiratory disease (Boskabady et al., 2018) . Heavy metals including lead were found to be higher in patients with COPD, being interrelated with pulmonary dysfunction and antioxidant activity (Gogoi et al., 2019) . Correspondingly, soil and water lead distribution was shown to be associated with patterns of respiratory disease burden in Iran (Ghias, Mohammadzadeh, 2016) . Several studies demonstrated a relationship between Pb exposure and susceptibility to viral infections, corroborating its role in suppression of antiviral immunity (Rashed, 2011; Emokpae, Mbonu, 2018; Sahin et al., 2019) , although no association between Pb and airborne viral infections exists. Pb is a known toxicant to many organs, however, its mechanisms of action on the immune system are not wellestablished (Fenga et al. 2017) (Fig. 3) . Briefly, lead exposure was shown to inhibit lymphocyte proliferation along with impaired IL-2 and calmodulin production (Li et al., 2012) . In addition, Pb exposure was shown to alter Th1/Th2 ratio in chicken blood lymphocytes (Fu et al., 2019) . Lead inhalation in sensitized guinea pigs was shown to alter IFN-γ/IL-4 ratio, being indicative of reduction in Th1/Th2 balance (Boskabady et al., 2012) . Pb 2+ was also shown to be toxic to both B-lymphocytes and especially macrophages, also resulting in reduced IFN-γ production and causing aberrant immune response to viral and bacterial pathogens (Han et al., 2020) . These findings corroborate the observed inverse correlation between blood lead levels and T cell count in Pb-exposed subjects (Mishra et al., 2010) . However, Pb exposure due to habitation in e-waste area is directly associated with increased number of memory T cells (Cao et al., 2018) . Exposure of chicken neutrophils to Pb 2+ resulted in a significant increase in IL-1β, 1R, 4, 8, 10, and 12β levels, whereas IL-2 and IFN-γ were down-regulated (Xing et al., 2018) Early-life Pb exposure was shown to inhibit stimulated thymocyte and splenocyte proliferation also resulting in a dose-dependent decrease in IL-2, IFN-γ, IL-4, IL-10, and TNF-α secretion (Ajouaoi et al., 2019) . In addition, Pb2+induced thymocyte apoptosis is considered as the potential mechanism of lead immunotoxicity (Nishizaki et al., 2003) . Dvorožňáková et al. (2016) evaluated the effects of Hg, Cd and Pb in the immune response using a parasiteinfection model. As regards Pb, BALB/c male mice exposed during 35 days and subsequently infected with Ascaris suum on the 21st day presented increase in the levels of IL-5 and IL-10 cytokine production, but TNF-α and IFN-γ production was suppressed. In this study, continuous intoxication with Pb caused susceptibility to the parasite infection. Arsenic (As) exposure is known to cause a wide spectrum of malignant and non-malignant respiratory diseases (Ramsey, 2015) . However, even subtoxic doses of arsenic may significantly affect respiratory functions. Particularly, a recent meta-analysis demonstrated that arsenic exposure is associated with restrictive impairments in lung function including reductions in forced expiratory volume in one second (FEV1), forced vital capacity (FVC) J o u r n a l P r e -p r o o f . Another study has demonstrated that As-associated FVC reduction is observed on males (Khan et al., 2020) . In addition, overweight and obesity were shown to aggravate As-induced lung dysfunction (Nardone et al., 2017) . Moreover, impaired lung function in As-exposed children (Ahmed et al., 2017) and adults Shih et al., 2020) was also associated with lung inflammation. Spirometric abnormalities in Asexposed children were also associated with higher matrix metalloproteinase-9 (MMP-9) level in sputum (Olivas-Calderón et al., 2015) . Early-life and lifetime As exposure were shown to be associated with reduced respiratory function, as well as higher incidence of respiratory diseases including chronic cough and chronic bronchitis (Steinmaus et al., 2016), even after adjustment for smoking status . As exposure was also associated with reversible lung obstruction (Siddique et al., 2020) . Doubling of maternal urinary As levels was associated with increased incidence of infections, respiratory symptoms, diarrhea, and fever resulting in a doctor visit or medication use in first-year children (Farzan et al., 2016) , with the strongest relationship observed for lower respiratory tract infections (Farzan et al., 2013) . Specifically, increased urinary As concentrations (≥6 μg/L) were associated with a more than twofold increase in pneumonia risk (odds ratio (OR) 95% confidence interval (CI) = 1.88 (1.01, 3.53)) in Bangladeshi children (George et al., 2015) . As exposure has been shown to increase airway inflammation, reactivity, and remodeling characterized