Trypanosoma cruzi Evades the Complement System as an Efficient Strategy to Survive in the Mammalian Host: The Specific Roles of Host/Parasite Molecules and Trypanosoma cruzi Calreticulin.

Galia Ramírez-Toloza,Arturo Ferreira

doi:10.3389/fmicb.2017.01667

Abstract

American Trypanosomiasis is an important neglected reemerging tropical parasitism, infecting about 8 million people worldwide. Its agent, Trypanosoma cruzi, exhibits multiple mechanisms to evade the host immune response and infect host cells. An important immune evasion strategy of T. cruzi infective stages is its capacity to inhibit the complement system activation on the parasite surface, avoiding opsonizing, immune stimulating and lytic effects. Epimastigotes, the non-infective form of the parasite, present in triatomine arthropod vectors, are highly susceptible to complement-mediated lysis while trypomastigotes, the infective form, present in host bloodstream, are resistant. Thus T. cruzi susceptibility to complement varies depending on the parasite stage (amastigote, trypomastigotes or epimastigote) and on the T. cruzi strain. To avoid complement-mediated lysis, T. cruzi trypomastigotes express on the parasite surface a variety of complement regulatory proteins, such as glycoprotein 58/68 (gp58/68), T. cruzi complement regulatory protein (TcCRP), trypomastigote decay-accelerating factor (T-DAF), C2 receptor inhibitor trispanning (CRIT) and T. cruzi calreticulin (TcCRT). Alternatively, or concomitantly, the parasite captures components with complement regulatory activity from the host bloodstream, such as factor H (FH) and plasma membrane-derived vesicles (PMVs). All these proteins inhibit different steps of the classical (CP), alternative (AP) or lectin pathways (LP). Thus, TcCRP inhibits the CP C3 convertase assembling, gp58/68 inhibits the AP C3 convertase, T-DAF interferes with the CP and AP convertases assembling, TcCRT inhibits the CP and LP, CRIT confers ability to resist the CP and LP, FH is used by trypomastigotes to inhibit the AP convertases and PMVs inhibit the CP and LP C3 convertases. Many of these proteins have similar molecular inhibitory mechanisms. Our laboratory has contributed to elucidate the role of TcCRT in the host-parasite interplay. Thus, we have proposed that TcCRT is a pleiotropic molecule, present not only in the parasite endoplasmic reticulum, but also on the trypomastigote surface, participating in key processes to establish T. cruzi infection, such as inhibition of the complement system and serving as an important virulence factor. Additionally, TcCRT interaction with key complement components, participates as an anti-angiogenic and anti-tumor molecule, inhibiting at least in important part, tumor growth in infected animals.

Highlights

Chagas’ disease or American Trypanosomiasis represents a serious burden for millions of people worldwide
These infective forms express on their surfaces different complement regulatory proteins or capture them from the host plasma to inhibit the complement system
Other components inactivate the catalytic activity of C3 convertase (PMV), or bind and inactivate specific complement components (TcCRT and C2 Receptor Inhibitor Trispanning Protein (CRIT))

Summary

INTRODUCTION

Chagas’ disease or American Trypanosomiasis represents a serious burden for millions of people worldwide. Trypanosoma cruzi, the etiological agent of Chagas disease, exhibits a variety of mechanisms to evade the host immune response These mechanisms enable the parasite to establish an infection and persist in the host, determining a chronic stage (Freire-de-Lima et al, 2016). T. cruzi metacyclic trypomastigotes, one of the infective forms of the parasite, are released in the feces or urine of triatomines after a blood meal These infective forms encounter mucosa or discontinuous regions of the epithelium, infecting mammalian host cells (Cardoso et al, 2015). The administration of normal chicken serum to T. cruzi infected mice generates a marked decrease in their parasitemias (Kierszenbaum et al, 1976) These results indicate that, in addition to the maturation of the immune response, the avian serum and its complement system destroy the parasite.

COMPLEMENT SYSTEM REGULATION IN PATHOGEN RESISTANCE TO COMPLEMENT

TcCRT Interactions with the Complement System Mediate Tumor Growth Inhibition

Findings

CONCLUSION