Dataset Information

Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2.

ABSTRACT: HAP2 is a transmembrane gamete fusogen found in multiple eukaryotic kingdoms and is structurally homologous to viral class II fusogens. Studies in Plasmodium have suggested that HAP2 is an attractive target for vaccines that block transmission of malaria. HAP2 has three extracellular domains, arranged in the order D2, D1, and D3. Here, we report monoclonal antibodies against the D3 fragment of Plasmodium berghei HAP2 and crystal structures of D3 in complex with Fab fragments of two of these antibodies, one of which blocks fertilization of Plasmodium berghei in vitro and transmission of malaria in mosquitoes. We also show how this Fab binds the complete HAP2 ectodomain with electron microscopy. The two antibodies cross-react with HAP2 among multiple plasmodial species. Our characterization of the Plasmodium D3 structure, HAP2 ectodomain architecture, and mechanism of inhibition provide insights for the development of a vaccine to block malaria transmission.

SUBMITTER: Feng J

PROVIDER: S-EPMC8806182 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2.

Feng Juan J Dong Xianchi X DeCosta Adam A Su Yang Y Angrisano Fiona F Sala Katarzyna A KA Blagborough Andrew M AM Lu Chafen C Springer Timothy A TA

eLife 20211223

HAP2 is a transmembrane gamete fusogen found in multiple eukaryotic kingdoms and is structurally homologous to viral class II fusogens. Studies in <i>Plasmodium</i> have suggested that HAP2 is an attractive target for vaccines that block transmission of malaria. HAP2 has three extracellular domains, arranged in the order D2, D1, and D3. Here, we report monoclonal antibodies against the D3 fragment of <i>Plasmodium berghei</i> HAP2 and crystal structures of D3 in complex with Fab fragments of two ...[more]

PMID: 34939934

Similar Datasets

Project description:Leishmania are protozoan parasites transmitted by the bite of sand fly vectors producing a wide spectrum of diseases in their mammalian hosts. These diverse clinical outcomes are directly associated with parasite strain and species diversity. Although Leishmania reproduction is mainly clonal, a cryptic sexual cycle capable of producing hybrid genotypes has been inferred from population genetic studies and directly demonstrated by laboratory crosses. Experimentally, mating competence has been largely confined to promastigotes developing in the sand fly midgut. The ability to hybridize culture promastigotes in vitro has been limited so far to low-efficiency crosses between two Leishmania tropica strains, L747 and MA37, that mate with high efficiency in flies. Here, we show that exposure of promastigote cultures to DNA damage stress produces a remarkably enhanced efficiency of in vitro hybridization of the L. tropica strains and extends to other species, including Leishmania donovani, Leishmania infantum, and Leishmania braziliensis, a capacity to generate intra- and interspecific hybrids. Whole-genome sequencing and total DNA content analyses indicate that the hybrids are in each case full genome, mostly tetraploid hybrids. Single-cell RNA sequencing of the L747 and MA37 parental lines highlights the transcriptome heterogeneity of culture promastigotes and reveals discrete clusters that emerge post-irradiation in which genes potentially involved in genetic exchange are expressed, including the ancestral gamete fusogen HAP2. By generating reporter constructs for HAP2, we could select for promastigotes that could either hybridize or not in vitro. Overall, this work reveals that there are specific populations involved in Leishmania hybridization associated with a discernible transcriptomic signature, and that stress facilitated in vitro hybridization can be a transformative approach to generate large numbers of hybrid genotypes between diverse species and strains.

Dataset Information

Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2.

Publications

Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets