Structure-guided insights into potential function of novel genetic variants in the malaria vaccine candidate PfRh5.

Autor: Mangou K; G4 - Malaria Experimental Genetic Approaches & Vaccines, Pôle Immunophysiopathologie et Maladies Infectieuses, Institut Pasteur de Dakar, Dakar, Senegal., Moore AJ; Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.; Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA., Thiam LG; G4 - Malaria Experimental Genetic Approaches & Vaccines, Pôle Immunophysiopathologie et Maladies Infectieuses, Institut Pasteur de Dakar, Dakar, Senegal., Ba A; G4 - Malaria Experimental Genetic Approaches & Vaccines, Pôle Immunophysiopathologie et Maladies Infectieuses, Institut Pasteur de Dakar, Dakar, Senegal., Orfanó A; Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA., Desamours I; Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA., Ndegwa DN; Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.; University of Embu, Embu, Kenya., Goodwin J; Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA., Guo Y; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA., Sheng Z; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA., Patel SD; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA., Diallo F; G4 - Malaria Experimental Genetic Approaches & Vaccines, Pôle Immunophysiopathologie et Maladies Infectieuses, Institut Pasteur de Dakar, Dakar, Senegal., Sene SD; G4 - Malaria Experimental Genetic Approaches & Vaccines, Pôle Immunophysiopathologie et Maladies Infectieuses, Institut Pasteur de Dakar, Dakar, Senegal., Pouye MN; G4 - Malaria Experimental Genetic Approaches & Vaccines, Pôle Immunophysiopathologie et Maladies Infectieuses, Institut Pasteur de Dakar, Dakar, Senegal., Faye AT; G4 - Malaria Experimental Genetic Approaches & Vaccines, Pôle Immunophysiopathologie et Maladies Infectieuses, Institut Pasteur de Dakar, Dakar, Senegal., Thiam A; G4 - Malaria Experimental Genetic Approaches & Vaccines, Pôle Immunophysiopathologie et Maladies Infectieuses, Institut Pasteur de Dakar, Dakar, Senegal., Nunez V; Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA., Diagne CT; MIVEGEC (Infectious Diseases and Vector: Ecology, Genetics, Evolution and Control), University of Montpelier, IRD, CNRS, Montpellier, France., Sadio BD; Pôle Virologie, Institut Pasteur de Dakar, Dakar, Senegal., Shapiro L; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA.; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.; Department of Biochemistry and Biophysics, Columbia University, New York, NY, USA., Faye O; Pôle Virologie, Institut Pasteur de Dakar, Dakar, Senegal., Mbengue A; G4 - Malaria Experimental Genetic Approaches & Vaccines, Pôle Immunophysiopathologie et Maladies Infectieuses, Institut Pasteur de Dakar, Dakar, Senegal., Bei AK; Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA. amy.bei@yale.edu.; G4 - Malaria Experimental Genetic Approaches & Vaccines, Pôle Immunophysiopathologie et Maladies Infectieuses, Institut Pasteur de Dakar, Dakar, Senegal. amy.bei@yale.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Nov 12; Vol. 12 (1), pp. 19403. Date of Electronic Publication: 2022 Nov 12.
DOI: 10.1038/s41598-022-23929-9
Abstrakt: The recent stall in the global reduction of malaria deaths has made the development of a highly effective vaccine essential. A major challenge to developing an efficacious vaccine is the extensive diversity of Plasmodium falciparum antigens. While genetic diversity plays a major role in immune evasion and is a barrier to the development of both natural and vaccine-induced protective immunity, it has been under-prioritized in the evaluation of malaria vaccine candidates. This study uses genomic approaches to evaluate genetic diversity in next generation malaria vaccine candidate PfRh5. We used targeted deep amplicon sequencing to identify non-synonymous Single Nucleotide Polymorphisms (SNPs) in PfRh5 (Reticulocyte-Binding Protein Homologue 5) in 189 P. falciparum positive samples from Southern Senegal and identified 74 novel SNPs. We evaluated the population prevalence of these SNPs as well as the frequency in individual samples and found that only a single SNP, C203Y, was present at every site. Many SNPs were unique to the individual sampled, with over 90% of SNPs being found in just one infected individual. In addition to population prevalence, we assessed individual level SNP frequencies which revealed that some SNPs were dominant (frequency of greater than 25% in a polygenomic sample) whereas most were rare, present at 2% or less of total reads mapped to the reference at the given position. Structural modeling uncovered 3 novel SNPs occurring under epitopes bound by inhibitory monoclonal antibodies, potentially impacting immune evasion, while other SNPs were predicted to impact PfRh5 structure or interactions with the receptor or binding partners. Our data demonstrate that PfRh5 exhibits greater genetic diversity than previously described, with the caveat that most of the uncovered SNPs are at a low overall frequency in the individual and prevalence in the population. The structural studies reveal that novel SNPs could have functional implications on PfRh5 receptor binding, complex formation, or immune evasion, supporting continued efforts to validate PfRh5 as an effective malaria vaccine target and development of a PfRh5 vaccine.
(© 2022. The Author(s).)
Databáze: MEDLINE
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