Structure and function of a family of tick-derived complement inhibitors targeting properdin

Abstract

Activation of the serum-resident complement system begins a cascade that leads to activation of membrane-resident complement receptors on immune cells, thus coordinating serum and cellular immune responses. Whilst many molecules act to control inappropriate activation, Properdin is the only known positive regulator of the human complement system. By stabilising the alternative pathway C3 convertase it promotes complement self-amplification and persistent activation boosting the magnitude of the serum complement response by all triggers. In this work, we identify a family of tick-derived alternative pathway complement inhibitors, hereafter termed CirpA. Functional and structural characterisation reveals that members of the CirpA family directly bind to properdin, inhibiting its ability to promote complement activation, and leading to potent inhibition of the complement response in a species specific manner. We provide a full functional and structural characterisation of a properdin inhibitor, opening avenues for future therapeutic approaches.

The tick and I: Parasite‐host interactions between ticks and humans

“…alternative complement activation pathway. The activity profiles of several CirpA homologs are species-dependent [124]; this notion is also likely to be relevant for potential therapeutic developments. Platelet aggregation and fibrinogen binding to platelets, for example, are inhibited by ixodegrins in tick saliva.…”

“…The therapeutic potential is further extended by the recent description of another lipocalin family of properdin inhibitors from the saliva of Rhipicephalus pulchellus (CirpA; Complement inhibitor from Rhipicephalus pulchellus of the alternative pathway) [124]. Properdin is the only known activator of the alternative pathway of the complement system.…”

“…CirpA1 binds to human properdin, thus inhibiting the alternative complement activation pathway. The activity profiles of several CirpA homologs are species‐dependent [124]; this notion is also likely to be relevant for potential therapeutic developments.…”

Die Zecke und ich: Parasiten‐Wirt‐Interaktionen zwischen Zecken und Menschen

“…Das therapeutische Potenzial wird möglicherweise durch die neueste Beschreibung einer weiteren Lipocalin‐Familie von Properdin‐Inhibitoren aus dem Speichel von Rhipicephalus pulchellus noch erweitert (CirpA; complement inhibitor from Rhipicephalus pulchellus of the alternative pathway ) [124]. Properdin ist der einzige bekannte Aktivator des alternativen Weges des Komplementsystems.…”

“…CirpA1 bindet an menschliches Properdin und hemmt so den alternativen Komplement-Aktivierungsweg. Die Aktivitätsprofile mehrerer CirpA-Homologe sind speziesabhängig [124]; dies dürfte auch für mögliche therapeutische Entwicklungen relevant sein.…”