IgG and IgM responses to the Plasmodium falciparum asexual stage antigens reflect respectively protection against malaria during pregnancy and infanthood.

BACKGROUND: Plasmodium falciparum malaria is a public health issue mostly seen in tropical countries. Until now, there is no effective malaria vaccine against antigens specific to the blood-stage of P. falciparum infection. Because the pathogenesis of malarial disease results from blood-stage infection, it is essential to identify the most promising blood-stage vaccine candidate antigens under natural exposure to malaria infection. METHODS: A cohort of 400 pregnant women and their infants was implemented in South Benin. An active and passive protocol of malaria surveillance was established during pregnancy and infancy to precisely ascertain malaria infections during the follow-up. Twenty-eight antibody (Ab) responses specific to seven malaria candidate vaccine antigens were repeatedly quantified during pregnancy (3 time points) and infancy (6 time points) in order to study the Ab kinetics and their protective role. Abs were quantified by ELISA and logistic, linear and cox-proportional hazard model were performed to analyse the associations between Ab responses and protection against malaria in mothers and infants, taking into account socio-economic factors and for infants an environmental risk of exposure. RESULTS: The levels of IgM against MSP1, MSP2 and MSP3 showed an early protective response against the onset of symptomatic malaria infections starting from the 18th month of life, whereas no association was found for IgG responses during infancy. In women, some IgG responses tend to be associated with a protection against malaria risk along pregnancy and at delivery, among them IgG3 against GLURP-R0 and IgG2 against MSP1. CONCLUSION: The main finding suggests that IgM should be considered in vaccine designs during infanthood. Investigation of the functional role played by IgM in malaria protection needs further attention.

Genomic selection models substantially improve the accuracy of genetic merit predictions for fillet yield and body weight in rainbow trout using a multi-trait model and multi-generation progeny testing.

BACKGROUND: In aquaculture, the proportion of edible meat (FY = fillet yield) is of major economic importance, and breeding animals of superior genetic merit for this trait can improve efficiency and profitability. Achieving genetic gains for fillet yield is possible using a pedigree-based best linear unbiased prediction (PBLUP) model with direct and indirect selection. To investigate the feasibility of using genomic selection (GS) to improve FY and body weight (BW) in rainbow trout, the prediction accuracy of GS models was compared to that of PBLUP. In addition, a genome-wide association study (GWAS) was conducted to identify quantitative trait loci (QTL) for the traits. All analyses were performed using a two-trait model with FY and BW, and variance components, heritability, and genetic correlations were estimated without genomic information. The data used included 14,165 fish in the pedigree, of which 2742 and 12,890 had FY and BW phenotypic records, respectively, and 2484 had genotypes from the 57K single nucleotide polymorphism (SNP) array. RESULTS: The heritabilities were moderate, at 0.41 and 0.33 for FY and BW, respectively. Both traits were lowly but positively correlated (genetic correlation; r = 0.24), which suggests potential favourable correlated genetic gains. GS models increased prediction accuracy compared to PBLUP by up to 50% for FY and 44% for BW. Evaluations were found to be biased when validation was performed on future performances but not when it was performed on future genomic estimated breeding values. CONCLUSIONS: The low but positive genetic correlation between fillet yield and body weight indicates that some improvement in fillet yield may be achieved through indirect selection for body weight. Genomic information increases the prediction accuracy of breeding values and is an important tool to accelerate genetic progress for fillet yield and growth in the current rainbow trout population. No significant QTL were found for either trait, indicating that both traits are polygenic, and that marker-assisted selection will not be helpful to improve these traits in this population.

Unraveling the phenotypic and genomic background of behavioral plasticity and temperament in North American Angus cattle.