by peribronchial thickening that may be related to NLRP3 inflammasome activation (Surolia et al., 2020). As-induced lung damage was also shown to be associated with apoptotic cell death due to oxidative and endoplasmic reticulum stress (Gu et al., 2016) , as well as mitochondrial dysfunction (Mahalanobish et al., 2019) . Both inflammatory and prooxidant effects of As exposure in lungs may be related to As-induced up-regulation of NF-kB and MAPK activity, as well as alteration of Nrf2 signaling, respectively (Li et al., 2017) (Fig. 2) . Particularly, As is capable of up-regulation of IKKα/β and NF-κB p65/50 mRNA and protein expression in parallel with a decrease in IκBα levels in lungs . It is noteworthy that low-dose As exposure was shown to increase autophagy and inflammation in murine lungs, whereas high-dose As aggravated inflammatory response with weak autophagy activation (Zhao et al., 2019) . Prenatal As exposure was shown to impair expression of genes involved in lung morphogenesis (Sox2), mucus production (Clca3, Muc5b), and ciliary function (Ttc21a) (Zosky et al., 2014) . Low-dose As exposure also resulted in partially reversible repression of MUC5AC and MUC5B at mRNA and protein levels through retinoic acid J o u r n a l P r e -p r o o f signaling pathway . TGF-β/Smad pathway signaling may be also involved in As-induced fibrosis (Dai et al., 2019) . As exposure was also shown to impair lung epithelial barrier function by causing aberrant localization and expression of tight junction proteins claudin and occludin, as well as impairing occludin phosphorylation (Sherwood et al., 2013) . These data are in agreement with the results of a more recent study demonstrating increased respiratory epithelial permeability and alveolar epithelial type 1 cell injury (Henderson et al., 2017) . As-induced decrease in lysozyme secretion was also observed in human bronchial epithelial cells increasing susceptibility to infectious agents (Goodale et al., 2017) . In contrast to other heavy metals, the role of As in viral diseases is dual. On the one hand, chronic As exposure is known to be tightly associated with the incidence of viral infections due to its immunotoxic effect, whereas on the other, As compounds are used as the potential antiviral agent also inhibiting SARS-CoV-2 viral proteins as assessed by in silico docking analysis (Chowdhury et al., 2020) . At the same time, arsenic exposure was shown to be associated with increased H1N1 influenza virus load, as well as reduction in FEV1 in a primarily adult population (Liao et al., 2011) . In turn, the relationship between As body burden and non-airborne hepatitis A (Cardenas et al., 2016) , B (Cardenas et al., 2018; Zhang et al., 2018) , and E (Heaney et al., 2015) viral infections may indirectly reflect negative impact of As on antiviral immunity. It is also notable that As toxicity may underlie impaired antiviral response in the organism (Fig. 3) . Particularly, it has been demonstrated that urinary As levels were found to be inversely associated with post-immunization mumpsspecific IgG levels (Raqib et al., 2017) . Experimental data corroborate clinical findings. For example, in chicks, As exposure significantly increased susceptibility to Newcastle disease virus resulting in higher virus titers and impaired antibody responses to Tdependent antigen (Sattar et al., 2016) . These data generally are in agreement with the earlier observation of impaired antiviral response and higher pulmonary virus titer in a model of H1N1 influenza infection in C57BL/6J mice (Kozul et al., 2009) . Moreover, chronic arsenite exposure significantly increased susceptibility to H1N1 influenza infection through sialic acid binding as well as decreased efficiency of oseltamivir (Amouzougan et al., J o u r n a l P r e -p r o o f 2020). In addition, prenatal As exposure significantly aggravated influenza A-induced pulmonary inflammation (Ramsey et al., 2013 ). An interesting study by Benyamin et al. (2006) demonstrated that coxsackievirus B3 infection in Balb/c mice results in reduced serum, liver, spleen, heart, pancreas, and kidney As levels along with clinical manifestation of the disease (Benyamin et al., 2006) . Nonetheless, several studies demonstrate potential antiviral activity of As compounds. Particularly, As 2 O 3 exposure significantly inhibits growth of human T-cell leukemia virus-infected T-cell lines through induction of apoptosis and cell cycle arrest (Ishitsuka et al., 2000) . Similarly, As administration was also shown to inhibit Epstein-Barr Virus replication and stimulates cell death in EBV-positive cells (Yin et al., 2017) . Due to the observed effects of As exposure on viral agents of leukemia, As and IFN-α is widely