A new analysis of lung epithelial cells from COVID-19 patients reveals how the protective complement branch of the immune system, which usually plays roles in both innate and adaptive immunity, can convert to a harmful system during COVID-19. Blocking excessive complement activity in lung epithelial cells with a combination of existing chemotherapy and antiviral medications - ruxolitinib and remdesivir, respectively - helped normalize the production of complement proteins by infected lung epithelial cells in human cell culture experiments, the researchers found.

Thus, the drug duo could serve as a promising strategy to treat damaging inflammation during severe COVID-19, the authors say.

Overactivation of complement proteins can contribute to diseases such as acute respiratory distress syndrome, and increasing evidence suggests that excessive complement responses also correlate with disease severity in patients with severe COVID-19. However, it remains unclear what rewires this normally protective system into a dangerous one during severe COVID-19.

To dig into this question, the authors analyzed bulk and single cell RNA-sequencing data from blood and lung tissues of patients with COVID-19 and compared them with those from healthy controls. In COVID-19 patients, the complement system was one of the most highly induced pathways in lung epithelial cells infected by SARS-CoV-2, as indicated by the high expression of genes that control expression and activation of complement protein C3.

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

Combining ruxolitinib with the antiviral drug remdesivir additionally blocked NF-κB activity, inhibiting overproduction of C3a by infected cells and further normalizing the transcription and production of complement protein fragments.

This heightened understanding of the complement system's contribution to COVID-19 could drive the discovery of much-needed treatments, the authors say.

https://immunology.sciencemag.org/content/6/58/eabg0833

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