BACKGROUND: Longitudinal records of temperament can be used for assessing behavioral plasticity, such as aptness to learn, memorize, or change behavioral responses based on affective state. In this study, we evaluated the phenotypic and genomic background of North American Angus cow temperament measured throughout their lifetime around the weaning season, including the development of a new indicator trait termed docility-based learning and behavioral plasticity. The analyses included 273,695 and 153,898 records for yearling (YT) and cow at weaning (CT) temperament, respectively, 723,248 animals in the pedigree, and 8784 genotyped animals. Both YT and CT were measured when the animal was loading into/exiting the chute. Moreover, CT was measured around the time in which the cow was separated from her calf. A random regression model fitting a first-order Legendre orthogonal polynomial was used to model the covariance structure of temperament and to assess the learning and behavioral plasticity (i.e., slope of the regression) of individual cows. This study provides, for the first time, a longitudinal perspective of the genetic and genomic mechanisms underlying temperament, learning, and behavioral plasticity in beef cattle. RESULTS: CT measured across years is heritable (0.38-0.53). Positive and strong genetic correlations (0.91-1.00) were observed among all CT age-group pairs and between CT and YT (0.84). Over 90% of the candidate genes identified overlapped among CT age-groups and the estimated effect of genomic markers located within important candidate genes changed over time. A small but significant genetic component was observed for learning and behavioral plasticity (heritability = 0.02 ± 0.002). Various candidate genes were identified, revealing the polygenic nature of the traits evaluated. The pathways and candidate genes identified are associated with steroid and glucocorticoid hormones, development delay, cognitive development, and behavioral changes in cattle and other species. CONCLUSIONS: Cow temperament is highly heritable and repeatable. The changes in temperament can be genetically improved by selecting animals with favorable learning and behavioral plasticity (i.e., habituation). Furthermore, the environment explains a large part of the variation in learning and behavioral plasticity, leading to opportunities to also improve the overall temperament by refining management practices. Moreover, behavioral plasticity offers opportunities to improve the long-term animal and handler welfare through habituation.

Across-country genetic and genomic analyses of foot score traits in American and Australian Angus cattle.

BACKGROUND: Hoof structure and health are essential for the welfare and productivity of beef cattle. Therefore, we assessed the genetic and genomic background of foot score traits in American (US) and Australian (AU) Angus cattle and investigated the feasibility of performing genomic evaluations combining data for foot score traits recorded in US and AU Angus cattle. The traits evaluated were foot angle (FA) and claw set (CS). In total, 109,294 and ~ 1.12 million animals had phenotypic and genomic information, respectively. Four sets of analyses were performed: (1) genomic connectedness between US and AU Angus cattle populations and population structure, (2) estimation of genetic parameters, (3) single-step genomic prediction of breeding values, and (4) single-step genome-wide association studies for FA and CS. RESULTS: There was no clear genetic differentiation between US and AU Angus populations. Similar heritability estimates (FA: 0.22-0.24 and CS: 0.22-0.27) and moderate-to-high genetic correlations between US and AU foot scores (FA: 0.61 and CS: 0.76) were obtained. A joint-genomic prediction using data from both populations outperformed within-country genomic evaluations. A genomic prediction model considering US and AU datasets as a single population performed similarly to the scenario accounting for genotype-by-environment interactions (i.e., multiple-trait model considering US and AU records as different traits), even though the genetic correlations between countries were lower than 0.80. Common significant genomic regions were observed between US and AU for FA and CS. Significant single nucleotide polymorphisms were identified on the Bos taurus (BTA) chromosomes BTA1, BTA5, BTA11, BTA13, BTA19, BTA20, and BTA23. The candidate genes identified were primarily from growth factor gene families, including FGF12 and GDF5, which were previously associated with bone structure and repair. CONCLUSIONS: This study presents comprehensive population structure and genetic and genomic analyses of foot scores in US and AU Angus cattle populations, which are essential for optimizing the implementation of genomic selection for improved foot scores in Angus cattle breeding programs. We have also identified candidate genes associated with foot scores in the largest Angus cattle populations in the world and made recommendations for genomic evaluations for improved foot score traits in the US and AU.

Implication of the order of blending and tuning when computing the genomic relationship matrix in single-step GBLUP.