used as an antileukemic agent (Hachiman et al., 2018) . At the same time, As 2 O 3 was also shown to reduce susceptibility to Simian immunodeficiency virus after provirus reactivation in macaques . Earlier studies have also demonstrated an inhibitory effect of As2O3 on HCV replication (Hwang et al., 2004) . Moreover, the results of in silico docking analysis demonstrated that certain arsenicals were capable of inhibiting SARS-CoV-2 RNA dependent RNA polymerase thus decreasing viral replication (Chowdhury et al., 2020), although in vitro and in vivo data are highly required to support this hypothesis. Generally, the observed difference in As activity is expected to be related to the mode of exposure, where long-term As exposure affects immunity and increases susceptibility to viral agents, whereas acute arsenic exposure may possess antiviral effect due to cytotoxic effect on virus-infected cell. Among its adverse outcomes, epidemiological, in vitro and in vivo evidences indicate that arsenic is an immunotoxic compound, acting as both immune system suppressor and stimulator mechanisms (Ferrario et al. 2016) . As was shown to impair proliferation, differentiation, and activation of macrophages, dendritic cells, and Tcells (Bellamri et al., 2018) , especially T regulatory cells (Haque et al., 2017) . Particularly, male BALB/c mice exposed to 0.038, 0.38 and 3.8 ppm sodium arsenite for 7, 15 and 30 days through oral gavage showed a significant dose-dependent increase in the ThPOK expression levels in thymus, suggesting an impairment in the regulation of CD4+ T cells differentiation. In the spleen, As increased the number of CD4+ T cells and promoted their differentiation into Treg cells, however, a low secretion of IFN-γ, TNF-α, IL-12, IL-4, IL-5 and IL-10 cytokines was observed in splenocytes (Gera et al. 2017) . Activation of NF-kB and downstream signaling was shown to induce Asassociated immune suppression (Choudhury et al., 2016). As 2 O 3 exposure resulted in a significant Nrf2-independent inhibition of both mRNA and protein production of IFNγ, IL-2, and GM-CSF in splenocytes (VanDenBerg et al., 2017) . It has been also demonstrated that As 2 O 3 inhibited IFN-α secretion in plasmacytoid dendritic cells (Ye et al., 2020) . Moreover, another study with lymphocytes isolated from the blood of healthy people, showed that exposure to As at a concentration range of 0.05-50 μM for 12 hours was able to induce apoptosis mainly through enhancement of intracellular calcium import which causes oxidative stress. Moreover, cellular proteolysis, activation of caspase-3 and lipid peroxidation with 2, 4 or 6 h of exposure, and stimulation of cytokines (IL-2, INF-γ and TNF-α) production after an exposure of 24 hours was also associated with As-induced toxicity in the isolated lymphocytes (Zarei et al. 2019) . Overall, these findings indicate that ROS generation followed by inflammation play a crucial role in the cytotoxicity. The alteration of cytokine levels found after As exposure can reflect a commitment of lymphocytes, which in turn impairs immune system in fighting against infection (Zarei et al. 2019) . In parallel with impaired lymphocyte functioning, As toxicity is also associated with chronic inflammation and reduced phagocytic receptors-Fcγ and complement receptors (CR) (Prasad, Sinha, 2017) . Correspondingly, As exposure was shown to affect innate immunity factors in children (Parvez et al., 2019) . In parallel with respiratory dysfunction, certain diseases are also considered as the most significant co-morbidity risk factors for COVID-19 severity, including obesity, diabetes, cardiovascular diseases (hypertension), and cancer. These diseases may also provide an additional link between COVID-19 severity and heavy metal toxicity. Earlier data demonstrate that obesity and diabetes may be associated with Hg (Tinkov et al., 2015; Roy et al., 2017) , Сd (Satarug et al., 2010; Tinkov et al., 2017) , Pb Leff et al., 2017) , and As (Farkhondeh et al., 2019) . Although these associations are rather contradictory and the underlying mechanisms are still unclear, it is proposed that the role of metals and endocrine disruptors may significantly contribute to metabolic disorders. Heavy metal pollution was also demonstrated to be significantly associated with cardiovascular morbidity predominantly through interference with atherogenesis (Solenkova et al., 2014) . Particularly, Cd (Tellez-Plaza et al., 2013; Tinkov et al., 2018) , Hg (Houston, 2011; Genchi et al., 2017) , Pb (Poręba et al., 2011; , and As (Moon et al., 2017; Navas-Acien et al., 2019) exposure levels were directly associated with prevalence of a wide range of cardiovascular diseases including atherosclerosis, coronary