COVID-19 Latest: Korean Researchers Identify NR3C1-CXCL8-Neutrophil Axis As Key Biomarker That Predicts Who Will Have To Endure Severe COVID-19
Source: COVID-19 Latest Oct 05, 2020 4 years, 2 months, 2 weeks, 6 days, 7 hours, 45 minutes ago
COVID-19 Latest: Researchers from
Korea Advanced Institute of Science and Technology (KAIST), by detail analysis of the airway cell transcriptome
have identified an activated immune axis that could pinpoint the
COVID-19
patients who will most benefit from targeted therapies.
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The study team re-analyzed published scRNA-seq data of COVID-19 patient bronchoalveolar lavage fluid to further classify and compare immunological features according to the patient’s disease severity. Patients with severe symptoms typically showed DNA damage and apoptotic features of epithelial cells.
The research findings suggested that epithelial damage was associated with neutrophil infiltration. Myeloid cells of severe patients showed higher expression of proinflammatory cytokines and chemokines such as CXCL8. As a result, neutrophils were abundant in lungs of patients from the severe group. Furthermore, recruited neutrophils highly expressed genes related to neutrophil extracellular traps. Neutrophil-mediated inflammation was regulated by glucocorticoid receptor expression and activity.
Based on these study results, the researchers suggested that severe COVID-19 symptoms may be determined by differential expression of glucocorticoid receptors and neutrophils.
The study results are published in the peer-reviewed journal:
Frontiers in Immunology.
https://www.frontiersin.org/articles/10.3389/fimmu.2020.02145/full
The study team says that these identified key markers that could help pinpoint patients who are bound to get a severe reaction to COVID-19 infection. This would help doctors provide the right treatments at the right time, potentially saving lives.
Each individual’s immune systems react differently to infection with
SARS-CoV-2, the virus that causes COVID-19, ranging from mild to severe, life-threatening responses.
In order to understand the differences in responses, Professor Dr Heung Kyu Lee and PhD candidate Dr Jang Hyun Park from the Graduate School of Medical Science and Engineering at KAIST analyzed ribonucleic
acid (
RNA) sequencing data extracted from individual airway cells of healthy controls and of mildly and severely ill patients with COVID-19. The data was available in a public database previously published by a group of Chinese researchers.
Dr Lee explained to Thailand Medical News, “Our analyses identified an association between immune cells called neutrophils and special cell receptors that bind to the steroid hormone glucocorticoid. This finding could be used as a biomarker for predicting disease severity in patients and thus selecting a targeted therapy that can help treat them at an appropriate time.”
It was observed in the study that severe illness in COVID-19 is associated with an exaggerated immune response that leads to excessive airway-damaging inflammation.
This chronic condition, known as
acute respiratory distress syndrome (ARDS), accounts for 70% of deaths in fatal COVID-19 infections.
Researchers already know that this excessive inflammation involves heightened neutrophil recruitment to the airways, but the detailed mechanisms of this reaction are still unclear.
The study team’s analyses found that a group of immune cells called myeloid cells produced excess amounts of neutrophil-recruiting chemicals in severely ill patients, including a cytokine called tumour necrosis factor (TNF) and a chemokine called CXCL8.
Subsequent detailed RNA analyses of neutrophils in severely ill patients showed they were less able to recruit very important T cells needed for attacking the virus.
Also at the same time, the neutrophils produced too many extracellular molecules that normally trap pathogens, but damage airway cells when produced in excess.
The study team additionally found that the airway cells in severely ill patients were not expressing enough glucocorticoid receptors. This was correlated with increased CXCL8 expression and neutrophil recruitment.
The team said that glucocorticoids, like the well-known drug dexamethasone, are anti-inflammatory agents that could play a role in treating COVID-19.
The team warned however that using them in early or mild forms of the infection could suppress the necessary immune reactions to combat the virus.
Also it should be noted that if airway damage has already happened in more severe cases, glucocorticoid treatment would be ineffective.
The team said that it was important to know who to give this treatment to and when is really important.
They said that COVID-19 patients showing reduced glucocorticoid receptor expression, increased CXCL8 expression, and excess neutrophil recruitment to the airways could benefit from treatment with glucocorticoids to prevent airway damage.
However further research is warranted to confirm the relationship between glucocorticoids and neutrophil inflammation at the protein level.
Professor Lee said. “Our research could serve as a springboard towards more accurate and reliable COVID-19 treatments.”
Importantly the study findings should be confirmed at the protein level and the detailed mechanism regulating neutrophils should be further studied. For example, although IL-17A is an important cytokine in neutrophil-mediated immune responses, the study results showed that IL-17A expression was not detectable.
The team also suggests that IL-8 blockade might be more effective than glucocorticoid treatment, which may be too broad in its targeting, and the efficacy of anti-IL-8 on SARS-CoV-2 is currently being tested in an ongoing phase 2 clinical trial (NCT04347226). Although the finding that glucocorticoids may be related with neutrophilic inflammation is novel, it should be confirmed at the protein level in future studies.
The team also points out that obesity has been recently shown to be a risk factor for COVID-19 and also a risk factor for influenza infection, and correlates with metabolic and respiratory dysfunction, as well as immune response dysfunction. Obesity can cause abnormalities of CD8 T cells, regulatory T cells, and lymphatic vessels. Thus, an abnormal immune system could be a mechanism of obesity-mediated COVID-19 disease severity.
A past study reported obesity-induced downregulation of GR in Kupffer cells. Reduction of GRs causes liver inflammation. Because the study results showed that GR expression negatively correlated with neutrophil recruitment, the reason that GR expression was differentially regulated is important. According to past results and the results of this study, metabolic stress could be a cause of reduced GR expression. Hence the team hypothesize that metabolic disorders such as obesity regulate GR expression and cause the neutrophil-mediated severe symptoms of COVID-19. This hypothesis should be confirmed by further study.
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