Single-step genomic BLUP (ssGBLUP) relies on the combination of the genomic ( G $$ \mathbf{G} $$ ) and pedigree relationship matrices for all ( A $$ \mathbf{A} $$ ) and genotyped ( A 22 $$ {\mathbf{A}}_{22} $$ ) animals. The procedure ensures G $$ \mathbf{G} $$ and A 22 $$ {\mathbf{A}}_{22} $$ are compatible so that both matrices refer to the same genetic base ('tuning'). Then G $$ \mathbf{G} $$ is combined with a proportion of A 22 $$ {\mathbf{A}}_{22} $$ ('blending') to avoid singularity problems and to account for the polygenic component not accounted for by markers. This computational procedure has been implemented in the reverse order (blending before tuning) following the sequential research developments. However, blending before tuning may result in less optimal tuning because the blended matrix already contains a proportion of A 22 $$ {\mathbf{A}}_{22} $$ . In this study, the impact of 'tuning before blending' was compared with 'blending before tuning' on genomic estimated breeding values (GEBV), single nucleotide polymorphism (SNP) effects and indirect predictions (IP) from ssGBLUP using American Angus Association and Holstein Association USA, Inc. data. Two slightly different tuning methods were used; one that adjusts the mean diagonals and off-diagonals of G $$ \mathbf{G} $$ to be similar to those in A 22 $$ {\mathbf{A}}_{22} $$ and another one that adjusts based on the average difference between all elements of G $$ \mathbf{G} $$ and A 22 $$ {\mathbf{A}}_{22} $$ . Over 6 million Angus growth records and 5.9 million Holstein udder depth records were available. Genomic information was available on 51,478 Angus and 105,116 Holstein animals. Average realized relationship estimates among groups of animals were similar across scenarios. Scatterplots show that GEBV, SNP effects and IP did not noticeably change for all animals in the evaluation regardless of the order of computations and when using blending parameter of 0.05. Formulas were derived to determine the blending parameter that maximizes changes in the genomic relationship matrix and GEBV when changing the order of blending and tuning. Algebraically, the change is maximized when the blending parameter is equal to 0.5. Overall, tuning G $$ \mathbf{G} $$ before blending, regardless of blending parameter used, had a negligible impact on genomic predictions and SNP effects in this study.

Naturally acquired antibodies from Beninese infants promote Plasmodium falciparum merozoite-phagocytosis by human blood leukocytes: implications for control of asymptomatic malaria infections.

BACKGROUND: Immunoglobulin G (IgG) antibodies are thought to play important roles in the protection against Plasmodium falciparum (P. falciparum) malaria. A longitudinal cohort study performed in the Southern part of Benin, identified a group of infants who were able to control asymptomatic malaria infections (CAIG). METHODS: IgG antibodies against distinct merozoite antigens were quantified in plasma from Beninese infants. Functionality of these antibodies was assessed by the merozoite-phagocytosis assay using THP-1 cells and primary neutrophils as effector cells. Gm allotypes were determined by a serological method of haemagglutination inhibition. RESULTS: Purified IgG from infants in CAIG promoted higher levels of merozoite-phagocytosis than did IgG from children who were unable to control asymptomatic infections (Ologit multivariate regression model, Coef. = 0.06, 95% CI 0.02;0.10, P = 0.002). High level of merozoite-phagocytosis activity was significantly associated with high levels of IgG against AMA1 (Coef. = 1.76, 95% CI 0.39;3.14, P = 0.012) and GLURP-R2 (Coef. = 12.24, 95% CI 1.35;23.12, P = 0.028). Moreover, infants of the G3m5,6,10,11,13,14,24 phenotype showed higher merozoite-phagocytosis activity (Generalized linear model multivariate regression, Coef. = 7.46, 95% CI 0.31;14.61, P = 0.041) than those presenting other G3m phenotypes. CONCLUSION: The results of the present study confirm the importance of antibodies to merozoite surface antigens in the control of asymptomatic malaria infection in Beninese infants. The study also demonstrated that G3m phenotypes impact the functional activity of IgG. This last point could have a considerable impact in the research of candidate vaccines against malaria parasites or other pathogens.

Theoretical accuracy for indirect predictions based on SNP effects from single-step GBLUP.