heart disease, hypertension, myocardial infarction, stroke, etc. Finally, As and Cd are considered as Group I carcinogens by International Agency for Research on Cancer (IARC). Taken together, the existing data demonstrate that As, Cd, Hg, and Pb exposure is associated with respiratory dysfunction (reduced FVC, FEV1) and respiratory diseases (COPD, bronchitis). These observations corroborate laboratory findings on the role of heavy metal exposure in impaired mucociliary clearance, reduced barrier function, airway inflammation, oxidative stress, and apoptosis. Both clinical and laboratory studies have shown the association between heavy metal exposure and severity of viral diseases, including influenza and respiratory syncytial virus. The latter may be considered a consequence of adverse effects of metal exposure on adaptive immunity (Table 1) . Although direct data linking heavy metal exposure and COVID-19 risk and/or severity are lacking, reduction in heavy metal emissions may significantly reduce lung immunopathology and inflammation, both of which are known to increase the risk of respiratory viral and bacterial diseases. In addition, avoiding heavy metal exposure at the individual level through the use of respirator masks or portable air filters, especially in highly-polluted environments including metropoles, could also contribute to reduction of risk of infection and its severity. The use of zinc, selenium, or other functional antagonists of heavy metals may also prevent adverse effects of heavy metals on respiratory system and immunity. At the same time, both epidemiological and laboratory studies are urgently required to characterize the direct association between heavy metal exposure and COVID-19 risk and pathogenetic mechanisms. The proposed role of heavy metals as a link between risk factors for COVID-19 severity. Both particulate (PM2.5) pollution and smoking are associated with heavy metal exposure that at least partially mediate adverse effects of these factors on the respiratory system. In addition, heavy metal exposure was shown to be associated with higher incidence of obesity, diabetes, and cardiovascular diseases. A simplified scheme depicting proinflammatory mechanisms of heavy metals. Briefly, heavy metal exposure results in increased ROS production and oxidative stress that latter may underlie heavy metal-induced activation of proinflammatory pathways NF-kB and MAPK with subsequent expression of target proinflammatory genes including cytokines, chemokines, enzymes, and adhesion molecules (Metryka et al., 2018; Pollard et al., 2019; Hossein-Khannazer et al., 2020; Hu et al., 2020) . The proposed impact of heavy metals on antiviral immunity. As, Cd, Hg, and Pb were shown to be toxic for both T and B lymphocytes, as well as macrophages, affecting its proliferation and further functioning. Taken Smoking upregulates angiotensin-converting enzyme-2 receptor: a potential adhesion site for novel coronavirus SARS Increased memory T cell populations in Pbexposed children from an e-waste-recycling area Tight junction disruption by cadmium in an in vitro human airway tissue model Arsenic exposure and the seroprevalence of total hepatitis A antibodies in the US population: NHANES Cross sectional association of arsenic and seroprevalence of hepatitis B infection in the United States (NHANES 2003-2014) Relation between lung dysfunction and blood cadmium and lead levels among welders Low-dose cadmium potentiates lung inflammatory response to 2009 pandemic H1N1 influenza virus in mice The environmental pollutant cadmium promotes influenza virus replication in MDCK cells by altering their redox state Effects of metals within ambient air particulate matter (PM) on human health Does Air Pollution Influence COVID-19 Outbreaks? Bi-directional regulation of TGF-β/Smad pathway by arsenic: A systemic review and meta-analysis of in vivo and in vitro studies Patients with cancer appear more vulnerable to SARS-COV-2: a multicenter study during the COVID-19 outbreak Selective effect of mercury on Th2-type cytokine production in humans A new threat from an old enemy: Re-emergence of coronavirus Discovering drugs to treat coronavirus disease 2019 (COVID-19) Heavy metal intoxication compromises the host cytokine response in Ascaris suum model infection Prenatal exposure to mercury in relation to infant infections and respiratory symptoms in the New Hampshire Birth Cohort Study Blood levels of some toxic metals in Human Immunodeficiency Virus (HIV) Type 1-infection The role of arsenic in obesity and diabetes Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system Current smoking, former smoking, and adverse outcome among hospitalized COVID-19 patients: a systematic review