The Presence, Persistence and Functional Properties of Plasmodium vivax Duffy Binding Protein II Antibodies Are Influenced by HLA Class II Allelic Variants

Background The human malaria parasite Plasmodium vivax infects red blood cells through a key pathway that requires interaction between Duffy binding protein II (DBPII) and its receptor on reticulocytes, the Duffy antigen/receptor for chemokines (DARC). A high proportion of P. vivax-exposed individuals fail to develop antibodies that inhibit DBPII-DARC interaction, and genetic factors that modulate this humoral immune response are poorly characterized. Here, we investigate if DBPII responsiveness could be HLA class II-linked. Methodology/Principal Findings A community-based open cohort study was carried out in an agricultural settlement of the Brazilian Amazon, in which 336 unrelated volunteers were genotyped for HLA class II (DRB1, DQA1 and DQB1 loci), and their DBPII immune responses were monitored over time (baseline, 6 and 12 months) by conventional serology (DBPII IgG ELISA-detected) and functional assays (inhibition of DBPII–erythrocyte binding). The results demonstrated an increased susceptibility of the DRB1*13:01 carriers to develop and sustain an anti-DBPII IgG response, while individuals with the haplotype DRB1*14:02-DQA1*05:03-DQB1*03:01 were persistent non-responders. HLA class II gene polymorphisms also influenced the functional properties of DBPII antibodies (BIAbs, binding inhibitory antibodies), with three alleles (DRB1*07:01, DQA1*02:01 and DQB1*02:02) comprising a single haplotype linked with the presence and persistence of the BIAbs response. Modelling the structural effects of the HLA-DRB1 variants revealed a number of differences in the peptide-binding groove, which is likely to lead to altered antigen binding and presentation profiles, and hence may explain the differences in subject responses. Conclusions/Significance The current study confirms the heritability of the DBPII antibody response, with genetic variation in HLA class II genes influencing both the development and persistence of IgG antibody responses. Cellular studies to increase knowledge of the binding affinities of DBPII peptides for class II molecules linked with good or poor antibody responses might lead to the development of strategies for controlling the type of helper T cells activated in response to DBPII.

[1]  C. King,et al.  Conserved and Variant Epitopes of Plasmodium vivax Duffy Binding Protein as Targets of Inhibitory Monoclonal Antibodies , 2012, Infection and Immunity.

[2]  B. Palmer,et al.  Frequency of beryllium-specific, TH1-type cytokine-expressing CD4+ T cells in patients with beryllium-induced disease. , 2005, The Journal of allergy and clinical immunology.

[3]  M. Boehnke,et al.  So many correlated tests, so little time! Rapid adjustment of P values for multiple correlated tests. , 2007, American journal of human genetics.

[4]  Hassan Belrhali,et al.  Structural basis for Duffy recognition by the malaria parasite Duffy-binding-like domain , 2006, Nature.

[5]  E A Thompson,et al.  A Monte Carlo method for combined segregation and linkage analysis. , 1992, American journal of human genetics.

[6]  Douglas E. V. Pires,et al.  mCSM-AB: a web server for predicting antibody–antigen affinity changes upon mutation with graph-based signatures , 2016, Nucleic Acids Res..

[7]  C. King,et al.  Mapping Epitopes of the Plasmodium vivax Duffy Binding Protein with Naturally Acquired Inhibitory Antibodies , 2009, Infection and Immunity.

[8]  Douglas E. V. Pires,et al.  Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma. , 2015, Cancer discovery.

[9]  C. Chitnis,et al.  Naturally acquired Duffy-binding protein-specific binding inhibitory antibodies confer protection from blood-stage Plasmodium vivax infection , 2008, Proceedings of the National Academy of Sciences.

[10]  P. Michon,et al.  Naturally Acquired and Vaccine-Elicited Antibodies Block Erythrocyte Cytoadherence of the Plasmodium vivaxDuffy Binding Protein , 2000, Infection and Immunity.

[11]  T. Karlsen,et al.  Refinement of the MHC Risk Map in a Scandinavian Primary Sclerosing Cholangitis Population , 2014, PloS one.

[12]  Douglas E. V. Pires,et al.  In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity , 2016, Scientific Reports.

[13]  M. Galinski,et al.  Influence of HLA-DRB1 and HLA-DQB1 Alleles on IgG Antibody Response to the P. vivax MSP-1, MSP-3α and MSP-9 in Individuals from Brazilian Endemic Area , 2012, PloS one.

[14]  L. Excoffier,et al.  Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. , 1995, Molecular biology and evolution.

[15]  Maíra R. Rodrigues,et al.  Origin and dynamics of admixture in Brazilians and its effect on the pattern of deleterious mutations , 2015, Proceedings of the National Academy of Sciences.