BACKGROUND: Although single-step GBLUP (ssGBLUP) is an animal model, SNP effects can be backsolved from genomic estimated breeding values (GEBV). Predicted SNP effects allow to compute indirect prediction (IP) per individual as the sum of the SNP effects multiplied by its gene content, which is helpful when the number of genotyped animals is large, for genotyped animals not in the official evaluations, and when interim evaluations are needed. Typically, IP are obtained for new batches of genotyped individuals, all of them young and without phenotypes. Individual (theoretical) accuracies for IP are rarely reported, but they are nevertheless of interest. Our first objective was to present equations to compute individual accuracy of IP, based on prediction error covariance (PEC) of SNP effects, and in turn, are obtained from PEC of GEBV in ssGBLUP. The second objective was to test the algorithm for proven and young (APY) in PEC computations. With large datasets, it is impossible to handle the full PEC matrix, thus the third objective was to examine the minimum number of genotyped animals needed in PEC computations to achieve IP accuracies that are equivalent to GEBV accuracies. RESULTS: Correlations between GEBV and IP for the validation animals using SNP effects from ssGBLUP evaluations were ≥ 0.99. When all available genotyped animals were used for PEC computations, correlations between GEBV and IP accuracy were ≥ 0.99. In addition, IP accuracies were compatible with GEBV accuracies either with direct inversion of the genomic relationship matrix (G) or using the algorithm for proven and young (APY) to obtain the inverse of G. As the number of genotyped animals included in the PEC computations decreased from around 55,000 to 15,000, correlations were still ≥ 0.96, but IP accuracies were biased downwards. CONCLUSIONS: Theoretical accuracy of indirect prediction can be successfully obtained by computing SNP PEC out of GEBV PEC from ssGBLUP equations using direct or APY G inverse. It is possible to reduce the number of genotyped animals in PEC computations, but accuracies may be underestimated. Further research is needed to approximate SNP PEC from ssGBLUP to limit the computational requirements with many genotyped animals.

The Impact of Maternal Depression and Parent-Child Interactions on Risk of Parasitic Infections in Early Childhood: A Prospective Cohort in Benin.

OBJECTIVES: Maternal depression occurs in 13-20% of women from low-income countries, which is associated with negative child health outcomes, including diarrheal disease. However, few studies have investigated its impact on child risk of infectious disease. We studied the impacts of maternal depressive symptoms and parent-child interactions, independently, on the risk of Plasmodium falciparum malaria and soil-transmitted helminth infection in Beninese children. METHODS: Our population included mothers and children enrolled in a clinical trial during pregnancy (MiPPAD) in Benin. The Edinburgh Postnatal Depression Scale (EPDS) assessed maternal depressive symptoms and the home observation measurement of the environment (HOME) assessed parent-child interactions. Blood and stool sample analyses diagnosed child malaria and helminth infection at 12, 18, and 24 months. Negative binomial and Poisson regression models with robust variance tested associations. RESULTS: Of the 302 mother-child pairs, 39 (12.9%) mothers had depressive symptoms. Median number of malaria episodes per child was 3 (0-14) and 29.1% children had at least one helminth infection. Higher EPDS scores were associated with lower HOME scores; relative risk (RR) 0.97 (95% confidence interval (CI) 0.95, 0.99), particularly with lower acceptance, involvement, and variety subscales; RR 0.92 (95% CI 0.85, 0.99), RR 0.82 (95% CI 0.77, 0.88), RR 0.93 (95% CI 0.88, 0.99), respectively. However, neither exposure was associated with risk of parasitic infection in children. CONCLUSIONS FOR PRACTICE: Maternal depressive symptoms are associated with poor parent-child interactions, particularly acceptance of behavior, involvement with children, and variety of interactions, but these exposures do not independently impact risk of parasitic infection in children.

Fc Gamma Receptor IIIB NA1/NA2/SH Polymorphisms Are Associated with Malaria Susceptibility and Antibody Levels to P. falciparum Merozoite Antigens in Beninese Children.