and meta-analysis In utero arsenic exposure and infant infection in a United States cohort: a prospective study Infant infections and respiratory symptoms in relation to in utero arsenic exposure in a US cohort Immunological effects of occupational exposure to lead (Review) Arsenic exposure and immunotoxicity: a review including the possible influence of age and sex COVID-19: The Conjunction of Events Leading to the Coronavirus Pandemic and Lessons to Learn for Future Threats Effect of selenium antagonist lead-induced damage on Th1/Th2 imbalance in the peripheral blood lymphocytes of chickens Total blood mercury and serum measles antibodies in US children Total blood mercury and rubella antibody concentrations in US children aged 6-11 years Cadmium in tobacco smokers: a neglected link to lung disease? Obesity-a risk factor for increased COVID-19 prevalence, severity and lethality Immunotoxic effects of mercury Mercury exposure and heart diseases Arsenic exposure is associated with pediatric pneumonia in rural Bangladesh: a case control study Arsenic exposure impels CD4 commitment in thymus and suppress T cell cytokine secretion by increasing regulatory T cells Relationship of Respiratory Diseases and the Lead Level in Tiran & Karvan Region Environmental cadmium enhances respiratory syncytial virus infection-caused lung injury via mitochondrial metabolic disruption and oxidative stress. Free Radic Circulatory heavy metals (cadmium, lead, mercury, and chromium) inversely correlate with plasma GST activity and GSH level in COPD patients and impair NOX4/Nrf2/GCLC/GST signaling pathway in cultured monocytes Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction underlie apoptosis induced by resveratrol and arsenic trioxide in A549 cells Clinical characteristics of coronavirus disease 2019 in China Immunosuppressive effects and associated compensatory responses in zebrafish after full life-cycle exposure to environmentally relevant concentrations of cadmium Effect of thimerosal, methylmercury, and mercuric chloride in Jurkat T Cell Line In vitro effects of arsenic trioxide, interferon α and zidovudine in adult T cell leukemia/lymphoma cells Lifestyle Risk Factors, Inflammatory Mechanisms, and COVID-19 Hospitalization: A Community-Based Cohort Study of 387,109 Adults in UK Modulatory Effects of Pb2+ on Virally Challenged Chicken Macrophage (HD-11) and B-Lymphocyte (DT40) Cell Lines In Vitro Comparative cytotoxicity of cadmium and mercury in a human bronchial epithelial cell line (BEAS-2B) and its role in oxidative stress and induction of heat shock protein 70 Immunomodulatory role of arsenic in regulatory T cells Drug Targets (Formerly Current Drug Targets-Immune Arsenic exposure and hepatitis E virus infection during pregnancy Brief report: low-level mercury exposure and risk of asthma in school-age children Effects of orally ingested arsenic on respiratory epithelial permeability to bacteria and small molecules in mice Evaluation of cadmium cytotoxicity using alveolar epithelial cells derived from human induced pluripotent stem cells Serum heavy metals and lung function in a chronic obstructive pulmonary disease cohort Prenatal cadmium exposure produces persistent changes to thymus and spleen cell phenotypic repertoire as well as the acquired immune response The effects of cadmium exposure in the induction of inflammation Role of mercury toxicity in hypertension, cardiovascular disease, and stroke Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis The role of reactive oxygen species in arsenic toxicity Grape seed proanthocyanidin extract alleviates arsenic-induced lung damage through NF-κB signaling Association between concentrations of metals in urine and adult asthma: a case-control study in Wuhan Cadmium nanoparticles citrullinate cytokeratins within lung epithelial cells: cadmium as a potential cause of citrullination in chronic obstructive pulmonary disease Inhibition of hepatitis C virus replication by arsenic trioxide Gastrointestinal uptake of trace elements are changed during the course of a common human viral (Coxsackievirus B3) infection in mice Selenium and mercury are redistributed to the brain during viral infection in mice Arsenic trioxide and the growth of human T-cell leukemia virus type I infected T-cell lines Methylmercury induces the expression of TNF-α selectively in the brain of mice Identification of a unique gene expression signature in mercury and 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin co-exposed cells An overview of safety assessment of the medicines currently used in the treatment of COVID-19 disease Ultrastructural changes in lung tissue after acute lead intoxication in the rat Long-term ultrastructural indices of