Combined polymorphisms involving the IgG heavy chain and Fc gamma receptors among Fulani and non-Fulani in Benin: implications for the natural protection of young Fulani against Plasmodium falciparum malaria infections.

A decreased susceptibility of Fulani populations to malaria infections has been shown in Africa. A previous longitudinal cohort study conducted in the Atacora region of northern Benin showed a high merozoite-phagocytosis capacity in young Fulani. Here, we explored the combined polymorphisms in the constant region of the IgG3 heavy chain (presence/absence of the G3m6 allotype) and in Fc gamma receptors (FcγRs) as potentially involved in the natural protection against malaria of young Fulani in Benin. An active malaria follow-up was conducted among individuals from Fulani, Bariba, Otamari and Gando ethnic groups living in sympatry in Atacora, over the full malaria transmission season. FcγRIIA 131R/H (rs1801274), FcγRIIC C/T (rs3933769) and FcγRIIIA 176F/V (rs396991) were determined using the TaqMan method; FcγRIIIB NA1/NA2 was assessed by polymerase chain reaction (PCR) using allele-specific primers and G3m6 using allotype by PCR-RFLP. Individual carriage of G3m6 (+) was associated with an increased risk of Pf malaria infection (logistic multivariate regression model (lmrm), OR = 2.25, 95% CI = 1.06;4.74, P = 0.034). Combined haplotype G3m6 (+) - FcγRIIA 131H - FcγRIIC T - FcγRIIIA 176F - FcγRIIIB NA2 was also associated with an increased risk of Pf malaria infection (lmrm, OR = 13.01, 95% CI = 1.69;99.76, P = 0.014). G3m6 (-), FcγRIIA 131R and FcγRIIIB NA1 were more prevalent in young Fulani (P = 0.002, P < 0.001 and P = 0.049, respectively), while no Fulani presented the combined G3m6 (+) - FcγRIIA 131H - FcγRIIC T - FcγRIIIA 176F - FcγRIIIB NA2 haplotype that was carried by a majority of infected children. Our results highlight the combined factors G3m6 - FcγR as potentially involved in the merozoite-phagocytosis capacity and in the natural protection of young Fulani individuals against P. falciparum malaria in Benin.

Susceptibility to malaria in fulani, Bariba, Otamari and gando individuals living in sympatry in Benin: Role of opsonizing antibodies to Plasmodium falciparum merozoites.

Objectives: Fulani in Africa are known to be less susceptible to Plasmodium falciparum (Pf) malaria. This study explored a potential involvement of antibody-mediated merozoite phagocytosis mechanism in this natural protection against malaria. Methods: Before the start of the malaria transmission season (MTS) in Benin, the functionality of antibodies against Pf merozoites was determined by the opsonic phagocytosis (OP) assay in plasma samples from Fulani, Bariba, Otamari and Gando groups. These individuals were actively followed-up for malaria detection from the beginning to the end of MTS. Anti-GLURP Immunoglobulin G antibody quantification, malaria Rapid Diagnostic Test (RDT) and spleen palpation were performed before and after MTS. Results: In Bariba, Otamari and Gando, but not in Fulani, plasma from adults promoted higher levels of OP than the children (P = 0.003; P = 0.012; P = 0.031 and P = 0.122). A high proportion of Fulani children had higher OP and anti-GLURP (P < 0.0001) antibody levels as compared to non-Fulani children; whereas this was not observed for Fulani adults (P = 0.223). High OP levels before MTS were significantly related to negative RDT after MTS (P = 0.011). Conclusion: Our results highlight the ability of opsonizing antibodies to potentially enhance natural protection of young Fulani individuals against Pf malaria in Benin.

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.

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.

Empirical Analysis of Health Assessment Objective and Subjective Methods on the Determinants of Health.