[16]  S. Hoffman,et al.  Acquired Antibody Responses against Plasmodium vivax Infection Vary with Host Genotype for Duffy Antigen Receptor for Chemokines (DARC) , 2010, PloS one.

[17]  P. Jungers,et al.  Distinct HLA class II alleles determine antibody response to vaccination with hepatitis B surface antigen. , 1998, Kidney international.

[18]  M. Loh,et al.  HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. , 2014, Blood.

[19]  Douglas E. V. Pires,et al.  CSM-lig: a web server for assessing and comparing protein–small molecule affinities , 2016, Nucleic Acids Res..

[20]  J. Bezerra.  The Brazilian Amazon , 2015, World Forests.

[21]  T. Wellems,et al.  The duffy receptor family of plasmodium knowlesi is located within the micronemes of invasive malaria merozoites , 1990, Cell.

[22]  Douglas E. V. Pires,et al.  mCSM: predicting the effects of mutations in proteins using graph-based signatures , 2013, Bioinform..

[23]  Daniel J. Wilson,et al.  Genetic variability and natural selection at the ligand domain of the Duffy binding protein in brazilian Plasmodium vivax populations , 2010, Malaria Journal.

[24]  C. Chitnis,et al.  Identification of the erythrocyte binding domains of Plasmodium vivax and Plasmodium knowlesi proteins involved in erythrocyte invasion , 1994, The Journal of experimental medicine.

[25]  L. H. Carvalho,et al.  The Duffy binding protein as a key target for a Plasmodium vivax vaccine: lessons from the Brazilian Amazon , 2014, Memorias do Instituto Oswaldo Cruz.

[26]  Richard B. Thomson,et al.  Real-Time PCR for Detection and Identification of Plasmodium spp , 2005, Journal of Clinical Microbiology.

[27]  Douglas E. V. Pires,et al.  Functional interactions between polypyrimidine tract binding protein and PRI peptide ligand containing proteins. , 2016, Biochemical Society transactions.

[28]  J. Adams,et al.  Limited immunological recognition of critical malaria vaccine candidate antigens. , 1988, Science.

[29]  J. Adams,et al.  A family of erythrocyte binding proteins of malaria parasites. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Burton H. Singer,et al.  Malaria risk on the Amazon frontier , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Douglas E. V. Pires,et al.  DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach , 2014, Nucleic Acids Res..

[32]  Jerome Wielens,et al.  Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA , 2014, Scientific Reports.

[33]  A Jawaid,et al.  Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis , 2008, The Pharmacogenomics Journal.

[34]  C. Bonini-Domingos,et al.  Plasmodium vivax infection among Duffy antigen-negative individuals from the Brazilian Amazon region: an exception? , 2007, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[35]  Mark D. Hoover,et al.  Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease , 2014, Proceedings of the National Academy of Sciences.

[36]  B. M. Sanchez,et al.  Naturally acquired antibodies to Plasmodium vivax Duffy binding protein (DBP) in Brazilian Amazon. , 2010, The American journal of tropical medicine and hygiene.

[37]  H. Zhuang,et al.  The effect of HLA on immunological response to hepatitis B vaccine in healthy people: a meta-analysis. , 2013, Vaccine.

[38]  Jennifer L. Johnson,et al.  Transcriptome Analysis in Domesticated Species: Challenges and Strategies , 2015, Bioinformatics and biology insights.

[39]  M. Hutz,et al.  The Genomic Ancestry of Individuals from Different Geographical Regions of Brazil Is More Uniform Than Expected , 2011, PloS one.

[40]  X. Montalban,et al.  HLA alleles as biomarkers of high-titre neutralising antibodies to interferon-β therapy in multiple sclerosis , 2014, Journal of Medical Genetics.

[41]  B. M. Sanchez,et al.  Duffy Antigen Receptor for Chemokine (DARC) Polymorphisms and Its Involvement in Acquisition of Inhibitory Anti-Duffy Binding Protein II (DBPII) Immunity , 2014, PloS one.

[42]  L. Garamszegi,et al.  Global distribution of malaria-resistant MHC-HLA alleles: the number and frequencies of alleles and malaria risk , 2014, Malaria Journal.

[43]  Morten Nielsen,et al.  Accurate pan-specific prediction of peptide-MHC class II binding affinity with improved binding core identification , 2015, Immunogenetics.

[44]  N. Tolia,et al.  Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein , 2016, Proceedings of the National Academy of Sciences.

[45]  F. Salzano,et al.  Interethnic admixture and the evolution of Latin American populations , 2013, Genetics and molecular biology.

[46]  D. Ménard,et al.  Plasmodium vivax clinical malaria is commonly observed in Duffy-negative Malagasy people , 2010, Proceedings of the National Academy of Sciences.

