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A complement atlas identifies interleukin-6-dependent alternative pathway dysregulation as a key druggable feature of

Karel F A Van Damme1,2,3, Levi Hoste1,4, Jozefien Declercq1,2,3

  • 1Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.

Science Translational Medicine
|August 23, 2023
PubMed

Insights

COVID-19 complement system dysregulation, primarily via the alternative pathway, drives tissue injury. Targeting complement C5 may reduce disease severity and epithelial damage in severe cases.

Area of Science:

  • Immunology
  • Pathology
  • Genomics

Background:

  • The complement system, vital for innate immunity, can exacerbate tissue injury in severe diseases.
  • Understanding complement's role in COVID-19 pathogenesis, particularly in critically ill patients, is crucial for treatment development.

Purpose of the Study:

  • To elucidate the specific complement pathways and cellular sources driving COVID-19 pathology.
  • To identify upstream regulators of complement activation and assess the therapeutic potential of complement inhibition.

Main Methods:

  • Proteomic and single-cell sequencing analyses of patient tissues.
  • Mapping complement alterations during respiratory deterioration.
  • Investigating the role of IL-6 and STAT signaling in complement responses.
  • Exploratory proteomic study on complement C5 inhibition.

Main Results:

  • Complement activation in COVID-19 is predominantly mediated by the alternative pathway.
  • A detailed atlas of complement alterations and cellular production (lung cells, liver) was generated.
  • Interleukin-6 (IL-6) and STAT1/3 signaling were identified as upstream drivers of complement dysregulation.
  • Complement C5 inhibition showed potential in reducing epithelial damage and disease severity markers.

Conclusions:

  • Complement dysregulation is a central mechanism in COVID-19-induced tissue injury.
  • The identified upstream drivers link complement activation to existing COVID-19 therapies.
  • Complement C5 represents a promising therapeutic target for severe COVID-19.

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