The Immunomodulatory Effect of IrSPI, a Tick Salivary Gland Serine Protease Inhibitor Involved in Ixodes ricinus Tick Feeding.

Adrien Blisnick,Ladislav Šimo,Catherine Grillon,Sandra Blaise-Boisseau,Jennifer Richardson,Sébastien Brûlé,Anthony Relmy,Maud Marsot,Sarah Bonnet,Eric Prina,Fabienne Fasani,Bernard Le Bonniec

doi:10.3390/vaccines7040148

Abstract

Ticks are the most important vectors of pathogens affecting both domestic and wild animals worldwide. Hard tick feeding is a slow process—taking up to several days—and necessitates extended control over the host response. The success of the feeding process depends upon injection of tick saliva, which not only controls host hemostasis and wound healing, but also subverts the host immune response to avoid tick rejection that creates a favorable niche for the survival and propagation of diverse tick-borne pathogens. Here, we report on the molecular and biochemical features and functions of an Ixodes ricinus serine protease inhibitor (IrSPI). We characterize IrSPI as a Kunitz elastase inhibitor that is overexpressed in several tick organs—especially salivary glands—during blood-feeding. We also demonstrated that when IrSPI is injected into the host through saliva, it had no impact on tissue factor pathway-induced coagulation, fibrinolysis, endothelial cell angiogenesis or apoptosis, but the protein exhibits immunomodulatory activity. In particular, IrSPI represses proliferation of CD4+ T lymphocytes and proinflammatory cytokine secretion from both splenocytes and macrophages. Our study contributes valuable knowledge to tick-host interactions and provides insights that could be further exploited to design anti-tick vaccines targeting this immunomodulator implicated in I. ricinus feeding.

Highlights

Ticks are obligate hematophagous arthropods able to feed on diverse vertebrate hosts including mammals, birds, amphibians, and reptiles
We showed that Ixodes ricinus serine protease inhibitor (IrSPI), though harboring Ala as its P1 residue, does inhibit elastase albeit to a lesser extent than that reported in the literature for other tick kunitz protease inhibitors [35,36]
We have shown that IrSPI mRNA is expressed in type 2 acini, which are responsible for saliva secretion, and using anti-IrSPI antibodies raised in tick-infested rabbits, that native IrSPI protein may be present in tick saliva and injected into the host during feeding

Summary

Introduction

Ticks are obligate hematophagous arthropods able to feed on diverse vertebrate hosts including mammals, birds, amphibians, and reptiles. They cause substantial economic losses in the livestock industry due to blood spoiling and secondary infection of bite wounds, which decrease food production and the value of leather. The hard tick Ixodes ricinus is the most widespread and abundant tick species in Europe, as well as the most efficient transmitter of pathogens that significantly impact both human and animal health [2] This tick species follows a three-host life cycle where each of the three distinct life stages (larvae, nymph and adult) feeds only once on its respective host

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