ABSTRACT
Malaria elimination requires tools that interrupt parasite transmission. Here, we characterize B cell receptor responses among Malian adults vaccinated against the first domain of the cysteine-rich 230 kDa gamete surface protein Pfs230, a key protein in sexual stage development of P. falciparum parasites. Among nine Pfs230 human monoclonal antibodies (mAbs) that we generated, one potently blocks transmission to mosquitoes in a complement-dependent manner and reacts to the gamete surface; the other eight show only low or no blocking activity. The structure of the transmission-blocking mAb in complex with vaccine antigen reveals a large discontinuous conformational epitope, specific to domain 1 of Pfs230 and comprising six structural elements in the protein. The epitope is conserved, suggesting the transmission-blocking mAb is broadly functional. This study provides a rational basis to improve malaria vaccines and develop therapeutic antibodies for malaria elimination.
Subject(s)
Antibodies, Monoclonal/pharmacology , Antibodies, Protozoan/pharmacology , Epitopes/immunology , Germ Cells/immunology , Malaria, Falciparum/prevention & control , Plasmodium falciparum/drug effects , Adult , Animals , Antibodies, Monoclonal/immunology , Antibodies, Protozoan/immunology , Antigens, Protozoan/chemistry , Antigens, Protozoan/immunology , Binding Sites , Cells, Cultured , Epitopes/chemistry , Host-Parasite Interactions/drug effects , Host-Parasite Interactions/immunology , Humans , Malaria Vaccines/administration & dosage , Malaria Vaccines/immunology , Malaria, Falciparum/parasitology , Malaria, Falciparum/transmission , Mosquito Vectors/parasitology , Plasmodium falciparum/immunology , Plasmodium falciparum/physiology , Protein Conformation , Protozoan Proteins/chemistry , Protozoan Proteins/immunologyABSTRACT
Precision medicine requires the translation of basic biological understanding to medical insights, mainly applied to characterization of each unique patient. In many clinical settings, this requires tools that can be broadly used to identify pathology and risks. Patients often present to the intensive care unit with broad phenotypes, including multiple organ dysfunction syndrome (MODS) resulting from infection, trauma, or other disease processes. Etiology and outcomes are unique to individuals, making it difficult to cohort patients with MODS, but presenting a prime target for testing/developing tools for precision medicine. Using multitime point whole blood (cellular/acellular) total transcriptomics in 27 patients, we highlight the promise of simultaneously mapping viral/bacterial load, cell composition, tissue damage biomarkers, balance between syndromic biology versus environmental response, and unique biological insights in each patient using a single platform measurement. Integration of a transcriptome workflow yielded unexpected insights into the complex interplay between host genetics and viral/bacterial specific mechanisms, highlighted by a unique case of virally induced genetics (VIG) within one of these 27 patients. The power of RNA-Seq to study unique patient biology while investigating environmental contributions can be a critical tool moving forward for translational sciences applied to precision medicine.
