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

Abstract

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

Keywords: Trichinella spiralis; binding site; calreticulin S-domain; classical complement activation; complement C1q; immune evasion; neutrophil; neutrophil extracellular traps.