lead intoxication in pulmonary tissue of the rat Prospective cohort study of respiratory effects at ages 14 to 26 following early life exposure to arsenic in drinking water Cadmium-induced ER stress and inflammation are mediated through C/EBP-DDIT3 signaling in human bronchial epithelial cells Low-level mercury exposure and risk of asthma in Blood lead levels, pulmonary function and agility in Polish schoolchildren Genomic analysis of the rat lung following elemental mercury vapor exposure Arsenic represses airway epithelial mucin expression by affecting retinoic acid signaling pathway Combined exposure to nanosilica and lead induced potentiation of oxidative stress and DNA damage in human lung epithelial cells Grape seed procyanidin extract protects against Pb-induced lung toxicity by activating the AMPK/Nrf2/p62 signaling axis Methylmercury chloride induces alveolar type II epithelial cell damage through an oxidative stress-related mitochondrial cell death pathway Effects of temperature variation and humidity on the death of COVID-19 in Wuhan Mangiferin alleviates arsenic induced oxidative lung injury via upregulation of the Nrf2-HO1 axis Urinary cadmium levels predict lower lung function in current and former smokers: data from the Third National Health and Nutrition Examination Survey Immunotoxicity of mercury: Pathological and toxicological effects Air pollution and the novel Covid-19 disease: a putative disease risk factor Lead (Pb) exposure enhances expression of factors associated with inflammation Association between total blood mercury and exhaled nitric oxide in US adults Effect of lead exposure on lymphocyte subsets and activation markers A dose-response meta-analysis of chronic arsenic exposure and incident cardiovascular disease Oral exposure to cadmium and mercury alone and in combination causes damage to the lung tissue of Sprague-Dawley rats The impact of BMI on non-malignant respiratory symptoms and lung function in arsenic exposed adults of Northern Chile Arsenic exposure and cardiovascular disease: evidence needed to inform the dose-response at low levels Increase in number of annexin V-positive living cells of rat thymocytes by intracellular Pb2+ Cord blood T cell subpopulations and associations with maternal cadmium and arsenic exposures Low-dose inorganic mercury increases severity and frequency of chronic coxsackievirus-induced autoimmune myocarditis in mice Blood cadmium levels are associated with a decline in lung function in males Lung inflammation biomarkers and lung function in children chronically exposed to arsenic Effects of lead, mercury, and cadmium coexposure on children's pulmonary function Induction of reactive oxygen species and apoptosis in BEAS-2B cells by mercuric chloride Epigenetics, obesity and early-life cadmium or lead exposure Exposure to low-dose arsenic in early life alters innate immune function in children Lung function assessment as an early biomonitor of mercury-induced health disorders in artisanal and small-scale gold mining areas in Indonesia Impact of cadmium in T lymphocyte subsets and cytokine expression: differential regulation by oxidative stress and apoptosis Female immune system is protected from effects of prenatal exposure to mercury Low-dose mercury heightens early innate response to coxsackievirus infection in female mice Mercury-induced inflammation and autoimmunity Environmental and occupational exposure to lead as a potential risk factor for cardiovascular disease Low-to-Moderate Arsenic Exposure and Respiratory Health in American Indian Communities Low-level arsenic causes chronic inflammation and suppresses expression of phagocytic receptors Dysregulation of immune response in patients with COVID-19 in Wuhan An Imperative Need for Research on the Role of Environmental Factors in Transmission of Novel Coronavirus (COVID-19) Arsenic and respiratory disease Early life arsenic exposure and acute and long-term responses to influenza A infection in mice Humoral immunity in arsenic-exposed children in rural Bangladesh: total immunoglobulins and vaccine-specific antibodies The role of trace elements on hepatitis virus infections: a review Relationship between hair cadmium levels, indoor ETS exposure and wheezing frequency in children Serum heavy metal and antioxidant element levels of children with recurrent wheezing Subtoxic doses of cadmium modulate inflammatory properties of murine RAW 264.7 macrophages Is mercury exposure causing diabetes, metabolic syndrome and insulin resistance? A systematic review of the literature Ecology of Ebola fever in terms of natural disease model Changes in liver tissue trace element concentrations during hepatitis B viral infection treatment A metaanalysis of arsenic