GENETICS OF PARASITIC INFECTIONS

ABSTRACT: Parasites cause much suffering mainly in countries of the southern hemisphere. Hundreds of millions of individuals are infected by schistosomes, leishmanias, plasmodiums, trypanosomes, and various other parasites, and severe clinical disease occurs in a sizable fraction of the infected population causing death and severe sequelae. The outcome, asymptomatic, subclinical or clinical disease, of an infection depends mostly on the parasite and on its host. Several groups analyzing the genetics of human susceptibility to parasites have began to identify the critical steps of the pathogenic mechanisms in a few parasitic infections such as malaria and schistosomiasis. The present article, which is not meant to be an exhaustive review of the field, illustrates the progresses made in this field from pioneer studies in animals to works in endemic populations using modern strategies of human genetics. A variety of parasites cause chronic infections that last for long periods of time in their human host without much clinical symptoms; in some subjects, however, parasites cause severe disease. These pathological disorders may become apparent after 10 to 20 years of infection as in subjects infected by Schistosoma mansoni or by Trypanosoma cruzi, or within a few weeks of infection in patients affected by Leishmania donovani or by Plasmodium falciparum. Various studies have attempted to identify the factors that cause disease to develop in only a fraction of the population exposed to parasites. Much attention has been given to the environment because parasite transmission depends markedly on environmental factors including vector density, vector distribution, and parasite virulence. Parasites, because they have a large genome, have developed very sophisticated mechanisms, like antigenic variation, to escape immune destruction. The plasticity of the parasite genome is so large that it is tempting to link the different clinical and subclinical forms caused by the infection to the existence of clones of different virulence/pathogenicity in the parasite population. This view is unlikely to apply to parasites such as Schistosoma mansoni that, in a given endemic area, express homogenous antigenic and pathogenic properties; it might apply, however, to infections by protozoan parasites such as plasmodium or leishmanias that are highly polymorph and multiply rapidly within their human hosts allowing for emerging variants. The importance of host genetics in disease development has been difficult to assess because of the multiplicity of the environmental factors, including parasite heterogeneity, that may determine disease. The role of genetics was first addressed in experimental models in which environmental variables can be controlled and measured. Animal studies allowed the discovery of the most interesting NRAMP1 gene, which likely plays an important role in innate immunity against intracellular pathogens. Studies on human genetics and susceptibility to parasitic infections began with observations of the high prevalence of mutated alleles of the ␤ globin gene in areas of malaria high endemicity, leading to the hypothesis that these alleles were protective against severe malaria. This observation was then further supported by the results of case control studies. Comparable strategies were used to demonstrate that certain HLA 1 haplotypes The present article will summarize the observations made in schistosome, leishmania and plasmodium infections. All three parasites are a major threat for human health in the southern hemisphere Genetics of Leishmania Infections in Experimental Models The first evidence for an important role of genetic factors in the control of infections was reported in experimental models. Studies of animals have the advantage over human studies to allow for the control of environmental factors and of the parasite (heterogeneity, size of the inoculum, etc.). In addition, genetic analysis is easier than in humans since animals can be bred. As discussed in another chapte

Variants of CTGF are associated with hepatic fibrosis in Chinese, Sudanese, and Brazilians infected with Schistosomes

Abnormal fibrosis occurs during chronic hepatic inflammations and is the principal cause of death in hepatitis C virus and schistosome infections. Hepatic fibrosis (HF) may develop either slowly or rapidly in schistosome-infected subjects. This depends, in part, on a major genetic control exerted by genes of chromosome 6q23. A gene (connective tissue growth factor [CTGF]) is located in that region that encodes a strongly fibrogenic molecule. We show that the single nucleotide polymorphism (SNP) rs9402373 that lies close to CTGF is associated with severe HF (P = 2 × 10−6; odds ratio [OR] = 2.01; confidence interval of OR [CI] = 1.51–2.7) in two Chinese samples, in Sudanese, and in Brazilians infected with either Schistosoma japonicum or S. mansoni. Furthermore, SNP rs12526196, also located close to CTGF, is independently associated with severe fibrosis (P = 6 × 10−4; OR = 1.94; CI = 1.32–2.82) in the Chinese and Sudanese subjects. Both variants affect nuclear factor binding and may alter gene transcription or transcript stability. The identified variants may be valuable markers for the prediction of disease progression, and identify a critical step in the development of HF that could be a target for chemotherapy

