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A complement atlas identifies interleukin-6-dependent alternative pathway dysregulation as a key druggable feature of COVID-19

Karel Van Damme (UGent) , Levi Hoste (UGent) , Jozefien Declercq (UGent) , Elisabeth De Leeuw (UGent) , Bastiaan Maes, Liesbet Martens (UGent) , Roos Colman (UGent) , Robin Browaeys (UGent) , Cedric Bosteels (UGent) , Stijn Verwaerde (UGent) , et al.
(2023) SCIENCE TRANSLATIONAL MEDICINE. 15(710).
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Abstract
Improvements in COVID-19 treatments, especially for the critically ill, require deeper understanding of the mechanisms driving disease pathology. The complement system is not only a crucial component of innate host defense but can also contribute to tissue injury. Although all complement pathways have been implicated in COVID-19 pathogenesis, the upstream drivers and downstream effects on tissue injury remain poorly defined. We demonstrate that complement activation is primarily mediated by the alternative pathway, and we provide a comprehensive atlas of the complement alterations around the time of respiratory deterioration. Proteomic and single-cell sequencing mapping across cell types and tissues reveals a division of labor between lung epithelial, stromal, and myeloid cells in complement production, in addition to liver-derived factors. We identify IL-6 and STAT1/3 signaling as an upstream driver of complement responses, linking complement dysregulation to approved COVID-19 therapies. Furthermore, an exploratory proteomic study indicates that inhibition of complement C5 decreases epithelial damage and markers of disease severity. Collectively, these results support complement dysregulation as a key druggable feature of COVID-19.
Keywords
HUMORAL INNATE IMMUNITY, INFLAMMATION, MACROPHAGES, ACTIVATION, SARS-COV-2, CELLS

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Citation

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MLA
Van Damme, Karel, et al. “A Complement Atlas Identifies Interleukin-6-Dependent Alternative Pathway Dysregulation as a Key Druggable Feature of COVID-19.” SCIENCE TRANSLATIONAL MEDICINE, vol. 15, no. 710, 2023, doi:10.1126/scitranslmed.adi0252.
APA
Van Damme, K., Hoste, L., Declercq, J., De Leeuw, E., Maes, B., Martens, L., … Lambrecht, B. (2023). A complement atlas identifies interleukin-6-dependent alternative pathway dysregulation as a key druggable feature of COVID-19. SCIENCE TRANSLATIONAL MEDICINE, 15(710). https://doi.org/10.1126/scitranslmed.adi0252
Chicago author-date
Van Damme, Karel, Levi Hoste, Jozefien Declercq, Elisabeth De Leeuw, Bastiaan Maes, Liesbet Martens, Roos Colman, et al. 2023. “A Complement Atlas Identifies Interleukin-6-Dependent Alternative Pathway Dysregulation as a Key Druggable Feature of COVID-19.” SCIENCE TRANSLATIONAL MEDICINE 15 (710). https://doi.org/10.1126/scitranslmed.adi0252.
Chicago author-date (all authors)
Van Damme, Karel, Levi Hoste, Jozefien Declercq, Elisabeth De Leeuw, Bastiaan Maes, Liesbet Martens, Roos Colman, Robin Browaeys, Cedric Bosteels, Stijn Verwaerde, Nicky Vermeulen, Sahine Lameire, Nincy Debeuf, Julie Deckers, Patrick Stordeur, Pieter Depuydt, Eva Van Braeckel, Linos Vandekerckhove, Martin Guilliams, Sjoerd Schetters, Filomeen Haerynck, Simon Tavernier, and Bart Lambrecht. 2023. “A Complement Atlas Identifies Interleukin-6-Dependent Alternative Pathway Dysregulation as a Key Druggable Feature of COVID-19.” SCIENCE TRANSLATIONAL MEDICINE 15 (710). doi:10.1126/scitranslmed.adi0252.
Vancouver
1.
Van Damme K, Hoste L, Declercq J, De Leeuw E, Maes B, Martens L, et al. A complement atlas identifies interleukin-6-dependent alternative pathway dysregulation as a key druggable feature of COVID-19. SCIENCE TRANSLATIONAL MEDICINE. 2023;15(710).
IEEE
[1]
K. Van Damme et al., “A complement atlas identifies interleukin-6-dependent alternative pathway dysregulation as a key druggable feature of COVID-19,” SCIENCE TRANSLATIONAL MEDICINE, vol. 15, no. 710, 2023.
@article{01HABW8GS55ZEK7G7W42JTN38D,
  abstract     = {{Improvements in COVID-19 treatments, especially for the critically ill, require deeper understanding of the mechanisms driving disease pathology. The complement system is not only a crucial component of innate host defense but can also contribute to tissue injury. Although all complement pathways have been implicated in COVID-19 pathogenesis, the upstream drivers and downstream effects on tissue injury remain poorly defined. We demonstrate that complement activation is primarily mediated by the alternative pathway, and we provide a comprehensive atlas of the complement alterations around the time of respiratory deterioration. Proteomic and single-cell sequencing mapping across cell types and tissues reveals a division of labor between lung epithelial, stromal, and myeloid cells in complement production, in addition to liver-derived factors. We identify IL-6 and STAT1/3 signaling as an upstream driver of complement responses, linking complement dysregulation to approved COVID-19 therapies. Furthermore, an exploratory proteomic study indicates that inhibition of complement C5 decreases epithelial damage and markers of disease severity. Collectively, these results support complement dysregulation as a key druggable feature of COVID-19.}},
  articleno    = {{eadi0252}},
  author       = {{Van Damme, Karel and Hoste, Levi and Declercq, Jozefien and De Leeuw, Elisabeth and Maes, Bastiaan and Martens, Liesbet and Colman, Roos and Browaeys, Robin and Bosteels, Cedric and Verwaerde, Stijn and Vermeulen, Nicky and Lameire, Sahine and Debeuf, Nincy and Deckers, Julie and Stordeur, Patrick and Depuydt, Pieter and Van Braeckel, Eva and Vandekerckhove, Linos and Guilliams, Martin and Schetters, Sjoerd and Haerynck, Filomeen and Tavernier, Simon and Lambrecht, Bart}},
  issn         = {{1946-6234}},
  journal      = {{SCIENCE TRANSLATIONAL MEDICINE}},
  keywords     = {{HUMORAL INNATE IMMUNITY,INFLAMMATION,MACROPHAGES,ACTIVATION,SARS-COV-2,CELLS}},
  language     = {{eng}},
  number       = {{710}},
  pages        = {{19}},
  title        = {{A complement atlas identifies interleukin-6-dependent alternative pathway dysregulation as a key druggable feature of COVID-19}},
  url          = {{http://doi.org/10.1126/scitranslmed.adi0252}},
  volume       = {{15}},
  year         = {{2023}},
}
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