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| LETTER TO THE EDITOR |
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| Year : 2021 | Volume
: 53
| Issue : 5 | Page : 415-416 |
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COVID-19 associated mucormycosis, host-iron assimilation: Probiotics can be a novel therapy
Ankit Bhardwaj1, Vandana Roy2
1 Department of Pharmacology, ABVIMS and Dr. RML Hospital, New Delhi, India
2 Department of Pharmacology, MAMC and LNJP Hospital, New Delhi, India
| Date of Submission | 24-May-2021 |
| Date of Decision | 10-Jun-2021 |
| Date of Acceptance | 28-Aug-2021 |
| Date of Web Publication | 24-Nov-2021 |
Correspondence Address:
Dr. Ankit Bhardwaj
Department of Pharmacology, ABVIMS and Dr. RML Hospital, Baba Kharak Singh Marg, Near Gurudwara Bangla Sahib, Connaught Place, New Delhi - 110 001
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijp.ijp_406_21
How to cite this article:
Bhardwaj A, Roy V. COVID-19 associated mucormycosis, host-iron assimilation: Probiotics can be a novel therapy. Indian J Pharmacol 2021;53:415-6 |
Sir,
Coronavirus-2 (SARS CoV-2) has caused havoc globally with 165,772,430 confirmed cases of COVID-19 and 3,437,545 deaths in the last 1 year. It causes diseases ranging from mild fever with respiratory and or gastrointestinal symptoms to life-threatening pneumonia with hypoxia, post-COVID-19 sepsis, and other complications. There is a dysregulated innate immune response, characterized by cytokine storm, ciliary dysfunction, thrombo-inflammation, microvascular coagulation, and exhaustion of immune response. Patients admitted and subjected to various emergency procedures, mechanical ventilation, prolonged hospital stay, and breaches in asepsis may have an opportunistic secondary infection with bacteria and fungus.
Preexisting diseases such as diabetes mellitus and acute or chronic respiratory pathologies; irrational use of broad-spectrum antibiotics, high doses of corticosteroids, and anti-interleukin-6 inhibiting strategies; and alteration in systemic immune responses in COVID-19 affect the gut microbiome.
In Indian hospital settings, COVID-19-associated invasive mucormycosis (Rhizopus Oryzae, a filamentous fungus) has emerged as a life-threatening complication recently. Mucormycosis is mainly acquired by the inhalation of spores and transported to the pharynx by cilia. In COVID-infected patients due to epithelium damage, ciliary dysfunction and immunosuppression infection begins in the nasal turbinates or alveoli. Once the fungus colonizes the nose and paranasal sinuses, the infection spreads along vascular structures and invades into base of the skull (eroding bones), which disseminates to the central nervous system or in the body. Sporangiospores produce by mucor are also capable in secreting various toxins or proteases enzymes which may further destroy the endothelial lining of mucosal membranes.[1]
An important virulence trait of the fungus is its ability of acquiring iron from the host.
High blood serum level of unbound iron in an acidic environment level plays a major predisposing role in the growth of mucormycosis. In COVID-19 patients with uncontrolled diabetes and diabetic ketoacidosis (DKA) with blood pH 7.3-6.8, there is temporary disruption of transferrin capacity to bind iron. Increase in serum concentration of ferritin and free iron levels can cause insulin resistance and dysfunction of pancreatic β-cells. This excess endogenous free iron is taken up efficiently by the fungus through siderophores, and iron permeases, further enhancing their growth and virulence. This way DKA abolishes an important host defense mechanism by decreasing pH and increasing free serum iron levels.[2]
In animal models of DKA, iron chelators such as deferiprone and deferasirox protected mice from mucormycosis. Deferoxamine obtained from the bacteria Streptomyces pilosus, acts as a siderophore, worsened mucormycosis by stimulating its growth, while deferasirox and deferiprone inhibit iron intake by mucormycosis and deplete its growth in vitro. Deferasirox proved effective in iron chelating from R. Oryzae and has fungicidal activity against mucormycosis. Deferasirox proved significant improvement in survival of mice infected with mucormycosis in DKA or neutropenia, in comparison to that of liposomal amphotericin B.[3]
In COVID-19 with its associated related opportunistic infections, probiotic supplements could be pivotal in maintaining an optimal immune system. Probiotics are live microorganisms and when consumed or administered in adequate quantities, confer multiple health benefits to the host. Bacteria from the genera Lactobacillus, Bifidobacterium, Enterococcus, Streptococcus, and Saccharomyces are used commonly as probiotics in various food supplements.
Epithelial cells of immune cells express series of multiple pattern recognition receptors which include toll-like receptors (TLRs). These TLRs interact with pathogen-associated molecular patterns from fungus which initiate appropriate signaling pathways that express different genes and produce subsequent immune mediators.
Probiotics used as nutritional supplements may play a key role in maintaining the internal immune homeostasis, with their ability to modulate gut microbiota. They have the ability to affect the redox status by their anti-oxidative potential in the gut lumen.
Isolates of Enterococcus and Bacillus SB10, JC13, and IFM22 have been found to produce a maximum number of siderophores (ranging from 65% to 90%) at an optimum pH 7. They have significant iron-chelating ability. They are nonhaemolytic in nature and show excellent tolerance to gastric acid and bile salts. Most of these strains showed high resistance against all the antibiotics tested. In addition, they have antimicrobial activity against Staphylococcus aureus, Klebsiella, and Escherichia More Details coli.[4] Another commercially available lactobacillus (L.) rhamnosus R0011, Streptococcus thermophilus  821, and Saccharomyces boulardii as singular treatment or in combination has significant iron chelation ability. Ferrichrome is a siderophore that is obtained from Lactobacillus casei ATCC 334 (L. casei). They are found to have a high antioxidants activity by acting as iron-chelating agents. This strategy of limiting free serum iron availability can play a major role in universal host defense mechanism against mucormycosis, in particular, as mucormycosis grows poorly in serum with less iron.[5]
The role of iron chelators in mucormycosis requires further elaboration. In view of the urgency of the increasing number of mucormycosis in COVID-19 patients, probiotic strains that have higher iron-reducing and iron-chelating ability can provide an effective strategy to combat the virulence of mucormycosis. In addition, these probiotics might help stabilize the altered gut microbiota which affects the immune response of the body.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| » References | |  |
| 1. | Kontoyiannis DP, Lewis RE. Invasive zygomycosis: Update on pathogenesis, clinical manifestations, and management. Infect Dis Clin North Am 2006;20:581-607.  |
| 2. | Ashourpour M, Djalali M, Djazayery A, Eshraghian MR, Taghdir M, Saedisomeolia A. Relationship between serum ferritin and inflammatory biomarkers with insulin resistance in a Persian population with Type 2 diabetes and healthy people. Int J Food Sci Nutr 2010;61:316-23. |
| 3. | Boelaert JR, Van Cutsem J, de Locht M, Schneider YJ, Crichton RR. Deferoxamine augments growth and pathogenicity of Rhizopus, while hydroxypyridinone chelators have no effect. Kidney Int 1994;45:667-71. |
| 4. | Gangadharan D, Sivaramakrishnan S, Pandey A, Madhavan Nampoothiri K. Folate-producing lactic acid bacteria from cow's milk with probiotic characteristics. Int J Dairy Technol 2010;63:339-48. |
| 5. | Boelaert JR, de Locht M, Van Cutsem J, Kerrels V, Cantinieaux B, Verdonck A, et al. Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies. J Clin Invest 1993;91:1979-86. |
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