Antibodies to protozoan variable surface antigens induce antigenic variation

Abstract

The genomes of most protozoa encode families of variant surface antigens, whose mutually exclusive changes in expression allow parasitic microorganisms to evade the host immune response1,2. It is widely assumed that antigenic variation in protozoan parasites is accomplished by the spontaneous appearance within the population of cells expressing antigenic variants that escape antibody-mediated cytotoxicity1,2. Here we show, both in vitro and in animal infections, that antibodies to Variant-specific Surface Proteins (VSPs) of the intestinal parasite Giardia lamblia are not cytotoxic, inducing instead VSP clustering into liquid-ordered phase membrane microdomains that trigger a massive release of microvesicles carrying the original VSP and switch in expression to different VSPs by a calcium-dependent mechanism. Surface microvesiculization and antigenic switching are also stimulated when Trypanosoma brucei and Tetrahymena thermophila are confronted to antibodies directed to their GPI-anchored variable surface glycoproteins. This novel mechanism of surface antigen clearance throughout its release into microvesicles coupled to the stochastic induction of new phenotypic variants not only changes the current paradigm of spontaneous antigenic switching but also provides a new framework for understanding the course of protozoan infections as a host/parasite adaptive process.

Species-Specific Duplication of Surface Antigen Genes in Paramecium

“…The anchor might also be involved in signal transduction. For instance, the addition of homologous antibodies to living paramecia induces serotype switches [22] and this was also reported recently for several other organisms, e.g., Giardia, Trypanosoma, and the ciliate Tetrahymena [23]. Furthermore, the GPI-anchored folate receptor on the Paramecium surface was shown to confer a folate-specific chemoresponse [24]; thus, GPI-mediated signal transduction appears to exist in Paramecium.…”

DNA damage drives antigen diversification through mosaic VSG formation inTrypanosoma brucei

“…The relatively "protected" tissue spaces may serve as a site for this iterative process to occur. Another intriguing possibility is that partial immune evasion is advantageous for the parasite: a recent study suggested that exposure to sublethal antibody concentrations can trigger a VSG switch in T. brucei 30 . Perhaps parasites expressing these partially evasive variants are more prone to switching to a completely new VSG.…”

Comprehensive characterization of Cysteine-rich protein-coding genes of Giardia lamblia and their role during antigenic variation

“…To identify differentially expressed genes (DEGs) that might be related to the process of antigenic variation triggered by antibodies, biological replicates of clone1 were incubated for 4 h with low concentrations of mAb 7C2 to induce VSP switching and RNA sequencing was performed [60]. Surprisingly, only 7 DEGs (FDR < 0.05) were found between trophozoites before and after treatment (Table S12).…”