This paper aimed to investigate the influence of polymorphisms in the FCGR2A gene encoding R131H FcgRIIA variants and in the FCGR3B gene (108G > C, 114C > T, 194 A > G, 233C > A, 244 G > A and 316G > A) encoding FcgRIIIB-NA1, -NA2 and -SH variants on malaria susceptibility and antibody responses against P. falciparum merozoite antigens in Beninese children. An active malaria follow-up was conducted in infants from birth to 24 months of age in Allada, Benin. FCGR3B exon 3 was sequenced and FCGR2A exon 4 was genotyped. Antibodies directed to GLURP and MSP3 were quantified by ELISA. Association studies were performed using mixed-effect models. Individual carriage of FCGR3B 194 AA genotype was associated with a high number of malaria infections and a low level of IgG1 against MSP3 and GLURP-R0. High parasitemia and increased malaria infections were observed in infants carrying the FCGR3B*05 108C-114T-194A-233C-244A-316A haplotype. A reduced risk of malaria infections and low parasitemia were related to the carriages of the FCGR3B 108C-114T-194G-233C-244G-316A (FCGR3B*06), FCGR3B 108C−114T−194G−233A−244A−316A (FCGR3B*03 encoding for FcgRIIIB-SH) haplotypes and FCGR3B 297 TT genotype. Our results highlight the impact of FCGR3B polymorphisms on the individual susceptibility to malaria and antibody responses against MSP3 and GLURP in Beninese children.

Genomic predictions for fillet yield and firmness in rainbow trout using reduced-density SNP panels.

BACKGROUND: One of the most important goals for the rainbow trout aquaculture industry is to improve fillet yield and fillet quality. Previously, we showed that a 50 K transcribed-SNP chip can be used to detect quantitative trait loci (QTL) associated with fillet yield and fillet firmness. In this study, data from 1568 fish genotyped for the 50 K transcribed-SNP chip and ~ 774 fish phenotyped for fillet yield and fillet firmness were used in a single-step genomic BLUP (ssGBLUP) model to compute the genomic estimated breeding values (GEBV). In addition, pedigree-based best linear unbiased prediction (PBLUP) was used to calculate traditional, family-based estimated breeding values (EBV). RESULTS: The genomic predictions outperformed the traditional EBV by 35% for fillet yield and 42% for fillet firmness. The predictive ability for fillet yield and fillet firmness was 0.19-0.20 with PBLUP, and 0.27 with ssGBLUP. Additionally, reducing SNP panel densities indicated that using 500-800 SNPs in genomic predictions still provides predictive abilities higher than PBLUP. CONCLUSION: These results suggest that genomic evaluation is a feasible strategy to identify and select fish with superior genetic merit within rainbow trout families, even with low-density SNP panels.

Genotyping complex structural variation at the malaria-associated human glycophorin locus using a PCR-based strategy.

Structural variation in the human genome can affect risk of disease. An example is a complex structural variant of the human glycophorin gene cluster, called DUP4, which is associated with a clinically significant level of protection against severe malaria. The human glycophorin gene cluster harbours at least 23 distinct structural variants, and accurate genotyping of this complex structural variation remains a challenge. Here, we use a polymerase chain reaction-based strategy to genotype structural variation at the human glycophorin gene cluster, including the alleles responsible for the U- blood group. We validate our approach, based on a triplex paralogue ratio test, on publically available samples from the 1000 Genomes project. We then genotype 574 individuals from a longitudinal birth cohort (Tori-Bossito cohort) using small amounts of DNA at low cost. Our approach readily identifies known deletions and duplications, and can potentially identify novel variants for further analysis. It will allow exploration of genetic variation at the glycophorin locus, and investigation of its relationship with malaria, in large sample sets at minimal cost, using standard molecular biology equipment.

A timed tally counter for microscopic examination of thick blood smears in malaria studies.

BACKGROUND: Despite many technological advances for malaria parasite detection (e.g. high resolution image acquisition), microscopic reading of thick blood smear (TBS) remains the gold standard. Even though available in low technology environment, the microscopy of TBS is slow and time consuming. Moreover microscopy may induce errors at many levels and has no quality control. METHODS: A electronic extension of the mechanical tally counter is proposed. In addition to the counting process it includes the process of counting itself that relies on the time elapsed between two successive pressures of the counting button leading to a timed tally counter (TTC). The microscopist performs the reading with the specific instruction starting by counting, in each high power fields, leucocytes first and then parasites. The time-stamp of all pressures of counting buttons are recorded along with the nature of the count. The data are recorded internally in CSV format and are exportable. The detection of HPFs locations and leukocyte/parasite counts per HPFs is performed through a hidden semi-Markov model (with outliers) allowing both to take into account the known distribution of leukocyte per HPFs (using a negative binomial distribution) and the pauses and hesitation of the microscopist during the reading. Parameters are estimated via the expectation-maximization algorithm. Hyper-parameters are calibrated using expert annotations. Forward/backward recursions are used to obtain the HPFs locations. RESULTS: This approach provides richer data at no extra cost. It has been demonstrated that the method can derive parasites per HPF, leukocytes per HPF, and parasite/leukocyte ratio with robust non-parametric confidence intervals. Moreover a direct digital data entry leads to a less expensive process and decreased time-consuming and error-prone manual data entry. Lastly the TTC allows detecting possible protocol break during reading and prevents the risk of fraud. DISCUSSION AND CONCLUSION: Introducing a programmed digital device in the data acquisition of TBS reading gives the opportunity to develop easily new (possible adaptive) reading protocols that will be easily followed by the reader since they will be embedded directly in the device. With the TTC the reader only has to read HPFs, counting leukocytes first and parasites second, and the counter will beep when the protocol is completed.

