Abstract
Malaria is a global health burden, with Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) responsible for the majority of infections worldwide. Circumsporozoite protein (CSP) is the most abundant protein on the surface of Plasmodium sporozoites, and antibodies targeting the central repeat region of CSP can prevent parasite infection. Although much has been uncovered about the molecular basis of antibody recognition of the PfCSP repeats, data remains scarce for PvCSP. Here, we performed molecular dynamics simulations for peptides comprising the PvCSP repeats from strains VK210 and VK247 to reveal how the PvCSP central repeats are highly disordered, with minor propensities to adopt turn conformations. Next, we solved eight crystal structures to unveil the interactions of two inhibitory monoclonal antibodies (mAbs), 2F2 and 2E10.E9, with PvCSP repeats. Both antibodies can accommodate subtle sequence variances in the repeat motifs and recognize largely coiled peptide conformations that also contain isolated turns. Our structural studies uncover various degrees of Fab-Fab homotypic interactions upon recognition of the PvCSP central repeats by these two inhibitory mAbs, similar to potent mAbs against PfCSP. These findings augment our understanding of host-Plasmodium interactions and contribute molecular details of Pv inhibition by mAbs to unlock structure-based engineering of PvCSP-based vaccines.
Highlights
IntroductionMalaria is a major public health concern, with an estimated 409,000 deaths in 2019
Malaria is a major public health concern, with an estimated 409,000 deaths in 2019(World Health Organization, 2020)
Due to the variety of PvCSP repeat sequence motifs, we created an extensive list of peptides for circular dichroism (CD) spectroscopy and molecular dynamics (MD) simulations studies (Supplementary File 1, Fig. 1A) to examine the structural propensities of 18- and 27-aa long motifs from the PvCSPvk210 and PvCSPvk247 repeats
Summary
Malaria is a major public health concern, with an estimated 409,000 deaths in 2019. Human malaria is caused by Plasmodium parasites, with the majority of cases attributed to Pf and Pv (Lover et al, 2018). Pv is the predominant Plasmodium spp. in circulation for a majority of countries outside of Africa Despite overall lower mortality compared to Pf malaria, Pv infection can cause debilitating disease, including fever, myalgia, chronic anemia, reduced birthweight and increased risk of neonatal death (Alexandre et al, 2010; Bardají et al., 2017; Genton et al, 2008). The PvCSP central region is composed of nonapeptides GDRA(A/D)GQPA and ANGAGNQPG characteristic of strains
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