Calreticulin S-Domain Binds to Human Complement C1q to Interfere With C1q-Mediated Immune Functions.

Helminths develop strategies to escape host immune responses that facilitate their survival in the hostile host immune environment. , a tissue-dwelling nematode, has developed a sophisticated strategy to escape complement attack. Our previous study demonstrated that secretes calreticulin (CRT) to inhibit host classical complement activation through binding to C1q; however, the C1q binding site in CRT and the specific mechanism involved with complement-related immune evasion remains unknown. Using molecular docking modeling and fragment expression, we determined that CRT-S, a 153-aa domain of CRT, is responsible for C1q binding. Recombinant CRT-S protein expressed in had the same capacity to bind and inhibit human C1q-induced complement and neutrophil activation, as full-length CRT. CRT-S inhibited neutrophil reactive oxygen species and elastase release by binding to C1q and reduced neutrophil killing of newborn larvae. Binding of CRT-S to C1q also inhibited formation of neutrophil extracellular traps (NETs), which are involved in autoimmune pathologies and have yet to be therapeutically targeted. These findings provide evidence that the CRT-S fragment, rather than the full-length CRT, is a potential target for vaccine or therapeutic development for trichinellosis, as well as for complement-related autoimmune disease therapies.