Multiplicity of Asymptomatic Plasmodium falciparum Infections and Risk of Clinical Malaria: A Systematic Review and Pooled Analysis of Individual Participant Data.

BACKGROUND: The malaria parasite Plasmodium falciparum holds an extensive genetic polymorphism. In this pooled analysis, we investigate how the multiplicity in asymptomatic P. falciparum infections-that is, the number of coinfecting clones-affects the subsequent risk of clinical malaria in populations living under different levels of transmission. METHODS: A systematic search of the literature was performed to identify studies in which P. falciparum infections were genotyped in asymptomatic individuals who were followed up prospectively regarding the incidence of clinical malaria. Individual participant data were pooled from 15 studies (n = 3736 individuals). RESULTS: Multiclonal asymptomatic infections were associated with a somewhat increased subsequent risk of clinical malaria in the youngest children, followed by an initial declining risk with age irrespective of transmission intensity. At approximately 5 years of age, the risk continued the gradual decline with age in high-transmission settings. However, in older children in moderate-, low-, and seasonal-transmission settings, multiclonal infections were either not significantly associated with the risk of subsequent febrile malaria or were associated with an increased risk. CONCLUSIONS: The number of clones in asymptomatic P. falciparum infections is associated with different risks of subsequent clinical malaria depending on age and transmission intensity.

Mixed logistic regression in genome-wide association studies.

BACKGROUND: Mixed linear models (MLM) have been widely used to account for population structure in case-control genome-wide association studies, the status being analyzed as a quantitative phenotype. Chen et al. proved in 2016 that this method is inappropriate in some situations and proposed GMMAT, a score test for the mixed logistic regression (MLR). However, this test does not produces an estimation of the variants' effects. We propose two computationally efficient methods to estimate the variants' effects. Their properties and those of other methods (MLM, logistic regression) are evaluated using both simulated and real genomic data from a recent GWAS in two geographically close population in West Africa. RESULTS: We show that, when the disease prevalence differs between population strata, MLM is inappropriate to analyze binary traits. MLR performs the best in all circumstances. The variants' effects are well evaluated by our methods, with a moderate bias when the effect sizes are large. Additionally, we propose a stratified QQ-plot, enhancing the diagnosis of p values inflation or deflation when population strata are not clearly identified in the sample. CONCLUSION: The two proposed methods are implemented in the R package milorGWAS available on the CRAN. Both methods scale up to at least 10,000 individuals. The same computational strategies could be applied to other models (e.g. mixed Cox model for survival analysis).

Schistosoma haematobium infection modulates Plasmodium falciparum parasite density and antimalarial antibody responses.

AIMS: Schistosomiasis and malaria are endemic in sub-Saharan Africa where Schistosoma haematobium (Sh) and Plasmodium falciparum (Pf) coinfections are thus frequent. We explored the effect of Sh infection on antibody responses directed to Pf merozoite antigens and on malaria susceptibility in Beninese children. METHODS AND RESULTS: A total of 268 children were followed during a malaria transmission season. Detection of Pf infection was performed by microscopy and rapid diagnostic tests. Sh infection was determined in urine by microscopy. Antimalarial antibody, cytokine and HLA-G concentrations were quantified by ELISA. The expression of HLA-G receptors by immune cells was assessed by flow cytometry. Children infected by Sh had higher concentrations of IgG1 directed to MSP3 and GLURPR0 , IgG2 directed to GLURPR0 and IgG3 directed to MSP3, GLURPR0 and GLURPR2 and have lower Pf densities than those uninfected by Sh. No difference in cytokine and HLA-G concentrations was observed between Sh egg carriers and non-carriers. CONCLUSION: Schistosoma haematobium modulates host immune responses directed to Pf antigens. The absence of immune downregulation usually observed during helminth infections is surprising in our study. We hypothesize that the stage of Sh development could partly explain the immune pathways leading to increased antibody levels that favour better control of Pf parasitemia.

