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

Abstract

Group B Streptococcus (GBS) colonizes the human lower intestinal and genital tracts and constitutes a major 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 the human C4b ligand and to interfere with the classical- and lectin-complement pathways. In the 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 B cells. By B-cell intracellular signaling assays, CIP was confirmed to down-regulate CR2/CD21-dependent B-cell activation. The CIP domain involved in C3d binding was mapped via hydrogen deuterium exchange–mass spectrometry. The data obtained reveal a new role for this GBS polypeptide at the interface between the innate and adaptive immune responses, adding a new member to 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.

Complement C4, Infections, and Autoimmune Diseases

“…Complement interfering protein (CIP) expressed on the surface of group B. Streptococcus (GBS) enables cell adhesion and penetration and impedes innate and adaptive immune responses. It was found that CIP was able to interact with the human C4b ligand and to interfere with the classical-and lectincomplement pathways (83). Clinical Staphylococcus aureus (S. aureus) strains can recruit complement regulator C4-binding protein (C4BP) to S. aureus surface to inhibit C4 complement effectors through binding significant amounts of the C4BP from serum.…”

Serious Bacterial Infections Associated with Eculizumab: A Pharmacovigilance Study

“…Streptococcal toxic shock syndrome is the most serious of these diseases and requires prompt treatment. Since S. agalactiae is also a capsular-bearing bacterium, we hypothesized that the mechanism of streptococcal toxic shock syndrome might involve inhibition of the C5 protein induced by eculizumab (16), although no streptococcal infections have been reported in phase III trials or post-market surveillance in Japan (13). Eculizumab inhibits membrane attack complex formation and may accelerate the growth of S. agalactiae.…”

Simultaneous Presentation of B-Acute Lymphoblastic Leukemia and Streptococcus agalactiae Meningitis in a 3-Year-old Girl

“…Complement and anti-GBS polysaccharide capsular antibodies are felt to be essential in host defense against invasive GBS disease, and both processes may be impaired in patients with ALL. [16][17][18] Determining the appropriate initial anti-neoplastic therapy posed a significant challenge in this case. Infection is a major cause of treatment-related mortality in pediatric ALL.…”