Abstract
Background9 million people are infected with Trypanosoma cruzi in Latin America, plus more than 300,000 in the United States, Canada, Europe, Australia, and Japan. Approximately 30% of infected individuals develop circulatory or digestive pathology. While in underdeveloped countries transmission is mainly through hematophagous arthropods, transplacental infection prevails in developed ones.Methodology/Principal FindingsDuring infection, T. cruzi calreticulin (TcCRT) translocates from the endoplasmic reticulum to the area of flagellum emergence. There, TcCRT acts as virulence factor since it binds maternal classical complement component C1q that recognizes human calreticulin (HuCRT) in placenta, with increased parasite infectivity. As measured ex vivo by quantitative PCR in human placenta chorionic villi explants (HPCVE) (the closest available correlate of human congenital T. cruzi infection), C1q mediated up to a 3–5-fold increase in parasite load. Because anti-TcCRT and anti-HuCRT F(ab′)2 antibody fragments are devoid of their Fc-dependent capacity to recruit C1q, they reverted the C1q-mediated increase in parasite load by respectively preventing its interaction with cell-bound CRTs from both parasite and HPCVE origins. The use of competing fluid-phase recombinant HuCRT and F(ab′)2 antibody fragments anti-TcCRT corroborated this. These results are consistent with a high expression of fetal CRT on placental free chorionic villi. Increased C1q-mediated infection is paralleled by placental tissue damage, as evidenced by histopathology, a damage that is ameliorated by anti-TcCRT F(ab′)2 antibody fragments or fluid-phase HuCRT.Conclusions/Significance T. cruzi infection of HPCVE is importantly mediated by human and parasite CRTs and C1q. Most likely, C1q bridges CRT on the parasite surface with its receptor orthologue on human placental cells, thus facilitating the first encounter between the parasite and the fetal derived placental tissue. The results presented here have several potential translational medicine aspects, specifically related with the capacity of antibody fragments to inhibit the C1q/CRT interactions and thus T. cruzi infectivity.
Highlights
Trypanosoma cruzi is the protozoan that causes Chagas’ disease [1], an acute and chronic illness affecting 9 million people in Latin America [2] and causing 50,000 deaths per year [3,4,5]
We have previously shown that T. cruzi induces ST destruction and detachment in human placenta chorionic villi explants (HPCVE), together with selective disorganization of the basal lamina and of collagen I in the connective tissue of the villous stroma [34], as well as apoptosis [35,36]
In order to determine the roles of T. cruzi calreticulin (TcCRT), fetal human calreticulin (HuCRT) and maternal C1q, in T. cruzi infectivity in HPCVE, the explants were co-cultured with combinations of the following reagents: i)
Summary
Trypanosoma cruzi is the protozoan that causes Chagas’ disease [1], an acute and chronic illness affecting 9 million people in Latin America [2] and causing 50,000 deaths per year [3,4,5]. In the United States, more than 300,000 cases have been reported [4,6] It is one of the most important neglected parasitic diseases in the Americas and no safe treatment is available [6]. One third of those infected develops incapacitating circulatory or digestive pathology [4]. Pharmacological treatment of the infection, effective in some cases, is complicated by the toxicity of the main drugs used (Nifurtimox and Benznidazole) [4,7]. 9 million people are infected with Trypanosoma cruzi in Latin America, plus more than 300,000 in the United States, Canada, Europe, Australia, and Japan. While in underdeveloped countries transmission is mainly through hematophagous arthropods, transplacental infection prevails in developed ones
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