Disruption of antigenic variation is crucial for effective parasite vaccine

Abstract

Giardia lamblia is a human intestinal pathogen. Like many protozoan microorganisms, Giardia undergoes antigenic variation, a mechanism assumed to allow parasites to evade the host's immune response, producing chronic and/or recurrent infections. Recently, we found that the mechanism controlling variant-specific surface protein (VSP) switching in Giardia involves components of the RNA interference machinery and that disruption of this pathway generates trophozoites simultaneously expressing many VSPs. Here we use these altered trophozoites to determine the role of antigenic variation in a gerbil model of giardiasis. Our results show that either primary infection with trophozoites simultaneously expressing many VSPs or immunization with purified VSPs from the transgenic cells protects gerbils from subsequent Giardia infections. These results constitute, to our knowledge, the first experimental evidence that antigenic variation is essential for parasite survival within hosts and that artificial disruption of this mechanism might be useful in generating vaccines against major pathogens that show similar behavior.

Giardial Triosephosphate Isomerase as Possible Target of the Cytotoxic Effect of Omeprazole in Giardia lamblia

“…This has led to the search for novel experimental strategies and the evaluation of other treatment regimens. Strategies ranging from the development of vaccines to the search for new molecular targets are currently being addressed (1,20). The enzymes of the glycolytic pathway in G. lamblia have been proposed as potential targets for drug design (21,22) because the organism lacks oxidative phosphorylation (23).…”

α1-giardin based live heterologous vaccine protects against Giardia lamblia infection in a murine model

“…The current study shows that this strategy can be successful against giardiasis, since expression of a particular conserved antigen, α1-giardin, in recombinant attenuated Salmonella conferred protection of the host against subsequent Giardia challenge. Although protection has so far not been absolute in a murine model, the results are encouraging, as they, together with those with variable Giardia surface antigens [17] and induction of herd immunity [9–11], indicate that effective defined vaccine strategies against giardiasis are feasible.…”

“…In a population of trophozoites, different VSPs are expressed simultaneously, and switches in the expression of specific VSPs occur rapidly during the course of Giardia infection [14,15]. It may be possible to develop pharmacological or genetic interventions that allow expression of multiple VSPs on single trophozoites, which could be useful for a vaccine based on attenuated Giardia [16,17]. However, different giardial strains have distinct VSP genetic repertoires [18,19], and no strategies are available to identify defined virulence mutants of the parasite.…”

Control of Giardiasis by Interleukin-17 in Humans and Mice—Are the Questions All Answered?

“…Each Giardia trophozoite carries 150 to 200 different VSP-encoding genes, but only 1 is expressed on the parasite surface at a time. Switch variants are selected in vivo by IgA, and the ability to switch VSP expression allows the parasite to evade this element of host immunity (8,9). Nevertheless, CD4…”