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High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages
Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more pro-inflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Notably, low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion.
Finally, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk kinase.
Fucosylation has been observed in vertebrates, invertebrates, plants, bacteria, and fungi. It is known to facilitate various functions including cellular adhesion and immune regulation. Fucosylation inhibition applications are being explored for a range of clinical application including some associated with sickle cell disease, rheumatoid arthritis, tumor inhibition, and chemotherapy improvements.[6] Fucosylation can help with immune response when a foreign pathogen is introduced in the body. Rapid fucosylation can occur in the epithelial lining of the small intestine as a protective mechanism to support the body’s symbiotic gut bacteria. This may regulate the bacterial genes responsible for quorum sensing or virulence, thus resulting in an increased tolerance of the infection
Psychological stress can cause dysfunction of the gastrointestinal tract by regulating its interaction with central nervous system (brain-gut axis). Chronic social defeat stress (CSDS) is widely used to produce a rodent model of stress-induced human mood disorders and depression. We previously showed that CSDS significantly affects the intestinal ecosystem including cecal and fecal microbiota, intestinal gene expression profiles and cecal metabolite profiles. Here, we investigated whether the glycosylation pattern in the intestinal epithelium was affected in C57BL/6 mice exposed to CSDS (hereinafter referred to as CSDS mice).
In addition, distal intestine expression levels of the genes encoding fucosyltransferase 1 and 2 (Fut1 and Fut2) were downregulated in CSDS mice. These findings suggest that CSDS alters the fucosylation pattern in the distal intestinal epithelium,
Fucose is an l-configuration sugar found abundantly in the mammalian gut. It has long been known to be induced there by the presence of bacteria, but only recently have some of the molecular mechanisms behind this process been uncovered. New work suggests that fucose can have a protective role in both gut-centered and systemic infection and inflammation. This review highlights recent studies showing that, in addition to acting as a food source for beneficial gut symbionts, host fucose can suppress the virulence of pathogens and pathobionts. The relevance of gut fucosylation to human diseases also is discussed.
The six-carbon sugar l-fucose was originally discovered in seaweed of the genus Fucus, but it is found in all branches of life. It is one of the few sugars in nature with L stereochemistry. Like all carbohydrates, it has many potential functions, whether as a monosaccharide or as part of a more complex glycan structure, but this review focuses on its presence in the mammalian gut and how it may moderate the host–microbiota relationship there.
originally posted by: asabuvsobelow
a reply to: dug88
I'm going to need a Medical Dictionary for this one .
I'll respond properly in a few hours.
originally posted by: carewemust
originally posted by: asabuvsobelow
a reply to: dug88
I'm going to need a Medical Dictionary for this one .
I'll respond properly in a few hours.
Summary: 9.4 out of every 10 Covid-19 deaths were individuals who had at least 2 existing medical conditions.
originally posted by: marg6043
a reply to: CharlesT
many doctors are finding out that is more of a vascular disease when bodies are opened up after a person dies from the disease.
originally posted by: marg6043
a reply to: carewemust
And many of the poor souls that got intubated did not needed to be and died from punctured lungs and damages, specially the elderly.