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 Table of Contents  
LETTER TO EDITOR
Year : 2022  |  Volume : 12  |  Issue : 1  |  Page : 40-42

Zinc and mucormycosis—Fact vs myth check


1 Department of Anaesthesia and Critical Care, Command Hospital, Chandimandir, Haryana, India
2 Department of Psychiatry, Command Hospital, Chandimandir, Haryana, India

Date of Submission28-Sep-2021
Date of Acceptance11-Feb-2022
Date of Web Publication18-Apr-2022

Correspondence Address:
Shibu Sasidharan
Department of Anaesthesia and Critical Care, Command Hospital, Chandimandir, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ajoim.ajoim_19_21

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How to cite this article:
Sasidharan S, Dhillon HS. Zinc and mucormycosis—Fact vs myth check. Assam J Intern Med 2022;12:40-2

How to cite this URL:
Sasidharan S, Dhillon HS. Zinc and mucormycosis—Fact vs myth check. Assam J Intern Med [serial online] 2022 [cited 2022 May 21];12:40-2. Available from: http://www.ajimedicine.com/text.asp?2022/12/1/40/343433



Dear Sir,

As on June 12, 2021, coronavirus disease 2019 (COVID-19) has totaled 176,104,156 cases with 3,802,165 deaths worldwide. In India, there has been 367,097 deaths so far.[1]

India’s second wave of COVID-19 turned out to be much more deadly than the milder first wave. Large crowds, political rallies, religious gatherings, and compact urban spaces were named as the driving reason for the uncontrolled spread of infection. Researches have also pinned the blame on the new variant of virus, which was first discovered in India (B.1.617.2), which is now assigned the name ‘Delta” by the World Health Organization for this alarming transmission.[2]

Before vaccines were available, there was a raging demand for vitamins C and D and zinc supplements as immunity boosters, which people thought would supercharge their immunity and give them the protection they need to deter the second wave of COVID-19. Zinc and vitamin D apparently helped former US President Donald Trump in his recovery when he was infected in October 2020.[3] The data available on the Internet (pan[info]demic), especially in the face in the pandemic, can be hugely misleading.[4]

Multivitamins’ mechanism of action in the body does build immunity and act as antioxidants, but there is no enough evidence to link its use and prevention of COVID-19.[5] We need solid phase 1 and 2 data, before a phase 3 administration is done in large populations of people. Thus, we should exercise caution in moving forward with the supplementation drive. Although supplements are generally thought of as benign, their excess use is not free from adverse effects.

As the COVID-19 wave ravaged through the country, there emerged a new challenge in the form of mucormycosis (aka black fungus). Mucormycosis (formerly termed zygomycosis) is a lethal but relatively rare fungal infection that is caused by a collection of molds that live throughout the environment called mucormycetes. This disease mainly affects people with comorbidities and those with an obtunded immunity. It usually affects the lungs and sinuses after fungal spores are inhaled from the air we breathe.[6] On May 20, 2021, the Union Health Ministry of India urged the states and union territories to make black fungus a notifiable disease under the Epidemic Diseases Act, 1897.[7]

Over the past few months, India has reported over 28,200 cases of mucormycosis.[8] There are various hypotheses making rounds. Some suggest the use of iron, whereas others blame the failure to use sterile water in oxygen concentrators to this outbreak. Reuse of masks and cannulas is another theory. But does zinc cause/add to the chances of developing mucormycosis?

The fungal cells need zinc for their proper development, even as saprophytes or during the infection process. As a defense mechanism, to halt the growth of pathogen, host animals usually reduce the levels of metals like zinc, making them unavailable to the pathogen.[9] This is called as “nutritional immunity”[10] where the host aggressively interrupts and counters metal uptake by microorganisms.[11]

This is done by various mechanisms:

  1. There is a pH dependency of zinc uptake. The host’s near-neutral pH lowers zinc solubility and reduces its accessibility for microorganisms.[10]


  2. Intracellularly, stimulated T cells, macrophages, and dendritic cells decrease their lysosomal zinc content via the expression of the zinc transporter ZIP8, inducing zinc limitation for pathogens in the phagolysosome.[12]


  3. Stimulated dendritic cells reduce their cytoplasmic zinc concentration by upregulating zinc exporters and downregulating zinc importers.[13]


  4. By binding to the metallothioneins (MTs) and by sequestering labile zinc, cytokine-activated macrophages restrict the intracellular growth of fungi.[14]


  5. The host protein calprotectin inhibits bacterial and fungal growth by chelating transition metals, including zinc.[15],[16]


In human tissues and fluids, the concentration of zinc varies dramatically (body fluids—0.2–8.7 μg/mL, lungs—10 μg/g, liver—83.2 μg/g).[17] Thus, these pathogenic fungi in order to overcome the limits set by the host have developed various operative strategies to uptake zinc.[18] The fungi primarily use the Zinc-regulated, Iron-regulated transporter-like Protein (ZIP) family transporters (eg, Zrt1 and Zrt2) for aiding the zinc transport into the cytoplasm across cellular membranes. Other fungal species also use additional mechanisms to confiscate zinc from host cells and tissues. This is a process very similar to iron chelation. Candida albicans for example secretes Pra1 (its antigenic protein), a zinc-binding protein to scavenge zinc from fungus-invaded tissues. Zrt3 is a ZIP transporter found in the membranes of zincosomes (vacuoles that accumulate zinc) and supplies zinc to the cytoplasm from zincosomes.[18]

This active mechanism of zinc deprivation by mammalian hosts against fungal infection (by the activity of the host zinc transporters or the expression of zinc-binding proteins) is compromised with the excess intake of zinc, which provides the deficient pathogen with the zinc supply it needs to regulate the expression of many proteins, which is required for infection.

