Structural characterization of host-parasite interactions in malaria

National Institute Of Allergy And Infectious Diseases

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Abstract

There is a fundamental lack of knowledge of the modalities and principles that govern parasite-host interactions, preventing rational design of approaches to effectively disrupt such interactions to achieve efficient parasite control. In the past, simple models of monomeric binding for receptor-ligand interactions have been invoked, simplifying experimental study but limiting our understanding of how interactions are truly manifested during pathogenesis. Recently, the larger view of interactions suggests that the induction of multimeric assemblies and higher order states upon binding, through oligomerization or tandem duplication of binding sites, are critical to the formation of strong interactions between the parasite and the host/vector. The identification of all multimeric contact interfaces within a complex, including interaction and oligomerization contacts, are not only fundamental to the structural understanding of interactions but also reveal additional targets for disruption as described below. We plan to comprehensively dissect the fundamental principles that drive multimeric assembly of parasite-host interactions, and that enable their efficient disruption at the molecular level. We focus on essential host-pathogen/receptor-ligand interactions required for host infection and vector transmission of the malaria parasites Plasmodium falciparum and Plasmodium vivax. Fundamental principles of this study include multimerization of interacting partners, creation of specific binding pockets, and characterization of structural changes upon binding, as well as the role of multiple binding sites within a complex with regards to cooperativity and avidity. The role of variable (polymorphic) and constant regions of interacting partners in engagement will also be uncovered. These fundamental principles will be revealed by studying the structural and mechanistic basis for assembly of parasite-host interaction, with well-validated roles as potential vaccine candidates and/or as required for parasite viability. In FY 2021, we took advantage of the Cryo-Electron Microscopy pipeline accessible through collaborations with Drs. Rick Huang (NCI) and Jiansen Jiang (NHLBI) to solve three atomic-resolution structures of VAR2CSA, a critical malaria vaccine candidate, alone and in complex with the host receptor CSA from two Plasmodium falciparum strains NF54 and FCR3. We published this work in Nature Microbiology. We also completed a structural study on P. falciparum Cpn60 bound to ATP, which differs significantly from any known structures of the Cpn60 superfamily. The structure provides new insights into the mechanism of Cpn60 in chaperonin assembly and function, and lays a solid foundation for vaccine design using Cpn60. The work was published in Scientific Reports.