exposure and lung function: is there evidence of restrictive or obstructive lung disease? Research directives toward deciphering adverse outcome pathways induced by environmental metallotoxins Cadmium, environmental exposure, and health outcomes Immunosuppressive effects of arsenic in broiler chicks exposed to Newcastle disease virus Early onset of virus infection and up-regulation of cytokines in mice treated with cadmium and manganese Arsenic compromises conducting airway epithelial barrier properties in primary mouse and immortalized human cell cultures Urinary arsenic concentration, airway inflammation, and lung function in the US adult population Cytokine release syndrome Association between chronic arsenic exposure and the characteristic features of asthma 1-6. between long-term effects of anthropogenic pollutants on viral epidemic/pandemic events and prevalence Chronic low-level cadmium exposure in rats affects cytokine production by activated T cells Immunology of COVID-19: current state of the science Inhibition of early T cell cytokine production by arsenic trioxide occurs independently of Nrf2 COVID-19 and smoking: A systematic review of the evidence Endothelial cell infection and endotheliitis in COVID-19 In vitro evaluation of inorganic mercury and methylmercury effects on the intestinal epithelium permeability Human arsenic exposure and lung function impairment in coal-burning areas in Guizhou Lead Exposure and Its Interactions with Oxidative Stress Polymorphisms on Lung Function Impairment: Results from A Longitudinal Population-based Study Low-level mercury causes inappropriate activation in T and B lymphocytes in the absence of antigen stimulation Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease Exposure to air pollution and COVID-19 mortality in the United States The antagonistic effect of selenium on lead-induced immune dysfunction via recovery of cytokine and heat shock protein expression in chicken neutrophils Disease-related responses induced by cadmium in an in vitro human airway tissue model Associations between lead concentrations and cardiovascular risk factors in US adolescents Body burden of heavy metals among HIV high risk population in USA Aberrant cytokine secretion and zinc uptake in chronic cadmiumexposed lung epithelial cells Serum Cadmium and Lead, Current Wheeze, and Lung Function in a Nationwide Study of Adults in the United States Arsenic Trioxide Impacts Viral Latency and Delays Viral Rebound after Termination of ART in Chronically SIV-Infected Macaques Arsenic trioxide induces regulatory functions of plasmacytoid dendritic cells through interferon-α inhibition Arsenic trioxide inhibits EBV reactivation and promotes cell death in EBV-positive lymphoma cells Association between short-term exposure to air pollution and COVID-19 infection: Evidence from China Combined toxicity of amorphous silica nanoparticles and methylmercury to human lung epithelial cells In vitro toxicity evaluation of heavy metals in urban air particulate matter on human lung epithelial cells COVID-19 pathophysiology: A review Toxicity of arsenic on isolated human lymphocytes: The key role of cytokines and intracellular calcium enhancement in arsenic induced cell death Prenatal and postnatal cadmium exposure and cellular immune responses among pre-school children Decreased lung function with mediation of blood parameters linked to e-waste lead and cadmium exposure in preschool children Decreased lung function with mediation of blood parameters linked to e-waste lead and cadmium exposure in preschool children Elevated Arsenic Exposure Is Associated with an Increased Risk of Chronic Hepatitis B Virus Infection: NHANES (2003-2014) in US Adults Cadmium modulates hematopoietic stem and progenitor cells and skews toward myelopoiesis in mice The impact of COPD and smoking history on the severity of Covid-19: A systemic review and meta-analysis Exposure of low-concentration arsenicinitiated inflammation and autophagy in rat lungs Acute exposure to waterborne cadmium induced oxidative stress and immunotoxicity in the brain, ovary and liver of zebrafish (Danio rerio) Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis Association between short-term exposure to air pollution and COVID-19 infection: Evidence from China In utero arsenic exposure via drinking water alters genes related to lung growth and mucociliary function The study was performed with the support of the Russian Ministry of Science and Higher Education, Project № 0856-2020-0008. MA was supported in part by grants from the National Institute of Environmental Health Sciences (NIEHS) R01ES07331 and R01ES10563. We further thank the German Research Foundation (DFG), DFG Research Unit FOR 2558.