key: cord-276715-d1nh2dvb
authors: Raha, Syamal; Mallick, Rahul; Basak, Sanjay; Duttaroy, Asim K.
title: Is Copper beneficial for COVID-19 patients?
date: 2020-05-05
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.109814
sha: 
doc_id: 276715
cord_uid: d1nh2dvb

Copper (Cu) is an essential micronutrient for both pathogens and the hosts during viral infection. Cu is involved in the functions of critical immune cells such as T helper cells, B cells, neutrophils natural killer (NK) cells, and macrophages. These blood cells are involved in the killing of infectious microbes, in cell-mediated immunity and the production of specific antibodies against the pathogens. Cu-deficient humans show an exceptional susceptibility to infections due to the decreased number and function of these blood cells. Besides, Cu can kill several infectious viruses such as bronchitis virus, poliovirus, human immunodeficiency virus type 1(HIV-1), other enveloped or nonenveloped, single- or double-stranded DNA and RNA viruses. Moreover, Cu has the potent capacity of contact killing of several viruses, including SARS‐CoV‐2. Since the current outbreak of the COVID-19 continues to develop, and there is no vaccine or drugs are currently available, the critical option is now to make the immune system competent to fight against the SARS‐CoV‐2. Based on available data, we hypothesize that enrichment of plasma copper levels will boost both the innate and adaptive immunity in people. Moreover, owing to its potent antiviral activities, Cu may also act as a preventive and therapeutic regime against COVID-19.

Copper (Cu) is an essential trace element for humans [1] . Dietary Cu is absorbed in the small intestine and is rapidly appeared in the circulation. In blood, Cu is distributed into a plasma pool associated with larger proteins, an exchangeable fraction of low molecular weight copper complexes, and a red cell pool that is partly nonexchangeable. Cu plays an important role in the function and maintenance of the human immune system. Cu is involved in the functions of T helper cells, B cells, neutrophils, natural killer cells and macrophages. These cells are involved in the killing of infectious microbes, cell-mediated immunity and production of specific antibodies. Cu deficiency symptoms in human include deficiencies in white blood cells, bone and connective tissue abnormalities, and immune reactions [2] . Adverse effects of insufficient Cu on immune function appear most pronounced in infants and older people.

Infants with genetic disorders that result in severe Cu deficiency suffer from frequent and severe infections [2, 3] . During infection, macrophages can attack invading microbes with high Cu load. Cu is also elevated at sites of lung infection during infection with a wide array of pathogens [4] . Cu deficiency and its excess levels can result in abnormal cellular function or damages that given its central role in host-pathogen interaction. profiling, proteomic analysis, and metabolite profiling, in both data-driven and targeted formats, promise to provide more mechanistic details in animal models that can be tested in human pathology. Cu also normalized impaired immunological functions by modulating neutrophil activity, blastogenic response to T helper cell mitogens, the balance between Th1 and Th2 cells [14] .

Cu has the potent capacity to neutralize infectious viruses such as bronchitis virus, poliovirus, human immunodeficiency virus type 1(HIV-1), and other enveloped or nonenveloped single-or double-stranded DNA and RNA viruses [15] . Cu can disrupt the lytic cycle of the Coccolithovirus, EhV86 with the increase in production of ROS [15] . Cu 2+ ions can inactivate five enveloped or nonenveloped, single-or double-stranded DNA or RNA viruses. The virucidal effect of this Cu is enhanced by the addition of peroxide as the mixtures of Cu 2+ ions and peroxide are more efficient than glutaraldehyde in activating Junin and herpes simplex viruses [15] . Copper exposure to human coronavirus 229E destroyed the viral genomes and irreversibly affected virus morphology, including disintegration of envelope and dispersal of surface spikes [16] . Cupric (II) chloride dihydrate showed the inhibitory effect on the replication of dengue virus, DENV-2 in a cell culture study [17] . Cu-chelating agent (ATN-