Cattle as natural host for Schistosoma haematobium (Bilharz, 1852) Weinland, 1858 x Schistosoma bovis Sonsino, 1876 interactions, with new cercarial emergence and genetic patterns.

Schistosomiasis remains a parasitic infection which poses serious public health consequences around the world, particularly on the African continent where cases of introgression/hybridization between human and cattle schistosomiasis are being discovered on a more frequent basis in humans, specifically between Schistosoma haematobium and S. bovis. The aim of this paper is to analyze the occurrence of S. bovis in cattle and its relationship with S. haematobium in an area where cattle and humans share the same site in Benin (West Africa). We used the chronobiology of cercarial emergence as an ecological parameter and both molecular biology (COI mtDNA and ITS rDNA) of the larvae and morphology of the eggs as taxonomic parameters. The results showed a chronobiological polymorphism in the cercarial emergence rhythm. They showed for the first time the presence of S. bovis in Benin, the presence of introgressive hybridization between S. bovis and S. haematobium in domestic cattle, and the presence of atypical chronobiological patterns in schistosomes from cattle, with typical S. haematobium shedding pattern, double-peak patterns, and nocturnal patterns. Our results showed that the chronobiological life-history trait is useful for the detection of new hosts and also may reveal the possible presence of introgressive hybridization in schistosomes. Our results, for the first time, place cattle as reservoir host for S. haematobium and S. bovis x S. haematobium. The consequences of these results on the epidemiology of the disease, the transmission to humans, and the control of the disease are very important.

Increased Risk of Malaria During the First Year of Life in Small-for-Gestational-Age Infants: A Longitudinal Study in Benin.

BACKGROUND: According to the Developmental Origins of Health and Diseases paradigm, the fetal period is highly vulnerable and may have profound effects on later health. Few studies assessed the effect of small-for-gestational age (SGA), a proxy for fetal growth impairment, on risk of malaria during infancy in Africa. METHODS: We used data from a cohort of 398 mother-child pairs, followed from early pregnancy to age 1 year in Benin. Malaria was actively and passively screened using thick blood smear. We assessed the effect of SGA on risk of malaria infection and clinical malaria from birth to 12 months, after stratifying on the infant's age using a logistic mixed regression model. RESULTS: After adjustment for potential confounding factors and infant's exposure to mosquitoes, SGA was associated with a 2-times higher risk of malaria infection (adjusted odds ratio [aOR] = 2.16; 95% confidence interval [CI], 1.04-4.51; P = .039) and clinical malaria (aOR = 2.33; 95% CI, 1.09-4.98; P = .030) after age 6 months. CONCLUSION: Results suggest higher risk of malaria during the second semester of life in SGA infants, and argue for better follow-up of these infants after birth, as currently for preterm babies.

First genome-wide association study of non-severe malaria in two birth cohorts in Benin.

Recent research efforts to identify genes involved in malaria susceptibility using genome-wide approaches have focused on severe malaria. Here, we present the first GWAS on non-severe malaria designed to identify genetic variants involved in innate immunity or innate resistance mechanisms. Our study was performed on two cohorts of infants from southern Benin (525 and 250 individuals used as discovery and replication cohorts, respectively) closely followed from birth to 18-24 months of age, with an assessment of a space- and time-dependent environmental risk of exposure. Both the recurrence of mild malaria attacks and the recurrence of malaria infections as a whole (symptomatic and asymptomatic) were considered. Post-GWAS functional analyses were performed using positional, eQTL, and chromatin interaction mapping to identify the genes underlying association signals. Our study highlights a role of PTPRT, a tyrosine phosphatase receptor involved in STAT3 pathway, in the protection against both mild malaria attacks and malaria infections (p = 9.70 × 10-8 and p = 1.78 × 10-7, respectively, in the discovery cohort). Strong statistical support was also found for a role of MYLK4 (meta-analysis, p = 5.29 × 10-8 with malaria attacks), and for several other genes, whose biological functions are relevant in malaria infection. Results shows that GWAS on non-severe malaria can successfully identify new candidate genes and inform physiological mechanisms underlying natural protection against malaria.

