Limits...
The genetic control of immunity to Plasmodium infection.

Grant AV, Roussilhon C, Paul R, Sakuntabhai A - BMC Immunol. (2015)

Bottom Line: Malaria remains a major worldwide public health problem with ~207 million cases and ~627,000 deaths per year, mainly affecting children under five years of age in Africa.Molecular pathways controlling phenotypes representing effectiveness of host immunity, notably parasitemia and IgG levels, are of particular interest given the current lack of an efficacious vaccine and the need for new treatment options.Genetic polymorphism may control any of these stages, such that preceding stages act as mediators of subsequent stages.

View Article: PubMed Central - PubMed

Affiliation: Unité de la Génétique Fonctionnelle des Maladies Infectieuses, Institut Pasteur, Paris, France. audrey.grant@pasteur.fr.

ABSTRACT

Background: Malaria remains a major worldwide public health problem with ~207 million cases and ~627,000 deaths per year, mainly affecting children under five years of age in Africa. Recent efforts at elaborating a genetic architecture of malaria have focused on severe malaria, leading to the identification of two new genes and confirmation of previously known variants in HBB, ABO and G6PD, by exploring the whole human genome in genome-wide association (GWA) studies. Molecular pathways controlling phenotypes representing effectiveness of host immunity, notably parasitemia and IgG levels, are of particular interest given the current lack of an efficacious vaccine and the need for new treatment options.

Results: We propose a global causal framework of malaria phenotypes implicating progression from the initial infection with Plasmodium spp. to the development of the infection through liver and blood-stage multiplication cycles (parasitemia as a quantitative trait), to clinical malaria attack, and finally to severe malaria. Genetic polymorphism may control any of these stages, such that preceding stages act as mediators of subsequent stages. A biomarker of humoral immunity, IgG levels, can also be integrated into the framework, potentially mediating the impact of polymorphism by limiting parasitemia levels. Current knowledge of the genetic basis of parasitemia levels and IgG levels is reviewed through key examples including the hemoglobinopathies, showing that the protective effect of HBB variants on malaria clinical phenotypes may partially be mediated through parasitemia and cytophilic IgG levels. Another example is the IgG receptor FcγRIIa, encoded by FCGR2A, such that H131 homozygotes displayed higher IgG2 levels and were protective against high parasitemia and onset of malaria symptoms as shown in a causal diagram.

Conclusions: We thus underline the value of parasitemia and IgG levels as phenotypes in the understanding of the human genetic architecture of malaria, and the need for applying GWA approaches to these phenotypes.

Show MeSH

Related in: MedlinePlus

Causal diagrams going fromPlasmodium spp. infection to severe malaria through parasitemia and clinical attack. A. Two possible pathways going from infection to parasitemia, via IgG-mediated acquired immunity or directly from infection to parasitemia, and multiple possible pathways for the impact of genetic polymorphism on IgG, parasitemia, clinical attack or severe malaria. B. An example specifying Plasmodium falciparum as the infective species, and the influence of genetic polyporphism at FcγRIIa distinguishing between FcγRIIa homozygotes for H131 vs. heterozygotes & homozygotes for R131 (recessive model) acting on parasitemia via IgG2 levels. The causal diagrams were created using DAGittyv.2.0 (http://www.dagitty.net/).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4374205&req=5

Fig1: Causal diagrams going fromPlasmodium spp. infection to severe malaria through parasitemia and clinical attack. A. Two possible pathways going from infection to parasitemia, via IgG-mediated acquired immunity or directly from infection to parasitemia, and multiple possible pathways for the impact of genetic polymorphism on IgG, parasitemia, clinical attack or severe malaria. B. An example specifying Plasmodium falciparum as the infective species, and the influence of genetic polyporphism at FcγRIIa distinguishing between FcγRIIa homozygotes for H131 vs. heterozygotes & homozygotes for R131 (recessive model) acting on parasitemia via IgG2 levels. The causal diagrams were created using DAGittyv.2.0 (http://www.dagitty.net/).

Mentions: Parasitemia can be considered to be the result of two opposing forces in a tug-of-war, the pressure exerted by the malarial parasite in its multiplicative red blood cell stage, versus the pressure of anti-malarial immunity. The higher the parasitemia, the greater the malarial force, and the lower the force of anti-malarial immunity. For the study of human genetics, it would be optimal to focus on a measure of parasitemia that represents the global effectiveness of anti-malarial host immunity, which would assume factors contributing to malarial parasite pressure to be homogeneous across the study population, including parasite species and strain, and that all other parameters impacting on parasitemia, such as the initial parasite dose, are homogeneous or controlled for. Also, factors such as nutritional status, which affect host immunity without reflecting innate effectiveness should be constant in the population. These assumptions are met in part in the longitudinal study design that is limited geographically with contained vectorial transmission, and focused on a community with a similar lifestyle and socio-economic status as in a longitudinal study following an endemic community in Senegal for 22 years [9]. Host immunity is also known to vary with age and sex, which can be adjusted for. Under such homogeneous, controlled conditions, causal diagrams can offer a heuristic framework with which to evaluate potential causal pathways, highlighting genetic factors of interest (see Figure 1A) [10]. A progression is implied, going from the initial infection with Plasmodium spp. to the development of the infection through liver and blood-stage multiplication cycles (parasitemia as a quantitative trait), to clinical malaria attack, and to severe malaria. The initial infection stimulates the immune system, elicits protective IgG antibodies that limit parasitemia levels and represent the humoral aspect of anti-malarial host immunity. The arrows imply a causal relationship but do not imply a particular direction (increase or decrease). Arrows point from genetic polymorphism to all malaria phenotypes, indicating that all hypotheses are possible until tested, and thus the causal framework can be thought of as summarizing the working hypotheses which can then be reduced and refined as study results are obtained. Parasitemia occurs early in the causal pathway, prior to clinical symptoms and can be considered a malaria endophenotype. Genetic association studies evaluating specific polymorphisms can be tested for association with any of the measurable phenotypes in the causal progression, including parasitemia and IgG levels. Previous parasitemia candidate gene studies will be reviewed with examples considered in the context of this causal framework for the complex scenarios involving mediation through IgG levels. The candidate gene studies of parasitemia involve evaluation of the causal arrow from genetic polymorphism to parasitemia.Figure 1


The genetic control of immunity to Plasmodium infection.

Grant AV, Roussilhon C, Paul R, Sakuntabhai A - BMC Immunol. (2015)

Causal diagrams going fromPlasmodium spp. infection to severe malaria through parasitemia and clinical attack. A. Two possible pathways going from infection to parasitemia, via IgG-mediated acquired immunity or directly from infection to parasitemia, and multiple possible pathways for the impact of genetic polymorphism on IgG, parasitemia, clinical attack or severe malaria. B. An example specifying Plasmodium falciparum as the infective species, and the influence of genetic polyporphism at FcγRIIa distinguishing between FcγRIIa homozygotes for H131 vs. heterozygotes & homozygotes for R131 (recessive model) acting on parasitemia via IgG2 levels. The causal diagrams were created using DAGittyv.2.0 (http://www.dagitty.net/).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4374205&req=5

Fig1: Causal diagrams going fromPlasmodium spp. infection to severe malaria through parasitemia and clinical attack. A. Two possible pathways going from infection to parasitemia, via IgG-mediated acquired immunity or directly from infection to parasitemia, and multiple possible pathways for the impact of genetic polymorphism on IgG, parasitemia, clinical attack or severe malaria. B. An example specifying Plasmodium falciparum as the infective species, and the influence of genetic polyporphism at FcγRIIa distinguishing between FcγRIIa homozygotes for H131 vs. heterozygotes & homozygotes for R131 (recessive model) acting on parasitemia via IgG2 levels. The causal diagrams were created using DAGittyv.2.0 (http://www.dagitty.net/).
Mentions: Parasitemia can be considered to be the result of two opposing forces in a tug-of-war, the pressure exerted by the malarial parasite in its multiplicative red blood cell stage, versus the pressure of anti-malarial immunity. The higher the parasitemia, the greater the malarial force, and the lower the force of anti-malarial immunity. For the study of human genetics, it would be optimal to focus on a measure of parasitemia that represents the global effectiveness of anti-malarial host immunity, which would assume factors contributing to malarial parasite pressure to be homogeneous across the study population, including parasite species and strain, and that all other parameters impacting on parasitemia, such as the initial parasite dose, are homogeneous or controlled for. Also, factors such as nutritional status, which affect host immunity without reflecting innate effectiveness should be constant in the population. These assumptions are met in part in the longitudinal study design that is limited geographically with contained vectorial transmission, and focused on a community with a similar lifestyle and socio-economic status as in a longitudinal study following an endemic community in Senegal for 22 years [9]. Host immunity is also known to vary with age and sex, which can be adjusted for. Under such homogeneous, controlled conditions, causal diagrams can offer a heuristic framework with which to evaluate potential causal pathways, highlighting genetic factors of interest (see Figure 1A) [10]. A progression is implied, going from the initial infection with Plasmodium spp. to the development of the infection through liver and blood-stage multiplication cycles (parasitemia as a quantitative trait), to clinical malaria attack, and to severe malaria. The initial infection stimulates the immune system, elicits protective IgG antibodies that limit parasitemia levels and represent the humoral aspect of anti-malarial host immunity. The arrows imply a causal relationship but do not imply a particular direction (increase or decrease). Arrows point from genetic polymorphism to all malaria phenotypes, indicating that all hypotheses are possible until tested, and thus the causal framework can be thought of as summarizing the working hypotheses which can then be reduced and refined as study results are obtained. Parasitemia occurs early in the causal pathway, prior to clinical symptoms and can be considered a malaria endophenotype. Genetic association studies evaluating specific polymorphisms can be tested for association with any of the measurable phenotypes in the causal progression, including parasitemia and IgG levels. Previous parasitemia candidate gene studies will be reviewed with examples considered in the context of this causal framework for the complex scenarios involving mediation through IgG levels. The candidate gene studies of parasitemia involve evaluation of the causal arrow from genetic polymorphism to parasitemia.Figure 1

Bottom Line: Malaria remains a major worldwide public health problem with ~207 million cases and ~627,000 deaths per year, mainly affecting children under five years of age in Africa.Molecular pathways controlling phenotypes representing effectiveness of host immunity, notably parasitemia and IgG levels, are of particular interest given the current lack of an efficacious vaccine and the need for new treatment options.Genetic polymorphism may control any of these stages, such that preceding stages act as mediators of subsequent stages.

View Article: PubMed Central - PubMed

Affiliation: Unité de la Génétique Fonctionnelle des Maladies Infectieuses, Institut Pasteur, Paris, France. audrey.grant@pasteur.fr.

ABSTRACT

Background: Malaria remains a major worldwide public health problem with ~207 million cases and ~627,000 deaths per year, mainly affecting children under five years of age in Africa. Recent efforts at elaborating a genetic architecture of malaria have focused on severe malaria, leading to the identification of two new genes and confirmation of previously known variants in HBB, ABO and G6PD, by exploring the whole human genome in genome-wide association (GWA) studies. Molecular pathways controlling phenotypes representing effectiveness of host immunity, notably parasitemia and IgG levels, are of particular interest given the current lack of an efficacious vaccine and the need for new treatment options.

Results: We propose a global causal framework of malaria phenotypes implicating progression from the initial infection with Plasmodium spp. to the development of the infection through liver and blood-stage multiplication cycles (parasitemia as a quantitative trait), to clinical malaria attack, and finally to severe malaria. Genetic polymorphism may control any of these stages, such that preceding stages act as mediators of subsequent stages. A biomarker of humoral immunity, IgG levels, can also be integrated into the framework, potentially mediating the impact of polymorphism by limiting parasitemia levels. Current knowledge of the genetic basis of parasitemia levels and IgG levels is reviewed through key examples including the hemoglobinopathies, showing that the protective effect of HBB variants on malaria clinical phenotypes may partially be mediated through parasitemia and cytophilic IgG levels. Another example is the IgG receptor FcγRIIa, encoded by FCGR2A, such that H131 homozygotes displayed higher IgG2 levels and were protective against high parasitemia and onset of malaria symptoms as shown in a causal diagram.

Conclusions: We thus underline the value of parasitemia and IgG levels as phenotypes in the understanding of the human genetic architecture of malaria, and the need for applying GWA approaches to these phenotypes.

Show MeSH
Related in: MedlinePlus