Structural characterization of host-pathogen interactions

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

There is a fundamental lack of knowledge of the modalities and principles that govern pathogen-host interactions, preventing rational design of approaches to effectively disrupt such interactions to achieve efficient pathogen 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 pathogen-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 2023, we completed a structural analysis of Plasmodium falciparum Pfs28, a transmission blocking vaccine candidate, published in Scientific Reports. The characterization of Pfs28 in this study provides new insight into the malaria parasite EGF-like family of proteins and lays a foundation for vaccine design to target Pfs28 to block transmission. In addition, we published a comprehensive review in Trends in Parasitology on the structural basis of the Plasmodium vivax Duffy Binding Protein (PvDBP) interaction with the host-receptor Duffy Antigen/Receptor for Chemokines (DARC) and the role of structure-based design in developing vaccine for P. vivax malaria.