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

Abstract

BackgroundThe 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 FindingsA 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/SignificanceThe 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.

Structure guided prediction of Pyrazinamide resistance mutations in pncA

“…We have developed a comprehensive in silico mutational analysis platform that uses graph-based signatures to represent the 3D structure of a protein and quantitatively predict the molecular consequences of point mutations on protein structure, function and interactions 30,[33][34][35][36]45 . This has been used to characterize and preemptively identify likely resistance mutations in drug targets 23,37,[46][47][48][49][50][51][52][53][54] . Using these tools, we assessed the molecular consequences of each mutation on the structure of PncA and drug activation.…”

Blood-stage Plasmodium vivax antibody dynamics in a low transmission setting: A nine year follow-up study in the Amazon region

“…The study was carried-out in the agricultural settlement of Rio Pardo (1°46’S—1°54’S, 60°22’W—60°10’W), in the municipality of Presidente Figueiredo, state of Amazonas, Brazil. The study site and malaria transmission patterns have been described in detail elsewhere [ 17 – 19 ]. Inhabitants in the settlement live on subsistence farming, and fishing along small streams.…”

“…A population-based open cohort study was initiated in November 2008. Six (May-June 2009) and 12 months later (November-December 2009), two similar cross-sectional surveys were undertaken, using the following procedures [ 17 – 19 ]: (i) administration of a structured questionnaire to all volunteers to obtain demographical, epidemiological, and clinical data; (ii) physical examination, including body temperature and spleen/liver size, recorded according to standard clinical protocols; (iii) venous blood collection for individuals aged five years or older (EDTA, 5 mL), or blood spotted onto filter paper (finger-prick) for those aged < 5 years; and (iv) examination of Giemsa-stained thick blood smears for the presence of malaria parasites by light microscopy. The geographical location of each dwelling was recorded using a hand-held 12-channel global positioning system (GPS) (Garmin 12XL, Olathe, KS, USA) with a positional accuracy of within 15 m. Additional cross-sectional surveys were subsequently carried-out 6 (August 2014), 7 (July 2015) and 9 years later (July 2017).…”

“…Only adults living in the study area were considered eligible for the current study because age-specific seroprevalence rates may not reflect exposure to malaria transmission in the Amazon area [ 26 ]. The sample size was calculated based on the ability of the least immunogenic protein to induce antibody responses in 40% of the study population [ 19 ]; a minimum sample size of 102 out of 300 adults was required to give a statistical power of 80% (assuming 15% error, a significance level of 5%, and 20% of expected loss).…”

“…In order to determine whether serology is useful for monitoring temporal changes in low transmission malaria setting, we evaluated, over a 9 year study period, the antibody response of adult individuals from a well-characterized rural Amazon population [ 17 – 19 ] against three leading P . vivax merozoite-stage vaccine candidate antigens: the Apical Membrane Antigen-1 (AMA-1), that is expressed by merozoites and sporozoites, as a type I integral membrane protein [ 20 ]; the 19-kDa C-terminal region of the Merozoite Surface Protein-1 (MSP-1 19 ), which is a processed fragment of the MSP-1 polypeptide that remains on the merozoite surface and is carried into the parasitized erythrocyte [ 21 ]; and the Duffy Binding Protein region II (DBPII), a key ligand involved in the main P .…”