C3 complement inhibition by Sicpin, a salivary protein from Simulium nigrimanum 2328025

Abstract

Complement inhibition is a key strategy used by many blood-feeding arthropods to ensure successful feeding. Mosquitoes, ticks, sand flies, and other hematophagous species secrete salivary proteins that block different steps of the complement cascade. These inhibitors prevent complement-mediated lysis and inflammation at the feeding site, allowing the arthropod to feed efficiently while also creating a more permissive environment for pathogen transmission Here, we characterize the anti-complement activity of Sicpin, a salivary protein from the blackfly Simulium nigrimanum. Sicpin was found to inhibit all three pathways of complement activation. Surface plasmon resonance analysis revealed a strong and specific interaction with C3, with no detectable binding to other complement components common to the pathways. The binding induces a conformational change in C3 that blocks the interaction with the C3 convertase, consequently inhibiting the deposition of downstream complement proteins. Additionally, in both acute lung injury and sepsis models, Sicpin enhances survival and exhibits anti-inflammatory activity. These findings support that Sicpin modulates the complement system, with potential implications for pathogen transmission, blood feeding, and therapeutic development NIH Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)