Importances des facteurs génétiques de l'hôte dans les maladies parasitaires: méthodes d'études et d'analyses des résultats obtenus dans la bilharziose.

Les facteurs de l'hôte dans la bilharzios

Apports de la génétique et de l'immunologie à l'identification de nouvelles cibles pour la chimiothérapie anti-infectieuse: rôle de la région 5q31-q33 dans la susceptibilité humaine à la bilharziose.

Localisation dans la région 5q31-q33 du gène SM1 contrôlant les niveaux d'infection en bilharzios

Genetics of infections and diseases caused by human parasites affecting the central nervous system.

International audienc

Genetics of parasitic infections

International audienceParasites cause much suffering mainly in countries of the southern hemisphere. Hundreds of millions of individuals are infected by schistosomes, leishmanias, plasmodiums, trypanosomes, and various other parasites, and severe clinical disease occurs in a sizable fraction of the infected population causing death and severe sequelae. The outcome, asymptomatic, subclinical or clinical disease, of an infection depends mostly on the parasite and on its host. Several groups analyzing the genetics of human susceptibility to parasites have began to identify the critical steps of the pathogenic mechanisms in a few parasitic infections such as malaria and schistosomiasis. The present article, which is not meant to be an exhaustive review of the field, illustrates the progresses made in this field from pioneer studies in animals to works in endemic populations using modern strategies of human genetics

Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33.

International audienc

Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33.

International audienc

Genetic localization of a locus predisposing to high infections by Schistosoma mansoni on chromosome 5q31-q33.

International audienc

In Vivo MRI Assessment of Hepatic and Splenic Disease in a Murine Model of Schistosmiasis

International audienceBackground Schistosomiasis (or bilharzia), a major parasitic disease, affects more than 260 million people worldwide. In chronic cases of intestinal schistosomiasis caused by trematodes of the Schistosoma genus, hepatic fibrosis develops as a host immune response to the helminth eggs, followed by potentially lethal portal hypertension. In this study, we characterized hepatic and splenic features of a murine model of intestinal schistosomiasis using in vivo magnetic resonance imaging (MRI) and evaluated the transverse relaxation time T-2 as a non-invasive imaging biomarker for monitoring hepatic fibrogenesis. Methodology/Principal Findings CBA/J mice were imaged at 11.75T two, six and ten weeks after percutaneous infection with Schistosoma mansoni. In vivo imaging studies were completed with histology at the last two time points. Anatomical MRI allowed detection of typical manifestations of the intestinal disease such as significant hepato-and splenomegaly, and dilation of the portal vein as early as six weeks, with further aggravation at 10 weeks after infection. Liver multifocal lesions observed by MRI in infected animals at 10 weeks post infection corresponded to granulomatous inflammation and intergranulomatous fibrosis with METAVIR scores up to A2F2. While most healthy hepatic tissue showed T-2 values below 14 ms, these lesions were characterized by a T-2 greater than 16 ms. The area fraction of increased T-2 correlated (r(S) = 0.83) with the area fraction of Sirius Red stained collagen in histological sections. A continuous liver T-2* decrease was also measured while brown pigments in macrophages were detected at histology. These findings suggest accumulation of hematin in infected livers. Conclusions/Significance Our multiparametric MRI approach confirms that this murine model replicates hepatic and splenic manifestations of human intestinal schistosomiasis. Quantitative T-2 mapping proved sensitive to assess liver fibrogenesis non-invasively and may therefore constitute an objective imaging biomarker for treatment monitoring in diseases involving hepatic fibrosis