title: Basigin is a druggable target for host-oriented antimalarial interventions.
abstract: Plasmodium falciparum is the parasite responsible for the most lethal form of malaria, an infectious disease that causes a large proportion of childhood deaths and poses a significant barrier to socioeconomic development in many countries. Although antimalarial drugs exist, the repeated emergence and spread of drug-resistant parasites limit their useful lifespan. An alternative strategy that could limit the evolution of drug-resistant parasites is to target host factors that are essential and universally required for parasite growth. Host-targeted therapeutics have been successfully applied in other infectious diseases but have never been attempted for malaria. Here, we report the development of a recombinant chimeric antibody (Ab-1) against basigin, an erythrocyte receptor necessary for parasite invasion as a putative antimalarial therapeutic. Ab-1 inhibited the PfRH5-basigin interaction and potently blocked erythrocyte invasion by all parasite strains tested. Importantly, Ab-1 rapidly cleared an established P. falciparum blood-stage infection with no overt toxicity in an in vivo infection model. Collectively, our data demonstrate that antibodies or other therapeutics targeting host basigin could be an effective treatment for patients infected with multi-drug resistant P. falciparum.
authors.affiliation: Cell Surface Signalling Laboratory and Malaria Program, Wellcome Trust Sanger Institute, Cambridge CB10 2DP, England, UK Cell Surface Signalling Laboratory and Malaria Program, Wellcome Trust Sanger Institute, Cambridge CB10 2DP, England, UK.
authors.forename: Zenon A
authors.initials: ZA
authors.lastname: Zenonos
authors.affiliation: SMART Singapore-MIT-Alliance for Research and Technology, Infectious Disease IRG, Singapore 138602, Singapore.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Dummler
authors.affiliation: Cell Surface Signalling Laboratory and Malaria Program, Wellcome Trust Sanger Institute, Cambridge CB10 2DP, England, UK.
authors.forename: Nicole
authors.initials: N
authors.lastname: Müller-Sienerth
authors.affiliation: SMART Singapore-MIT-Alliance for Research and Technology, Infectious Disease IRG, Singapore 138602, Singapore Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02420.
authors.forename: Jianzhu
authors.initials: J
authors.lastname: Chen
authors.affiliation: SMART Singapore-MIT-Alliance for Research and Technology, Infectious Disease IRG, Singapore 138602, Singapore Nanyang Technological University, School of Biological Sciences, Singapore 637551, Singapore.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Preiser
authors.affiliation: Cell Surface Signalling Laboratory and Malaria Program, Wellcome Trust Sanger Institute, Cambridge CB10 2DP, England, UK.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Rayner
authors.affiliation: Cell Surface Signalling Laboratory and Malaria Program, Wellcome Trust Sanger Institute, Cambridge CB10 2DP, England, UK Cell Surface Signalling Laboratory and Malaria Program, Wellcome Trust Sanger Institute, Cambridge CB10 2DP, England, UK gw2@sanger.ac.uk.
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Wright
mesh_terms: D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000494:pharmacology*; D001483:Base Sequence; D051926:Basigin / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D003001:Cloning, Molecular; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D034982:Integration Host Factors / Q000378:metabolism*; D008288:Malaria / Q000517:prevention & control*; D051379:Mice; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D020349:Surface Plasmon Resonance
chemical_list: D000906:Antibodies; D002352:Carrier Proteins; D034982:Integration Host Factors; C531020:RH5 protein, Plasmodium falciparum; D011993:Recombinant Fusion Proteins; D051926:Basigin