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

No Evidence for a Major Effect of Tumor Necrosis Factor Alpha Gene Polymorphisms in Periportal Fibrosis Caused by Schistosoma mansoni Infection

International audienceHepatic periportal fibrosis (PPF), associated with portal hypertension, is a major pathological consequence of infections with Schistosoma mansoni and Schistosoma japonicum. Indeed, affected subjects may die from portal hypertension. Previous studies have indicated that tumor necrosis factor alpha (TNF-␣) may aggravate fibrosis. We therefore investigated whether PPF was associated with certain polymorphisms of the TNF-␣ gene. Four polymorphisms (TNF-␣ ؊376 G/A, ؊308 G/A, ؊238 G/A, and ؉488 G/A) were investigated in two Sudanese populations living in an area in which S. mansoni is endemic. These polymorphisms were analyzed for 105 Sudanese subjects with various grades of PPF, from mild to advanced; all subjects were from two neighboring villages (Taweela and Umzukra). They were then analyzed for 70 subjects with advanced liver disease and for 345 matched controls from the Gezira region. We found no evidence of associations between these four polymorphisms and PPF in both of these studies. Thus, these four polymorphisms, two of which (TNF-␣ ؊376 and ؊308) were found to increase TNF-␣ gene transcription, are unlikely to have a major effect on PPF progression in these populations. However, this result does not exclude the possibility that these polymorphisms have a minor effect on PPF development. Schistosomiasis is a serious public health problem affecting over 200 million people in developing countries (15, 41). Most of the infections occurring in areas where schistosomes are endemic are asymptomatic. However, 5 to 15% of infected individuals develop severe disease with Symmers fibrosis. Schistosomes (Schistosoma mansoni) produce several hundred eggs per day, and a proportion of these eggs are trapped in hepatic tissues and in presinusoidal venules. There, they induce a granulomatous inflammation that leads, in certain subjects , to the accumulation of scar tissue in the periportal spaces. Periportal fibrosis (PPF) causes venous obstruction and portal blood hypertension and contributes to the development of splenomegaly. Severely affected patients develop esopha-geal varices, ascites, and cachexia, resulting in death in the absence of treatment. Fibrosis, which involves stellate (Ito) cells derived from fibroblasts, results from an imbalance between the positive and negative regulatory mechanisms controlling the production and degradation of extracellular matrix proteins (ECMP). The production of collagen and ECMP is stimulated by a variety of cytokines and growth factors (inter-leukin-1 [IL-1], IL-4, IL-13, tumor necrosis factor alpha [TNF-␣]), monocyte chemotactic protein 1, platelet-derived growth factors, and transforming growth factor ␤), which stimulate fibroblast differentiation and the production of ECMP by fi-broblasts, Kupffer cells, and endothelial cells (14, 16, 22, 30). Other cytokines, such as alpha interferon (IFN-␣) and IFN-␥

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

Multifaceted Population Structure and Reproductive Strategy in Leishmania donovani Complex in One Sudanese Village

Leishmania species of the subgenus Leishmania and especially L. donovani are responsible for a large proportion of visceral leishmaniasis cases. The debate on the mode of reproduction and population structure of Leishmania parasites remains opened. It has been suggested that Leishmania parasites could alternate different modes of reproduction, more particularly clonality and frequent recombinations either between related individuals (endogamy) or between unrelated individuals (outcrossing) within strongly isolated subpopulations. To determine whether this assumption is generalized to other species, a population genetics analysis within Leishmania donovani complex strains was conducted within a single village. The results suggest that a mixed-mating reproduction system exists, an important heterogeneity of subsamples and the coexistence of several genetic entities in Sudanese L. donovani. Indeed, results showed significant genetic differentiation between the three taxa (L. donovani, L. infantum and L. archibaldi) and between the human or canine strains of such taxa, suggesting that there may be different imbricated transmission cycles involving either dogs or humans. Results also are in agreement with an almost strict specificity of L. donovani stricto sensu to human hosts. This empirical study demonstrates the complexity of population structure in the genus Leishmania and the need to pursue such kind of analyses at the smallest possible spatio-temporal and ecological scales

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

Facteurs de risque du paludisme grave de l'enfant à Bamako (Mali)

Ce travail met en évidence une association entre le paludisme grave et des facteurs liés à l'enfant et son environnement familial à Bamako, une zone urbaine mésoendémique. Nos résultats valident des indicateurs robustes de mauvais pronostic et montrent que le neuropaludisme et l'anémie palustre grave ont des facteurs de risques et un pronostic distincts. Nous avons trouvé une agrégation familiale significative du neuropaludisme et de l'anémie palustre grave, reflétant vraisemblablement l'expression de facteurs génétiques. Les effets de l'environnement familial avec, au premier plan, les connaissances, attitudes et pratiques des mères, paraissent trop modestes pour expliquer l'agrégation familiale des cas dans la population d'étude. Pour conclure, nous soulignons la nécessité de cibler les études à venir sur des phénotypes précis pour progresser dans la compréhension de la physiopathologie ou le traitement des formes potentiellement mortelles du paludisme de l'enfant africain.This work intended to uncover risk factors, either related to the child or its household, associated with severe malaria in Bamako, a mesoendemic urban setting. Independently of age, our results validate robust prognostic indicators and evidence that cerebral malaria and severe malarial anemia have distinct risk factors and prognoses. We detected a significant familial aggregation of both cerebral malaria and severe malarial anemia. This familial aggregation is probably chiefly related to genetic factors rather than to shared environment, since household related factors, the most important of which were associated to the mothers' knowledge, attitude, and practices, had only relatively marginal effects on the risk of developing severe malaria in the study population. We conclude that focusing on very precise phenotype should be mandatory in further studies aiming to illuminate the pathophysiology or improve the treatment of lifethreatening malaria in African children.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF