Molecular mechanisms involved in the inactivation of the first component of human complement by Trypanosoma cruzi calreticulin.
Trypanosoma cruzi (T. cruzi), the agent of Chagas' disease, the sixth most important neglected tropical disease worldwide, causes 50,000 deaths per year in Latin America. T. cruzi calreticulin (TcCRT), a highly pleiotropic chaperone molecule, plays important roles in several host/parasite interactions. Among other functions, we have previously shown that TcCRT, translocated from the endoplasmic reticulum to the area of flagellar emergence, binds human C1q and inhibits activation of the classical pathway in vitro. Based on a series of in vitro experiments, we propose here two mechanisms to explain how TcCRT inhibits the classical pathway at the initial stages of C1 (q, r, s) activation. First, TcCRT interacts in vitro with both solid phase bound active C1s and C1, but impairment of C4 activating capacity is evident only when the serine proteases are within the structural context of the macromolecular first component. Although C1s activity, in this context, is inhibited by TcCRT, the serine protease is not displaced from the C1 complex. Second, TcCRT prevents C1 formation, by interfering with the ability of the (C1r-C1s)(2) tetramer to bind C1q. These complement inhibitory effects are better explained by direct interaction of the parasite protein with C1, rather than by the TcCRT capacity to bind calcium, an essential element for the functional integrity of C1.
Programa Disciplinario de Inmunología, ICBM, Universidad de Chile, Independencia 1027, Santiago, Chile.
Carolina
C
Valck
Galia
G
Ramírez
Nandy
N
López
Carolina H
CH
Ribeiro
Ismael
I
Maldonado
Gittith
G
Sánchez
Viviana P
VP
Ferreira
Wilhelm
W
Schwaeble
Arturo
A
Ferreira
D000818:Animals; D002118:Calcium / Q000378:metabolism; D037282:Calreticulin / Q000276:immunology* / Q000378:metabolism; D003167:Complement Activation; D003165:Complement System Proteins / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D015800:Protozoan Proteins / Q000276:immunology* / Q000378:metabolism; D057057:Serine Proteases / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000276:immunology* / Q000378:metabolism
D037282:Calreticulin; D015800:Protozoan Proteins; D003165:Complement System Proteins; D057057:Serine Proteases; D002118:Calcium