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Study finds chemokine receptor inhibition can overcome immune hyperactivation in COVID-19 patients

A new single-cell analysis study of airway samples of COVID-19 patients has found that drugs targeting chemokine receptors may be able to subdue the hyperactive immune response in critical patients.

The study was performed by a team of researching using single-cell RNA sequencing of nasopharyngeal and bronchial samples isolated with 19 patients diagnosed with COVID-19 with either moderate or critical disease. They then compared the samples from patients and healthy controls and discovered the increased expression of ACE2. They also noted stronger interactions between epithelial and immune cells among severely ill COVID-19 patients compared with moderate disease – particularly increased expression of chemokine and cytokine-encoding genes.

Senior author Roland Eils and his colleagues wrote that their data “suggests that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19”.

The team performed 3’ scRNA-seq on nasopharyngeal or bronchial samples collected from the patients at either Charité or University Hospital Leipzig. Of the nineteen 19 patients tested, 8 had moderate disease, 11 had critical disease of which, 2 died. They also collected samples from 5 patients who tested negative for the disease. In total, the team generated transcriptional profiles for over 160,000 cells.

The research found that epithelial cells from COVID-19 patients had a three-fold increase in the expression of ACE2, the gene that encodes for the receptor protein that SARS-CoV-2 uses for entry, compared to the controls, and a correlation between the ACE2 regulation upregulation and interferon signals in immune cells.

The infected epithelial cells had increased expression of chemokine-encoding genes compared to controls, but patients with severe disease had an even higher chemokine and chemokine receptor expression. This indicates higher recruitment of immune cells to inflammation sites in more severe disease.

Finally, the researchers found an increased epithelial-immune cell interaction in critically ill patients. In particular, they found that non-resident macrophages had a highly inflammatory profile marked by increased expression of chemokine genes (CCL2, CCL3, CCL20, CXCL1 and CXCL3) and the pro-inflammatory cytokines (IL1B, IL8, IL18 and TNF). The researchers noted that this might contribute to the excessive inflammation observed in the severe cases of COVID-19 and chemokine receptors like CCR1 and CCR5 could represent anti-inflammatory targets for severe COVID-19.

However, the study was limited by its size and the inability to include patients with mild disease who did not require hospitalisation.

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