Laboratory studies have already proven that zinc chelation can reduce fungal growth in both rich and defined media.[15]

An excess of zinc can however be also toxic for cell. This is because of the fact that zinc does not participate in Fenton chemistry.[19] This is mainly due to a competition with other metals for metal-binding sites in enzymes.[20]

Although scientifically, easy availability of zinc via multivitamin tablets aids molecular mechanisms of pathogenic microorganisms to circumvent host metal restriction and provides a fertile ground for expression; however, for the associating mucormycosis with zinc supplementation, we need more data to ascertain a direct cause–effect relationship.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Worldometer. COVID live update: 160,416,106 cases and 3,333,785 deaths from the coronavirus. Worldometer; 2021 [cited 12 Jun 2021]. Available from: http://www.worldometers.info/coronavirus/. [Last accessed on 23 Oct 2021].  Back to cited text no. 1
    
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Times TNY. Coronavirus variant is indeed more transmissible, new study suggests. The New York Times. [cited 12 Jun 2021]. Available from: http://www.nytimes.com/2021/05/31/health/covid-variant-names-india-delta.html. [Last accessed on 25 Dec 2021].  Back to cited text no. 2
    
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A timeline of Trump’s symptoms and treatments. The New York Times. [cited 12 Jun 2021]. Available from: http://www.nytimes.com/2020/10/04/us/trump-covid-symptoms-timeline.html. [Last accessed on 2 Oct 2021].  Back to cited text no. 3
    
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Sasidharan S, Harpreet Singh D, Vijay S, Manalikuzhiyil B COVID-19: Pan(info)demic. Turk J Anaesthesiol Reanim 2020;48:438-42.  Back to cited text no. 4
    
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Michos ED, Cainzos-Achirica M Supplements for the treatment of mild COVID-19—Challenging health beliefs with science from A to Z. JAMA Netw Open 2021;4:e210431.  Back to cited text no. 5
    
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CDC. Mucormycosis | Fungal Diseases | CDC. Centers for Disease Control and Prevention; 2021. [cited 12 Jun 2021]. Available from: http://www.cdc.gov/fungal/diseases/mucormycosis/index.html. [Last accessed on 9 Dec 2021].  Back to cited text no. 6
    
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Times H Make Mucormycosis a notifiable disease under epidemic act, urges Centre | Latest News India.Hindustan Times. [cited 12 Jun 2021]. Available from: http://www.hindustantimes.com/india-news/make-mucormycosis-a-notifiable-disease-under-epidemic-act-urges-centre-101621501157362.html. [Last accessed on 23 Oct 2021].  Back to cited text no. 7
    
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Over 28,200 “black fungus” cases recorded in India. [cited 12 Jun 2021]. Available from: http://www.aa.com.tr/en/asia-pacific/over-28-200-black-fungus-cases-recorded-in-india/​2266396. [Last accessed on 16 Sep 2021].  Back to cited text no. 8
    
9.
Kehl-Fie TE, Skaar EP Nutritional immunity beyond iron: A role for manganese and zinc. Curr Opin Chem Biol 2010;14:218-24.  Back to cited text no. 9
    
10.
Sasidharan S, Singh V, Singh J, Madan GS, Dhillon HS, Dash PK, et al. COVID-19 ARDS: A multispecialty assessment of challenges in care, review of research, and recommendations. J Anaesthesiol Clin Pharmacol 2021;37:179.  Back to cited text no. 10
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Sasidharan S, Dhillon HS. MStress and burnout among health-care workers in the coronavirus disease 2019 intensive care unit. Int J Crit Illn Inj Sci 2021;11:257.  Back to cited text no. 11
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12.
Begum NA, Kobayashi M, Moriwaki Y, Matsumoto M, Toyoshima K, Seya T Mycobacterium bovis BCG cell wall and lipopolysaccharide induce a novel gene, BIGM103, encoding a 7-TM protein: Identification of a new protein family having Zn-transporter and Zn-metalloprotease signatures. Genomics 2002;80:630-45.  Back to cited text no. 12
    
13.
Kitamura H, Morikawa H, Kamon H, Iguchi M, Hojyo S, Fukada T, et al. Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function. Nat Immunol 2006;7:971-7.  Back to cited text no. 13
    
14.
Subramanian Vignesh K, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival. Immunity 2013;39:697-710. Available from: https://pubmed.ncbi.nlm.nih.gov/24138881/. [Last accessed on 20 Dec 2021].  Back to cited text no. 14
    
15.
Lulloff SJ, Hahn BL, Sohnle PG Fungal susceptibility to zinc deprivation. J Lab Clin Med 2004;144:208-14.  Back to cited text no. 15
    
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Corbin BD, Seeley EH, Raab A, Feldmann J, Miller MR, Torres VJ, et al. Metal chelation and inhibition of bacterial growth in tissue abscesses. Science 2008;319:962-5.  Back to cited text no. 16
    
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Lech T, Sadlik JK Zinc in postmortem body tissues and fluids. Biol Trace Elem Res 2011;142:11-7.  Back to cited text no. 17
    
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Staats CC, Kmetzsch L, Schrank A, Vainstein MH Fungal zinc metabolism and its connections to virulence. Front Cell Infect Microbiol 2013;3:65.  Back to cited text no. 18
    
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Prousek J Fenton chemistry in biology and medicine. Pure Appl Chem2007;79:2325-38. Available from: http://www.degruyter.com/document/doi/10.1351/pac200779122325/html. [Last accessed on 25 Dec 2021].  Back to cited text no. 19
    
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McDevitt CA, Ogunniyi AD, Valkov E, Lawrence MC, Kobe B, McEwan AG, et al. A molecular mechanism for bacterial susceptibility to zinc. PLoS Pathog 2011;7:e1002357.  Back to cited text no. 20
    




 

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