ABSTRACT
Calreticulin, a calcium-binding protein that is highly conserved in its multiple functions, is present in a wide spectrum of subcellular compartments in virtually every cell of higher organisms. In this article, we propose a dual role for parasite calreticulin, with emphasis on the Trypanosoma cruzi model. By modulating the vertebrate complement system, calreticulin might provide the parasite with an effective immune-escape mechanism. Alternatively, by inhibiting angiogenesis, the parasite molecule might protect the host from ongoing neoplasic aggressions. Many questions are still unanswered, particularly those regarding the consequences that these interactions could have in vivo for both the parasite and the host.
Subject(s)
Angiogenesis Modulating Agents/metabolism , Calreticulin/physiology , Chagas Disease/metabolism , Complement Inactivator Proteins/physiology , Host-Parasite Interactions/physiology , Trypanosoma cruzi/metabolism , Animals , Calreticulin/metabolism , Complement Inactivator Proteins/metabolism , Complement System Proteins/metabolism , HumansABSTRACT
The high resistance of Trypanosoma cruzi trypomastigotes, the causal agent of Chagas' disease, to complement involves several parasite strategies. In these in vitro studies, we show that T. cruzi calreticulin (TcCRT) and two subfragments thereof (TcCRT S and TcCRT R domains) bind specifically to recognition subcomponents of the classical and lectin activation pathways (i.e., to collagenous tails of C1q and to mannan-binding lectin) of the human complement system. As a consequence of this binding, specific functional inhibition of the classical pathway and impaired mannan-binding lectin to mannose were observed. By flow cytometry, TcCRT was detected on the surface of viable trypomastigotes and, by confocal microscopy, colocalization of human C1q with surface TcCRT of infective trypomastigotes was visualized. Taken together, these findings imply that TcCRT may be a critical factor contributing to the ability of trypomastigotes to interfere at the earliest stages of complement activation.
Subject(s)
Calreticulin/physiology , Complement Inactivator Proteins/physiology , Complement Pathway, Classical/immunology , Immunosuppressive Agents , Trypanosoma cruzi/immunology , Animals , Binding, Competitive/immunology , Calreticulin/metabolism , Collagen/metabolism , Complement C1q/antagonists & inhibitors , Complement C1q/metabolism , Complement Inactivator Proteins/metabolism , Humans , Immunosuppressive Agents/metabolism , Mannose/metabolism , Mannose-Binding Lectin/antagonists & inhibitors , Mannose-Binding Lectin/metabolism , Membrane Proteins/metabolism , Membrane Proteins/physiology , Microscopy, Confocal , Peptide Fragments/metabolism , Peptide Fragments/physiology , Protein Binding/immunology , Protein Structure, Tertiary , Trypanosoma cruzi/growth & development , Trypanosoma cruzi/pathogenicityABSTRACT
Decay-accelerating factor (DAF) is a 70-kD membrane glycoprotein that prevents complement (C)-mediated hemolysis by blocking the assembly or accelerating the decay of C3 convertase. Purified DAF is known to incorporate into the membrane of DAF-deficient cells, inhibiting lysis. Since Schistosoma mansoni is a blood-dwelling parasite, we investigated whether DAF can be transferred from human erythrocytes to the worm and protect it against C-mediated killing in vitro. We have found that schistosomula (schla) incubated with normal human erythrocytes (N-HuE), but not with DAF-deficient erythrocytes, become resistant to C damage in vitro. Protected parasites acquire a 70-kD surface protein which can be immunoprecipitated by anti-DAF antibodies. The acquired resistance is abrogated by treatment of N-HuE-incubated parasites with anti-DAF antibody. These results indicate that, in vitro, N-HuE DAF can be transferred to schla, and suggest its participation in preventing their C-mediated killing. This could represent an important strategy of parasites to evade the host's immune response in vivo.