(oHSV) indicating the importance of Cu 2+ ions in this process. Thujaplicin-Cu chelates inhibit influenza virus-induced apoptosis of MDCK cells and also inhibit the virus replication and release from the infected cells [18] . Cu 2+ ions inactivate herpes simplex virus by oxidatively damaging its genome [15] . Cu surfaces can significantly reduce the number of infectious influenza A virus particles. Cu ions can damage the viral genomic DNA by binding and cross-linking between and within strands of the genome [19] . Replication of influenza A virus was inhibited by Cu by damaging the negative-sense RNA genome [19] . The contact killing of microbes by Cu is mediated by the degradation of genomic and plasmid DNA of microbes [20] .

Human coronavirus was rapidly inactivated on a range of Cu alloys Cu/Zn brasses were very effective at lower Cu concentration that Cu (I) and Cu(II) moieties were responsible for the inactivation which was enhanced by ROS generation on alloy surfaces [21] . Novel coronavirus (SARS-CoV-2), responsible for current COVID-19 pandemic is very sensitive to the copper surface [22] . In a cell-based study, Cu 2+ was shown to block papain-like protease-2, a protein that SARS-CoV-1 requires for replication [23, 24] . Oxidized Cu oxide (CuO) nanoparticles (CuONPs) are widely used as catalysts so that the ability of CuONPs to reduce virus application is enhanced [25] . Nanosized Cu(I) iodide particles also show inactivation activity against H1N1 influenza virus. Gold/Cu Sulfide core-shell nanoparticles (Au/CuS NPs) exhibit variable virucidal efficacy against human norovirus (HuNoV) via inactivation of viral capsid protein [25] .

The current outbreak of the novel coronavirus SARS-CoV-2 (coronavirus disease 2019, , infected around the world. There are nearly 1.9 million confirmed cases of coronavirus in 185 countries, and at least 120,000 people have died, as of April 14, 2020.

Coronaviruses are enveloped, positive single-stranded large RNA viruses that infect humans, but also a wide range of animals. Coronaviruses were first described in 1966 by Tyrell and Bynoe, who cultivated the viruses from patients with common colds [26] . At present, no vaccines exist that protect people against infections by SARS-CoV-2, which causes COVID- [29] ; however, it is not known whether they had lowered Cu levels too. Several studies have shown that lower total cholesterol level may be related in part due to lower Cu level in adults [21, 30, 31] . Disruption of lipid rafts by cholesterol depletion caused an enhancement of virus particles released from infected cells and a decrease in the infectivity of virus particles [32] . Plasma Cu may affect all these above processes. Cu oxide nanoparticles and Cu 2+ ions are involved in the inhibition of viral entry and replication, and degradation of mRNA and capsid proteins that are involved in the viral life cycle. Cu deficiency is not always about a lack of Cu but also could be the result of an imbalance of Cu and other minerals in the diet that may often occur in an older population. In older people, Cu deficiency can also result from malnutrition, malabsorption, or excessive zinc intake and can be acquired or inherited [28] . Copper deficiency could lead a decreased number of circulatory blood cells with a greater susceptibility towards infection in older people In a study of 11 men on a low-Cu diet (0.66 mg Cu/day for 24 days and 0.38 mg/day for another 40 days) showed a decreased proliferation response of their white blood cells when presented with an immune challenge in cell culture [33] . Recent mechanistic studies support a role for Cu in the innate immune response against infections [34] . In the condition of specific intestinal malabsorption (such as celiac disease, bowel syndrome, long-term parenteral nutrition) or bone abnormalities or in well genetically determined disease (Menkes' disease), Cu deficiency is severe with dysfunctions on immune response, antioxidant activity and bone metabolism [35] . Altered plasma and tissue levels of Cu in acute or chronic inflammation reflect the changes in the metabolism of Cu [36, 37] . We hypothesize that copper supplementation can help fight 

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We hereby declare that any of the data contained in the above-mentioned manuscript have not been submitted for publication or under consideration to be published. All the listed authors have seen and approved the manuscript as submitted now


