Alternative Complement Pathway Inhibition Abrogates Pneumococcal Opsonophagocytosis in Vaccine-Naïve, but Not in Vaccinated Individuals

Frontiers in Immunology

Thomas Holbro²  Christine Thorburn³  Michael Kammüller⁴  Natasa Zamurovic⁴  Anna Schubart⁴  Gerd Pluschke⁵  Lukas Muri⁵  Emma Ispasanie⁵ 

[1] Molecular Immunology Unit, Swiss Tropical and Public Health Institute, Basel, Switzerland;Novartis Pharma AG, Global Drug Development, Basel, Switzerland;Novartis Pharma AG, Global Drug Development, London, United Kingdom;Translational Medicine-Preclinical Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland;University of Basel, Basel, Switzerland;

关键词: complement system;    Streptococcus pneumoniae;    opsonophagocytosis;    alternative pathway inhibitor;    microbial immunology;    innate immunity;   

DOI  :  10.3389/fimmu.2021.732146

来源: DOAJ

【 摘 要 】

To assess the relative contribution of opsonisation by antibodies, classical and alternative complement pathways to pneumococcal phagocytosis, we analyzed killing of pneumococci by human blood leukocytes collected from vaccine-naïve and PCV13-vaccinated subjects. With serotype 4 pneumococci as model, two different physiologic opsonophagocytosis assays based on either hirudin-anticoagulated whole blood or on washed cells from EDTA-anticoagulated blood reconstituted with active serum, were compared. Pneumococcal killing was measured in the presence of inhibitors targeting the complement components C3, C5, MASP-2, factor B or factor D. The two assay formats yielded highly consistent and comparable results. They highlighted the importance of alternative complement pathway activation for efficient opsonophagocytic killing in blood of vaccine-naïve subjects. In contrast, alternative complement pathway inhibition did not affect pneumococcal killing in PCV13-vaccinated individuals. Independent of amplification by the alternative pathway, even low capsule-specific antibody concentrations were sufficient to efficiently trigger classical pathway mediated opsonophagocytosis. In heat-inactivated or C3-inhibited serum, high concentrations of capsule-specific antibodies were required to trigger complement-independent opsonophagocytosis. Our findings suggest that treatment with alternative complement pathway inhibitors will increase susceptibility for invasive pneumococcal infection in non-immune subjects, but it will not impede pneumococcal clearance in vaccinated individuals.

【 授权许可】

Unknown