The Streptococcus agalactiae complement interfering protein combines multiple complement-inhibitory mechanisms by interacting with both C4 and C3 ligands

Group B Streptococcus (GBS) colonizes thehumanlower intestinal andgenital tracts andconstitutes amajor threat to neonates from pregnant carrier mothers and to adults with underlying morbidity. The pathogen expresses cell-surface virulence factors that enable cell adhesion and penetration and that counteract innate and adaptive immune responses. Among these, the complement interfering protein (CIP)was recently described for its capacity to interact with thehuman C4bligand andto interferewiththe classical- and lectin-complement pathways. Inthe present study, we provide evidence that CIP can also interact with C3, C3b, and C3d. Immunoassay-based competition experiments showed that binding of CIP to C3d interferes with the interaction between C3d and the complement receptor 2/cluster of differentiation 21 (CR2/CD21) receptor on Bcells.ByB-cell intracellular signaling assays,CIP was confirmed to down-regulate CR2/CD21-dependent B-cell activation. The CIP domain involved in C3d bindingwas mapped via hydrogen deuterium exchange-mass spectrometry. The data obtained reveal a new role for this GBS polypeptide at theinterfacebetween the innateandadaptive immuneresponses, adding anewmemberto the growing list of virulence factors secreted by gram-positive pathogens that incorporate multiple immunomodulatory functions.-Giussani, S., Pietrocola, G., Donnarumma, D., Norais, N., Speziale, P., Fabbrini, M., Margarit, I. The Streptococcus agalactiae complement interfering protein combines multiple complement-inhibitory mechanisms by interacting with both C4 and C3 ligands. FASEB J. 33, 000-000 (2019). www.fasebj.org.