[47]  M. Póvoa,et al.  Influence of HLA-DRB-1 alleles on the production of antibody against CSP, MSP-1, AMA-1, and DBP in Brazilian individuals naturally infected with Plasmodium vivax. , 2012, Acta tropica.

[48]  L. Excoffier,et al.  Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows , 2010, Molecular ecology resources.

[49]  T. Blundell,et al.  Germline Mutations in the CDKN 2 B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma , 2015 .

[50]  L. Miller,et al.  The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. , 1976, The New England journal of medicine.

[51]  A. Moreno,et al.  Evaluation of Naturally Acquired IgG Antibodies to a Chimeric and Non-Chimeric Recombinant Species of Plasmodium vivax Reticulocyte Binding Protein-1: Lack of Association with HLA-DRB1*/DQB1* in Malaria Exposed Individuals from the Brazilian Amazon , 2014, PloS one.

[52]  Douglas G. Mack,et al.  Crystal structure of HLA-DP2 and implications for chronic beryllium disease , 2010, Proceedings of the National Academy of Sciences.

[53]  C. King,et al.  Age-Dependent Cellular Immune Responses to Plasmodium vivax Duffy Binding Protein in Humans1 , 2002, The Journal of Immunology.

[54]  T. Perneger.  What's wrong with Bonferroni adjustments , 1998, BMJ.

[55]  L. H. Carvalho,et al.  Anti-Plasmodium vivax duffy binding protein antibodies measure exposure to malaria in the Brazilian Amazon. , 2005, The American journal of tropical medicine and hygiene.

[56]  J. Barnwell,et al.  Evidence for transmission of Plasmodium vivax among a duffy antigen negative population in Western Kenya. , 2006, The American journal of tropical medicine and hygiene.

[57]  L. K. Christopher,et al.  ヒト赤血球ダッフィ抗原のFya/Fyb抗原多型性はPlasmodium vivaxマラリアに対する感受性に影響する , 2011 .

[58]  Walter Ricciardi,et al.  The link between genetic variation and variability in vaccine responses: systematic review and meta-analyses. , 2014, Vaccine.

[59]  Douglas E. V. Pires,et al.  mCSM-lig: quantifying the effects of mutations on protein-small molecule affinity in genetic disease and emergence of drug resistance , 2016, Scientific Reports.

[60]  D. Alling,et al.  Differential non-responsiveness in humans of candidate Plasmodium falciparum vaccine antigens. , 1989, The American journal of tropical medicine and hygiene.

[61]  Vasant G Honavar,et al.  In Silico Prediction of Linear B-Cell Epitopes on Proteins. , 2017, Methods in molecular biology.

[62]  J. Adams,et al.  Fya/Fyb antigen polymorphism in human erythrocyte Duffy antigen affects susceptibility to Plasmodium vivax malaria , 2011, Proceedings of the National Academy of Sciences.

[63]  B. M. Sanchez,et al.  Plasmodium vivax Duffy binding protein: baseline antibody responses and parasite polymorphisms in a well‐consolidated settlement of the Amazon Region , 2012, Tropical medicine & international health : TM & IH.

[64]  E. Riley,et al.  Selective recognition of malaria antigens by human serum antibodies is not genetically determined but demonstrates some features of clonal imprinting. , 1996, International immunology.

[65]  R. Cherny,et al.  Regulation of insulin-regulated membrane aminopeptidase activity by its C-terminal domain. , 2011, Biochemistry.

[66]  R. Udomsangpetch,et al.  Characterization of Inhibitory Anti-Duffy Binding Protein II Immunity: Approach to Plasmodium vivax Vaccine Development in Thailand , 2012, PloS one.

[67]  Robert M. Plenge,et al.  Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis , 2011, Nature Genetics.

[68]  J. Barnwell,et al.  Plasmodium vivax interaction with the human Duffy blood group glycoprotein: identification of a parasite receptor-like protein. , 1989, Experimental parasitology.

[69]  L. H. Carvalho,et al.  Inhibitory Properties of the Antibody Response to Plasmodium vivax Duffy Binding Protein in an Area with Unstable Malaria Transmission , 2008, Scandinavian journal of immunology.

[70]  Weida Tong,et al.  Machine Learning Methods for Predicting HLA–Peptide Binding Activity , 2015, Bioinformatics and biology insights.

[71]  B. M. Sanchez,et al.  Naturally acquired inhibitory antibodies to Plasmodium vivax Duffy binding protein are short‐lived and allele‐specific following a single malaria infection , 2009, Clinical and experimental immunology.

[72]  Weltgesundheitsorganisation.  World malaria report , 2005 .

[73]  Daniel J Schaid,et al.  Prospective validation of HLA-DRB1*07:01 allele carriage as a predictive risk factor for lapatinib-induced liver injury. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.