Response to a press release that could be read to mean that glucosamine might exacerbate the "cytokine storms" seen in COVID-19

Tonight I came across this press release--https://www.eurekalert.org/pub_releases/2020-04/aaft-hbg041320.php--in which one of the authors of a 2020 paper on the influenza A virus said that their findings might be applicable to help understand why diabetes can lead to higher COVID-19 mortality. Unfortunately, one could come away from reading the press release with an impression that because glucosamine resulted in increased levels of inflammatory cytokines in mice infected with influenza A, glucosamine might do the same to COVID-19 patients. Here is a link to the actual study, "O-GlcNAc transferase promotes influenza A virus–induced cytokine storm by targeting interferon regulatory factor–5" by Wang et al.: https://advances.sciencemag.org/content/6/16/eaaz7086

While glucose metabolism issues can undoubtedly promote a state of inflammation in the body via a number of mechanisms, the Wang study does not appear to otherwise apply to COVID-19. Cytokine storms can result from a wide variety of infectious and noninfectious diseases. (See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294426/.) In 2017, Wang and his colleagues discovered that influenza A virus induces cytokine storms via interferon regulatory factor–5 (IRF5), (see https://www.jbc.org/content/292/52/21291), and their 2020 paper states, "results suggest that IRF5 is at least the major, if not the only, functional [O-GlcNAc transferase] target that promotes [influenza A virus]-regulated cytokine storm." A search in the PubMed database turns up 0 results for a search on "IRF5" combined with "COVID-19," even though there are currently 9509 papers about COVID-19 in the PubMed database.

Viruses differ. A study about influenza A virus does not necessarily advance our understanding of a different virus such as COVID-19.

I think that glucosamine is more likely to calm rather than exacerbate a COVID-19 cytokine storm because of its role in protecting cartilage. (See my previous post, https://petticoatgovernment.blogspot.com/2020/05/working-hypothesis-of-how-cartilage.html.) Moreover, glucosamine can suppress secretion of the inflammatory cytokine interleukin-6 in bronchial epithelial cells (see https://www.sciencedirect.com/science/article/abs/pii/S001429991000186X) and even keep interleukin-6 from binding to some cells (see https://cancerci.biomedcentral.com/articles/10.1186/1475-2867-14-45). Lastly, the extremely low COVID-19 case and death rates in regions that frequently eat fermented shrimp paste--the only widely eaten food source of appreciable, bioavailable glucosamine--are strong evidence in support of a hypothesis that glucosamine provides a net benefit to those infected with COVID-19.

Working hypothesis: how cartilage damage is connected to respiratory tract symptom progression, particularly within the context of COVID-19.

The body senses the presence of virus-infected cells, so the immune system starts to produce messenger molecules (cytokines) as part of its attack on those cells. Some of the cytokines--IL-1beta, IL-6, and TNFa--induce degradation of hyaline cartilage in the nose, larynx, trachea, bronchi, and other locations throughout the body. The degraded cartilage releases atypical or virus-bound forms of chondroitin sulfate or other glycosaminoglycans (GAGs) that the immune system perceives as a threat. The body then begins to have a delayed hypersensitivity reaction to those atypical or virus-bound GAG molecules. The hypersensitivity reaction increases the very cytokines that cause degradation of cartilage, thus creating a positive feedback loop, so symptoms--which include fever, pain, and increased secretions of protective and cartilage matrix reparative substances--continue to worsen. Underlying conditions that predispose to higher levels of those cytokines contribute to strengthening that feedback loop. The increased secretions of protective and reparative cartilage matrix substances contribute to "clogging" the lungs, some of which reparative substances have adhesive properties; their presence in the alveoli counteracts the surfactant that usually keeps the alveoli clear, and if they are not cleared, hyaline membranes--a characterizing feature of diffuse alveolar damage--form in the lung lobes. 

[I'll be returning to this post frequently over the next few days to post supporting evidence and explanations below. And likely to edit the paragraph above, for it is a work in progress. I apologize for any sloppiness of language. My formal educational/employment background is in law, computer programming, and math, so while I'm good at logic and analysis, my use of biology terms is sometimes imprecise.]