Plasmodium falciparum merozoite surface antigen-specific cytophilic IgG and control of malaria infection in a Beninese birth cohort.

BACKGROUND: Substantial evidence indicates that cytophilic IgG responses to Plasmodium falciparum merozoite antigens play a role in protection from malaria. The specific targets mediating immunity remain unclear. Evaluating antibody responses in infants naturally-exposed to malaria will allow to better understand the establishment of anti-malarial immunity and to contribute to a vaccine development by identifying the most appropriate merozoite candidate antigens. METHODS: The study was based on parasitological and clinical active follow-up of infants from birth to 18 months of age conducted in the Tori Bossito area of southern Benin. For 399 infants, plasma levels of cytophilic IgG antibodies with specificity for five asexual stage malaria vaccine candidate antigens were determined by ELISA in infants' peripheral blood at 6, 9, 12 and 15 months of age. Multivariate mixed logistic model was used to investigate the association between antibody levels and anti-malarial protection in the trimester following the IgG quantification. Moreover, the concentrations of merozoite antigen-specific IgG were compared between a group of infants apparently able to control asymptomatic malaria infection (CAIG) and a group of infants with no control of malaria infection (Control group (NCIG)). Protective effect of antibodies was also assessed after 15 months of malaria exposure with a Cox regression model adjusted on environmental risk. RESULTS: Cytophilic IgG responses to AMA1, MSP1, MSP2-3D7, MSP2-FC27, MSP3 and GLURP R2 were associated with increasing malarial infection risk in univariate analysis. The multivariate mixed model showed that IgG1 and IgG3 to AMA1 were associated with an increased risk of malarial infection. However infants from CAIG (n = 53) had significantly higher AMA1-, MSP2-FC27-, MSP3-specific IgG1 and AMA1-, MSP1-, MSP2-FC27-, MSP3 and GLURP-R2-specific IgG3 than those from NCIG (n = 183). The latter IgG responses were not associated with protection against clinical malaria in the whole cohort when protective effect is assessed after 15 months of malaria exposition. CONCLUSION: In this cohort, merozoite antigen-specific cytophilic IgG levels represent a marker of malaria exposure in infants from 6 to 18 months of age. However, infants with resolution of asymptomatic infection (CAIG) seem to have acquired naturally immunity against P. falciparum. This observation is encouraging in the context of the development of multitarget P. falciparum vaccines.

Is Placental Malaria a Long-term Risk Factor for Mild Malaria Attack in Infancy? Revisiting a Paradigm.

Background: Children born to mothers with placental malaria (PM) have been described as more susceptible to the occurrence of a first malaria infection. However, whether or not these children remain more at risk during infancy has never been explored. We aimed to determine if children born to mothers with PM are more susceptible to malaria and remain at higher risk between birth and 18 months. Methods: Five hundred fifty children were followed up weekly with control of temperature and, if >37.5°C, both a rapid diagnostic test for malaria and a thick blood smear were performed. Taking into account environmental risk of infection, the relationship between occurrences of malaria attacks from birth to 18 months was modeled using Cox models for recurrent events. Results: PM is not associated with an overall susceptibility to malaria but only with the delay of occurrence of the first malaria attack. Children born from mothers with PM tend to have an increased risk for the first malaria attack (hazard ratio [HR] = 1.33; P = .048) but not for subsequent ones (HR = 0.9; P = .46). Children who experienced 1 malaria attack were strongly at risk to develop subsequent infections independent of placental infection and environmental exposure. Conclusions: These results are consistent with the existence of an individual susceptibility to malaria unrelated to PM. From a public health point of view, protecting children born to infected placenta remains a priority, but seems insufficient to account for other frail children for whom a biomarker of frailty needs to be found.