Articulo
The Interaction of Classical Complement Component C1 with Parasite and Host Calreticulin Mediates Trypanosoma cruzi Infection of Human Placenta
Plos Neglected Tropical Diseases
Registro en:
1130099
1130099
Autor
Castillo, Christian
Ramírez, Galia
Valck, Carolina
Aguilar-Gúzman, Lorena
Maldonado, Ismael
Rosas, Carlos
Galanti, Norbel
Kemmerling, Ulrike
Ferreira-Vigouroux, Luis Arturo
Institución
Resumen
Background: 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. 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 Findings: During 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. Keywords. KeyWords Plus:ALKALINE-PHOSPHATASE PLAP; CHAGAS-DISEASE; TOXOPLASMA-GONDII; MATRIX METALLOPROTEINASES; LISTERIA-MONOCYTOGENES; CHORIONIC VILLI; VIRAL-INFECTION; 1ST COMPONENT; LATIN-AMERICA; TROPHOBLAST