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Dual inhibition of complement C5 and CD14 attenuates inflammation in a cord blood model

Pediatric Research volume 94, pages 512–519 (2023)Cite this article

Abstract

Background

Escherichia coli and Group B streptococci (GBS) are the main causes of neonatal early-onset sepsis (EOS). Despite antibiotic therapy, EOS is associated with high morbidity and mortality. Dual inhibition of complement C5 and the Toll-like receptor co-factor CD14 has in animal studies been a promising novel therapy for sepsis.

Methods

Whole blood was collected from the umbilical cord after caesarean section (n = 30). Blood was anti-coagulated with lepirudin. C5 inhibitor (eculizumab) and anti-CD14 was added 8 min prior to, or 15 and 30 min after adding E. coli or GBS. Total bacterial incubation time was 120 min (n = 16) and 240 min (n = 14). Cytokines and the terminal complement complex (TCC) were measured using multiplex technology and ELISA.

Results

Dual inhibition significantly attenuated TCC formation by 25-79% when adding inhibitors with up to 30 min delay in both E. coli- and GBS-induced inflammation. TNF, IL-6 and IL-8 plasma concentration were significantly reduced by 28–87% in E. coli-induced inflammation when adding inhibitors with up to 30 min delay. The dual inhibition did not significantly reduce TNF, IL-6 and IL-8 plasma concentration in GBS-induced inflammation.

Conclusion

Dual inhibition of C5 and CD14 holds promise as a potential future treatment for severe neonatal EOS.

Impact

  • Neonatal sepsis can cause severe host inflammation with high morbidity and mortality, but there are still no effective adjunctive immunologic interventions available.

  • Adding CD14 and complement C5 inhibitors up to 30 min after incubation of E. coli or Group B streptococci in a human umbilical cord blood model significantly reduced complement activation and cytokine release.

  • Dual inhibition of C5 and CD14 is a potential future therapy to modulate systemic inflammation in severe cases of neonatal sepsis.

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Fig. 1: Graphical abstract: cartoon of the dual inhibition of complement C5 and the TLR CD14 co-receptor.
Fig. 2
Fig. 3: TCC cord plasma concentrations after 120 min incubation time.
Fig. 4: TCC cord plasma concentrations after 240 min incubation time.
Fig. 5: Cytokine cord plasma concentrations after 120 min incubation time.

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Data availability

The data sets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank all participating mothers for their contributions to this study and the personnel at the Department of Obstetrics at University Hospital of North Norway for important collaboration and help to organise the study.

Funding

The first author was funded by UiT-The Arctic University of Norway as a medical research student.

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Authors and Affiliations

  1. Paediatric Research Group, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway

    Aline U. Bjerkhaug, Hildegunn N. Granslo, Jorunn Pauline Cavanagh, Ina Høiland & Claus Klingenberg

  2. Department of Paediatrics and Adolescence Medicine, University Hospital of North Norway, Tromsø, Norway

    Hildegunn N. Granslo & Claus Klingenberg

  3. Research Laboratory, Nordland Hospital, Bodø, and K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway

    Judith Krey Ludviksen, Corinna Lau & Tom Eirik Mollnes

  4. Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway

    Terje Espevik & Tom Eirik Mollnes

  5. Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway

    Tom Eirik Mollnes

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  1. Aline U. Bjerkhaug
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Contributions

Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data: A.U.B., H.N.G., J.P.C., I.H., J.K.L., C.L., T.E., T.E.M., C.K. Drafting the article: A.U.B. and C.K. Critically revised the manuscript and approved the final version to be published: all authors.

Corresponding author

Correspondence to Aline U. Bjerkhaug.

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The authors declare no competing interests.

Ethics approval and consent to participate

The study was approved by the Regional Ethical Committee (2019/834/REK nord). All participating women gave informed written consent to participate in the study. All participants signed a written consent.

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Bjerkhaug, A.U., Granslo, H.N., Cavanagh, J.P. et al. Dual inhibition of complement C5 and CD14 attenuates inflammation in a cord blood model. Pediatr Res 94, 512–519 (2023). https://doi.org/10.1038/s41390-023-02489-2

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