Trypanosoma cruzi calreticulin: a novel virulence factor that binds complement C1 on the parasite surface and promotes infectivity.
In Trypanosoma cruzi, calreticulin (TcCRT) translocates from the endoplasmic reticulum (ER) to the area of flagellum emergence. We propose herein that the parasite uses this molecule to capture complement C1, in an infective apoptotic mimicry strategy. Thus, TcCRT/C1 interactions, besides inhibiting the classical pathway of complement activation as previously shown in our laboratories, will also promote infectivity. This fact correlates with significant increases in TcCRT mRNA levels during early infection stages of a VERO cell line. In vitro, the collagenous and globular C1q domains simultaneously bind TcCRT and antigen aggregated Igs, respectively. Accordingly, mouse immunizations with TcCRT induced humoral responses that, after challenge, correlated with increased parasitemia. Thus, on the parasite surface, whole Igs anti-TcCRT promote C1 deposits on trypomastigotes while, as expected, F(ab')₂ fragments decrease it. Likewise, pretreatment of the parasites with whole anti-TcCRT antibodies augmented parasitemia and mortality in mice. In contrast, pretreatment with F(ab')₂ fragments anti-TcCRT, devoid of their capacity to provide additional C1q binding sites, was protective. Most important, while pretreatment of trypomastigotes with C1q increased infectivity in the RAW murine cell line, as well as mice mortality and parasitemia, the F(ab')₂ fragments significantly interfered with the C1q-dependent infectivity. Differently from other surface molecules involved in infectivity, TcCRT uses C1 as an adaptor molecule to recognize host cells. As expected, since TcCRT is one of several cell surface parasite molecules participating in infectivity, attempts to interfere with the C1/TcCRT interactions with F(ab')₂ fragments, were moderately but significantly effective, both in vitro and in vivo.
Ramírez
Galia
G
Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile.
Valck
Carolina
C
Molina
María C
MC
Ribeiro
Carolina H
CH
López
Nandy
N
Sánchez
Gittith
G
Ferreira
Viviana P
VP
Billetta
Rosario
R
Aguilar
Lorena
L
Maldonado
Ismael
I
Cattán
Pedro
P
Schwaeble
Wilhelm
W
Ferreira
Arturo
A
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D000953:Antigens, Protozoan / Q000276:immunology; D037282:Calreticulin / Q000276:immunology; D002460:Cell Line; D014355:Chagas Disease; D003172:Complement C1 / Q000276:immunology / Q000378:metabolism*; D056724:Immunity, Humoral; D007114:Immunization; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D051379:Mice; D018512:Parasitemia; D011485:Protein Binding / Q000276:immunology; D014349:Trypanosoma cruzi / Q000472:pathogenicity / Q000502:physiology*; D014774:Virulence
D000936:Antigen-Antibody Complex; D000953:Antigens, Protozoan; D037282:Calreticulin; D003172:Complement C1