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Single-Cell COVID-19 Study Suggests Chemokine Receptor Inhibition Could Quell Immune Hyperactivation

NEW YORK – Drugs targeting chemokine receptors may be able to subdue the hyperactive immune response observed in critical COVID-19 patients, according to a new single-cell analysis of airway samples obtained from patients.

A team of researchers in Germany performed single-cell RNA sequencing of nasopharyngeal and bronchial samples isolated from 19 COVID-19 patients with either moderate or critical disease. While more than three-quarters of COVID-19 patients exhibit mild, moderate, or no symptoms of disease, 14 percent experience severe symptoms and 5 percent have critical disease.

By comparing samples from patients and healthy controls, the researchers uncovered increased expression of ACE2, the receptor the virus uses for entry into the cell, among COVID-19 patients. Additionally, as they reported Friday in Nature Biotechnology, the researchers noted stronger interactions between epithelial and immune cells among severely ill COVID-19 patients, as compared to those with more moderate disease. In particular, they noted increased expression of chemokine- and cytokine-encoding genes.

"Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19," senior author Roland Eils from Charité - Universitätsmedizin Berlin and his colleagues wrote in their paper.

The researchers performed 3' scRNA-seq on nasopharyngeal or bronchial samples collected from 19 COVID-19 patients at either Charité - Universitätsmedizin Berlin or University Hospital Leipzig. Eight patients had moderate disease and 11 critical disease, two of whom died. They also collected samples from five individuals who tested negative for COVID-19.

In all, they generated transcriptional profiles for more than 160,000 cells.

Epithelial cells from COVID-19 patients, the researchers found, had a threefold increase in expression of ACE2, the gene that encodes the receptor protein SARS-CoV-2 uses for entry, as compared to controls. The researchers also noted a correlation between ACE2 upregulation and interferon signals in immune cells.

Additionally, infected epithelial cells secrete chemokines to recruit and activate immune cells, and patients with moderate COVID-19 had increased expression of CXCL1, CXCL3, CXCL6, CXCL16, and CXCL17, as compared to controls. The expression of these chemokine-encoding genes likely helps recruit neutrophils, T cells, and mast cells, the researchers noted.

Patients with more severe disease, meanwhile, had even higher chemokine and chemokine receptor expression, as compared to the moderate cases, indicating even higher recruitment of immune cells to inflammation sites among these patients.

Additionally, the researchers reported increased epithelial-immune cell interactions among critical COVID-19 patients. In particular, non-resident macrophages had a highly inflammatory profile marked by increased expression of the chemokine genes CCL2, CCL3, CCL20, CXCL1, and CXCL3 and the proinflammatory cytokines IL1B, IL8, IL18, and TNF. This, the researchers noted, might contribute to the excessive inflammation observed in severe COVID-19 patients. 

Chemokine receptors like CCR1 and CCR5 could represent anti-inflammatory targets for severe COVID-19, they wrote. 

The study, though, was limited by its inability to include patients with mild disease, as they did not need hospitalization. Also, the patient population on which they drew was small, which limited the researchers' ability to stratify patients by age, gender, and co-morbidities.

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