Identification and Characterization of the Trypanosoma cruzi B-cell Superantigen Tc24

Abstract

Trypanosoma cruzi causes life-long disease after infection and leads to cardiac disease in 30% of infected individuals. After infection, the parasites are readily detectable in the blood during the first few days before disseminating to infect numerous cell types. Preliminary data suggested that the Tc24 protein that localizes to the T. cruzi membrane during all life stages possesses B-cell superantigenic properties. These antigens facilitate immune escape by interfering with antibody-mediated responses, particularly the avoidance of catalytic antibodies. These antibodies are an innate host defense mechanism present in the naive repertoire, and catalytic antibody–antigen binding results in hydrolysis of the target. We tested the B-cell superantigenic properties of Tc24 by comparing the degree of Tc24 hydrolysis by IgM purified from either Tc24 unexposed or exposed mice and humans. Respective samples were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis, silver stained, and the degree of hydrolysis was measured. Data presented in this report suggest that the T. cruzi Tc24 is a B-cell superantigen based on the observations that 1) Tc24 was hydrolyzed by IgM present in serum of unexposed mice and humans and 2) exposure to Tc24 eliminated catalytic activity as early as 4 days after T. cruzi infection.

Covalent vaccination with Trypanosoma cruzi Tc24 induces catalytic antibody production

“…Full‐length T . cruzi 24 kDa Tc24 flagellar calcium‐binding protein was expressed as a recombinant protein in Escherichia coli as previously described . Tc24‐C4, an isoform of Tc24 with the four naturally occurring cysteine (Cys) residues (positions 4, 66, 74 and 124) mutated to alanines (Ala), was expressed using E .…”

“…Expression of the B‐cell superantigen (BC‐SAg) Tc24 is one immune evasion strategy employed by T . cruzi which protects the parasite against IgM‐mediated hydrolysis of native Tc24 by the catalytic antibodies present in the preimmune repertoire of both mice and humans . BC‐SAgs have evolved to neutralize this innate natural antibody defence mechanism and are an immune evasion strategy also utilized by bacteria and viruses .…”

“…Expression of the B-cell superantigen (BC-SAg) Tc24 is one immune evasion strategy employed by T. cruzi which protects the parasite against IgM-mediated hydrolysis of native Tc24 by the catalytic antibodies present in the preimmune repertoire of both mice and humans. 12,13 BC-SAgs have evolved to neutralize this innate natural antibody defence mechanism and are an immune evasion strategy also utilized by bacteria and viruses. [14][15][16][17][18][19] BC-SAgs are defined by (a) the presence of antibodies in the preimmune or naive repertoire with specificity for these antigens, for example Staphylococcal Protein A and the extracellular fibrinogen-binding protein (Efb) and HIV gp120, 14,15,17,20,21 and (b) the depletion of the B-cell subsets producing BC-SAg-specific catalytic antibodies following exposure to the BC-SAg ( Figure 1).…”

“…[14][15][16][17][18][19] BC-SAgs are defined by (a) the presence of antibodies in the preimmune or naive repertoire with specificity for these antigens, for example Staphylococcal Protein A and the extracellular fibrinogen-binding protein (Efb) and HIV gp120, 14,15,17,20,21 and (b) the depletion of the B-cell subsets producing BC-SAg-specific catalytic antibodies following exposure to the BC-SAg ( Figure 1). 13,19,21 The T. cruzi Tc24 molecule is a recently described BC-SAg that is hydrolyzed by IgM antibodies naturally occurring in unexposed humans or mice. 12,13 Furthermore, catalytic activity is lost following Tc24 exposure (parasite infection or active Tc24 immunization) as a consequence of clonal B-cell deletion or inactivation.…”

“…12,13 Furthermore, catalytic activity is lost following Tc24 exposure (parasite infection or active Tc24 immunization) as a consequence of clonal B-cell deletion or inactivation. 12,13 We previously demonstrated that the catalytic IgM response specific for Tc24 diminished rapidly following T. cruzi infection, suggesting that "silencing" of the anti-Tc24 catalytic response early in the infection process may represent a key immune evasion mechanism employed by the parasite to establish infection. 12,13 This may allow the parasite to survive in the bloodstream following infection subsequently leaving the host at an increased risk to subsequent infections.…”