A promising strategy for treating inflammation during severe COVID-19

A new analysis of the lung epithelial cells of patients with COVID-19 reveals how a branch of the protective complement of the immune system, which usually plays a role in both innate and adaptive immunity, can turn into a harmful system during COVID-19.

Blocking excessive complement activity in lung epithelial cells by a combination of existing chemotherapy and antiviral drugs – ruxolitinib and remdesivir – helped normalize complement protein production to infected lung epithelial cells in human cell culture experiments, the researchers found. Therefore, the drug duo could serve as a promising strategy for treating harmful inflammation during severe COVID-19, the authors say.

Excessive activation of complement proteins may contribute to diseases such as acute respiratory distress syndrome, and a growing body of evidence suggests that excessive complement responses also correlate with disease severity in patients with severe COVID-19. However, it remains unclear what this normally protective system reconnects to dangerous during severe COVID-19.

To investigate this issue, Bingyu Yan and colleagues analyzed data on RNA sequencing in mass and single-cell blood from lung tissue and COVID-19 patients and compared them with those from healthy controls. In patients with COVID-19, the complement system was one of the most indicated pathways in SARS-CoV-2-infected lung epithelial cells, as indicated by the high expression of genes that control the expression and activation of complement C3 proteins.

Further analyzes showed that the inflammatory pathway IFN-JAK1 / 2-STAT1 and the transcription factor NF-κB were largely involved in the transcription of the complement gene in infected lung epithelial cells. Blocking these pathways using a chemotherapeutic drug against cancer, ruxolitinib, helped normalize the expression of complement-controlling and IFN genes in human lung epithelial cell lines.

The combination of ruxolitinib and the antiviral drug remdesivir further blocked NF-κB activity, inhibiting excessive C3a production by infected cells, and further normalizing transcription and production of complement protein fragments. This enhanced understanding of the contribution of the COVID-19 complement system could trigger the discovery of much-needed treatments, the authors say.

Source:

American Association for the Advancement of Science

Journal reference:

Yan, B., and others. (2021) SARS-CoV-2 initiates JAK1 / 2-dependent local complement hyperactivation. Scientific immunology. doi.org/10.1126/sciimmunol.abg0833.

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