Mucormycosis and COVID

Mucormycosis is uncommon and is largely confined to patients with serious pre-existing diseases Mucormycosis originating in paranasal sinuses and nose predominantly affects patients with poorly controlled diabetes mellitus. Patients who have undergone organ transplantation, who have a hematologic malignancy or who are receiving long-term deferoxamine therapy are predisposed to mucormycosis of either sinus or lung. The survival rate is found to be rare among patients who have received deferoxamine and among those with pulmonary, gastrointestinal or disseminated mucormycosis In all forms of mucormycosis, vascular invasion by hyphae is found to be a prominent feature. It has been suggested that the regulation of diabetes mellitus and a decrease in the dose of immune-suppressive drugs facilitate treatment. Intravenous amphotericin B has been found to be clearly of value.

Although immune-suppressants will weaken the defence mechanism of the body and make it difficult to recover, but the prime question which I seek is the cause behind it, with particular focus on (a) why this post-COVID complication is happening during the second wave and  wasn’t seen before and (b) why is it specific to India. I believe that there must be certain practices specific to India which has brought this catastrophe uniquely in India.

In order to explore this, I consulted some doctors regarding the COVID related medication which is generally given to infected patients in earlier stages. I found that most prescriptions included Doxycycline and many included deferoxamine.

Interestingly, literature suggests that the three tetracyclines (tetracycline, doxycycline and minocycline)  possess iron chelating activity in a colorimetric siderophore assay. Determination of MICs (minimum inhibitory concentration – think like minimum dose) indicated that the MICs of doxycycline and minocycline against the Actinobacillus actinomycetemcomitans were significantly lower under iron-poor conditions than under iron-rich conditions. Continuing onto the literature, it was found that deferoxamine is also a chelating agent, which is used to treat iron or aluminium toxicity and some blood transfusion-dependent anaemias. Deferoxamine works by binding trivalent (ferric) iron, forming ferrioxamine, a stable complex. However, it is found that deferoxamine chelate iron in a form that the fungus can utilize. Therefore, Deferoxamine actually acts as a siderophore for the agents of mucormycosis, supplying previously unavailable iron to fungi.

Having said that, now a suspicion is raised about the properties of the chelate formed by doxycycline. Is it possible that the fungus is also able to utilize its chelate as well?

Before that, it would be good to know that despite Iron being the most abundant element on earth, why do microbes and even mammals require these chelating mechanisms? Actually, despite the abundance, iron is not bio-available because it exists mostly in form of Fe⁺³, which is insoluble. This calls for the need of siderophores. Siderophores are amongst the strongest solution Fe⁺³ binding agents known. It is siderophores, the small, high-affine iron-chelating compounds, that serve primarily to transport iron across cell membranes.

In mammalian hosts, the iron is tightly bound to proteins like haemoglobin, ferritin etc. Scarcity of iron for bacteria and fungi who need to feed on these evolved them develop and release siderophores to scavenge iron by forming Fe⁺³ complexes which can be taken by active transport mechanisms. But in order for us to survive, our systems need to outperform those of other microbes.

This brings us to the two major types of iron-binding proteins present in most animals which provide protection against microbial chelation of their iron. The extracellular protection in mammals is achieved by the transferrin family of proteins whereas intracellular protection is achieved by ferritin.

In addition to these two classes of iron-binding proteins, a hormone, liver-peptide hepcidin, is involved in controlling the release of iron from absorptive enterocytes, iron-storing hepatocytes and macrophages. The infection leads to inflammation which releases interleukin-6 (IL-6) and stimulates hepcidin expression. In humans, IL-6 production results in low serum iron, making it difficult for invading pathogens to infect. In this way, iron depletion restricts microbial growth.

It is interesting to know that citric acid acts as a siderophore as well. It is, therefore, the reason behind the prescribed citrus item consumption, like lemon, suggested in Indian prescriptions.

Coming back to the track, hepcidin regulates iron metabolism as it controls ferroportin. Ferroportin is a transmembrane protein that transports iron from inside the cell to outside the cell. It is the only known iron exporter. Note that there’s a difference between ferroportin and ferritin. While the former regulates the iron level in the serum, the latter stores unutilized iron.

The study by (Abobaker) stated that potentially COV-2 attacks one of the beta chains of hemoglobulin, which leads to increased free iron levels in the body and can explain the high ferritin levels. Alongside it is believed, not yet proven, that COVID mimics hepcidin and binds with ferroportin receptors on cells. In this way and would limit the release of iron and increase intracellular iron. In addition, he adds that high iron levels generate reactive oxygen species which can cause oxidative stress and damage lungs, lead to lung fibrosis and decline lung function, which is observed in COVID patients. There’s also evidence in studies about the positive relationship between iron overload and viral replication.  This does suggest that iron-chelating agents would be beneficial to the treatment of COVID, however, I believe what has been overlooked is the fact that the chelate formed might mimic the siderophore for other microbes, in the Indian case – fungus.  

Bibliography

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