* A delayed hypersensitivity reaction to an atypical GAG is plausible and has been proven to happen. A 2012 case study reports how a middle-aged man inadvertently gave himself fever, dry cough, and lung congestion (the described symptoms are strikingly similar to the main ones seen with serious COVID-19 cases) merely by taking sodium chondroitin sulfate as a supplement:

"A case of drug-induced pneumonia caused by sodium chondroitin sulfate"
T. Itoh, Y. Hamanaka,
Japanese Journal of Chest Diseases 71(6):593-598, June 2012

Abstract: A 49-year-old man was admitted to the hospital with complaints of fever and dry cough. Chest X-ray film revealed ground-glass attenuation in both lung fields, so he was transferred to our hospital for further examination. Chest CT film showed ground-glass attenuation in both lung fields. A transbronchial lung biopsy revealed infiltration of lymphocytes and neutrophils, thickening of alveolar walls and proliferation of type II pneumocytes. By careful history taking, he admitted he had taken sodium chondroitin sulfate for one month before admission. The lymphocyte-stimulation test was positive for sodium chondroitin sulfate. Based on the above findings, we diagnosed this case as drug-induced pneumonia caused by sodium chondroitin sulfate. He recovered after discontinuation of the drug without corticosteroid therapy.

https://www.researchgate.net/publication/287575000_A_case_of_drug-induced_pneumonia_caused_by_sodium_chondroitin_sulfate

* The envelope protein of the Zika virus (a flavivirus) was found to bind tightly to chondroitin sulfate and heparin sulfate. See https://pubmed.ncbi.nlm.nih.gov/28151637/. Like other coronaviruses, Covid-19 has a viral envelope. See https://cen.acs.org/biological-chemistry/infectious-disease/know-novel-coronaviruss-29-proteins/98/web/2020/04

* This hypothesis indicates two ways to interfere with symptom progression:

1) Protect the hyaline cartilage from damage, and
2) Reduce secretions of cartilage glycosaminoglycans that can contribute to covering the alveolar surfaces and, if atypical or virus-bound, increase the immune system's attacks.

COVID-19 researchers are already successfully investigating how to reduce cytokines that help cause degradation of cartilage, but I don't know if they are looking at which proteins are involved in secreting adesive molecules that could promote accumulations within the lung lobes; I recommend looking at reducing activity of SOX9, for it is increased by EGCG (found in tea) and pomegranate juice, which could partially explain the rapid increase in serious cases seen in Hubei (where panicked people contributed to damaging cartilage by spraying everyone down with bleach) and then Iran. Another possibility is temporary suppression of the body's own production of chondroitin sulfate, perhaps via an inhibitor of glycosyltransferases.

A preliminary finding that highlights the important role of interleukin-6 in causing COVID-19 symptoms

A few days ago, researchers out of China announced some good news about their preliminary trials of tocilizumab, an interleukin-6 (IL-6) blocker used to treat arthritis:

The drug is a monoclonal antibody -- a cloned immune cell -- that is intended to bind to interleukin-6, or IL-6, a type of cytokine protein research suggests is part of an overactive immune response that causes serious illness in some of those infected with the new coronavirus.
By binding to IL-6, the researchers said, tocilizumab effectively works to disrupt this immune response, allowing patients to recover.
***
After treatment with tocilizumab, all patients' body temperatures returned to normal on the first day and remained stable thereafter. Within five days of treatment, 15 patients were able to reduce oxygen intake, and lung lesions were resolved in 19 patients after treatment, the study's authors wrote.
All participants were discharged between 10 and 31 days after treatment, and no side effects were reported.

https://www.upi.com/Health_News/2020/04/30/Monoclonal-antibody-used-for-arthritis-may-help-severe-COVID-19-study-suggests/1791588189875 Yale Health System is now recommending tocilizumab as the second-line treatment (right after hydroxychloroquine) for COVID-19 cases.

Guess what else inhibits IL-6 and is used for arthritis? Yes, glucosamine. Which I've been trying, with little effect, to tell people about as a potential preventive for pneumonia for over two years (see https://petticoatgovernment.blogspot.com/2018/02/glucosamine-to-protect-cartilage-during.html and https://youtu.be/JnN_OL1J8Vw).

These past three months have been extraordinarily stressful as I've watched evidence for my cartilage damage-pneumonia hypothesis mount in connection with this new virus amidst a relentless death toll that has hit my country and a former home in Ecuador especially hard. I was not able to get this idea to a wider audience (my blog is quite obscure) because I am hampered by a lack of professional connections in medical research fields. I have decided to seek a degree in an appropriate field, for being a "lawyer-housewife who is good at research and math and knows regional cuisines" is not sufficient to allow me effectively to spread information about my discoveries.