Background: There are several methods for assessing health status. The aims of this study were to investigate the empirical differences between health assessment objective and subjective methods, to identify a possible long-term relationship between methods and health determinants and the influence of these methods on the perceived level of risk according to health determinants. Methods: Using data from 1970 to 2018 in the United States, health status was assessed by perception of health, absence from work due to self-reported illness, life expectancy at birth and mortality rate. Health determinants were tobacco and alcohol consumptions, number of physicians per 1,000 persons, stay in hospitalization unit, curative care, release of greenhouse gases, per capita gross domestic product (GDP) and urbanization. The differences between health objective and subjective assessment methods were investigated through a Generalized linear model, a structural break date of health methods was investigated by Chow test and the long-term relationship between health assessment methods and health determinants by Engle and Granger cointegration test. Results: Tobacco consumption was associated with a decrease of life expectancy while no long-term causal relationship was found between them. There was a positive correlation between alcohol consumption and perception of good health with a long-term causal relationship. Although per capita GDP positively influenced life expectancy, there was no cointegration between them. The release of greenhouse gases was positively correlated with both the absence from work due to self-reported illness and the perception of good health. Finally, curative care was associated with a decrease of mortality and absence from work due to self-reported illness and an increase of life expectancy and perception of good health while hospitalization is positively correlated with mortality and negatively correlated with life expectancy with a long-term causal relationship. Finally, the number of physicians per 1,000 persons was not correlated with health assessment methods used. Conclusion: Our results highlight the influence of health assessment methods on the determinants of health and the fact that the perceived risk of health determinants changes according to the method used. Thus, the impact of health assessment methods must be considered in order to prioritize the determinants of health.

Susceptibility to Plasmodium falciparum Malaria: Influence of Combined Polymorphisms of IgG3 Gm Allotypes and Fc Gamma Receptors IIA, IIIA, and IIIB.

The binding of immunoglobulin (Ig) to Fc gamma receptors (FcgR) at the immune cell surface is an important step to initiate immunological defense against malaria. However, polymorphisms in receptors and/or constant regions of the IgG heavy chains may modulate this binding. Here, we investigated whether polymorphisms located in FcgR and constant regions of the heavy chain of IgG are associated with susceptibility to P. falciparum malaria. For this purpose, a clinical and parasitological follow-up on malaria was conducted among 656 infants in southern Benin. G3m allotypes (from total IgG3) were determined by a serological method of hemagglutination inhibition. FcgRIIA 131R/H and FcgRIIIA 176F/V genotypes were determined using the TaqMan method and FcgRIIIB NA1/NA2 genotypes were assessed by polymerase chain reaction using allele-specific primers. Association analyses between the number of malaria infections during the follow-up and polymorphisms in IgG G3m allotypes and FcgR were studied independently by zero inflated binomial negative regression. The influence of combinations of G3m allotypes and FcgRIIA/FcgRIIIA/FcgRIIIB polymorphisms on the number of P. falciparum infections, and their potential interaction with environmental exposure to malaria was assessed by using the generalized multifactor dimensionality reduction (GMDR) method. Results showed that individual carriage of G3m24 single allotype and of G3m5,6,10,11,13,14,24 phenotype was independently associated with a high risk of malaria infection. A risk effect for G3m6 was observed only under high environmental exposure. FcgRIIIA 176VV single genotype and combined carriage of FcgRIIA 131RH/FcgRIIIA 176VV/FcgRIIIB NA1NA2, FcgRIIA 131HH/FcgRIIIA 176FF/FcgRIIIB NA1NA1, FcgRIIA 131HH/FcgRIIIA 176VV/FcgRIIIB NA2NA2 and FcgRIIA 131HH/FcgRIIIA 176VV/FcgRIIIB NA1NA2 genotypes were related to a high number of malaria infections. The risk was accentuated for FcgRIIIA 176VV when considering the influence of environmental exposure to malaria. Finally, the GMDR analysis including environmental exposure showed strengthened associations with a malaria risk when FcgRIIA/FcgRIIIA/FcgRIIIB genotypes were combined to G3m5,6,11,24 and G3m5,6,10,11,13,15,24 phenotypes or G3m10 and G3m13 single allotypes. Our results highlight the relevance of studying IgG heavy chain and FcgR polymorphisms, independently as well as in combination, in relation to the individual susceptibility to P. falciparum infection. The intensity of individual exposure to mosquito bites was demonstrated to impact the relationships found.