Recent Advances in the Characterization of Genetic Factors Involved in Human Susceptibility to Infection by Schistosomiasis

Human resistance to infection by schistosomes is associated to a strong Th2 immune. However a persistent Th2 response can cause severe kidney and liver disease in human. In this review, we mainly focused on the control of infection levels caused by schistosomes. Several experimental models allowed us to better understand the immunological mechanisms of the host against schistosome infection. High IgE and eosinophil levels are associated with resistance to infection by schistosomes and this effect is counterbalanced by IgG4. IgE and eosinophils are highly dependent on IL-4, IL-13, and Il-5, which are three main Th2 cytokines. We also examined the genetic factors involved in human susceptibility to infection by schistosomiasis. Infection levels are mainly regulated by a major locus SM1, in 5q31-q33 region, which contains the genes encoding for the IL-4, IL-13, and Il-5 cytokines. An association between an IL13 polymorphism, rs1800925, and infection levels has been shown. This polymorphism synergistically acts with another polymorphism (rs324013) in the STAT6 gene, encoding for the signal transducer of the IL13 pathway. This pathway has also been involved in atopic disorders. As helminthiasis, atopy is the result of aberrant Th2 cytokine response to allergens, with an increased production of IL-4, IL-13, Il-9 and Il-5, with high amounts of allergen-specific and total IgE and eosinophilia. However, the Th2 immune response is protective in helminthiasis but aggravating in atopic disorders. Several studies reported interplay between helminthic infections and allergic reactions. The different results are discussed here

A dissipative random velocity field for fully developed fluid turbulence

We investigate the statistical properties, based on numerical simulations and analytical calculations, of a recently proposed stochastic model for the velocity field of an incompressible, homogeneous, isotropic and fully developed turbulent flow. A key step in the construction of this model is the introduction of some aspects of the vorticity stretching mechanism that governs the dynamics of fluid particles along their trajectory. An additional further phenomenological step aimed at including the long range correlated nature of turbulence makes this model depending on a single free parameter $\gamma$ that can be estimated from experimental measurements. We confirm the realism of the model regarding the geometry of the velocity gradient tensor, the power-law behaviour of the moments of velocity increments (i.e. the structure functions), including the intermittent corrections, and the existence of energy transfers across scales. We quantify the dependence of these basic properties of turbulent flows on the free parameter $\gamma$ and derive analytically the spectrum of exponents of the structure functions in a simplified non dissipative case. A perturbative expansion in power of $\gamma$ shows that energy transfers, at leading order, indeed take place, justifying the dissipative nature of this random field.Comment: 38 pages, 5 figure

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-␥

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

TSF Experiment for comparision of high Reynold's number turbulence in He I and He II : first results

International audienceSuperfluid turbulence (TSF) project uses liquid helium for the fundamental study of turbulent phenomena behind a passive grid and is able to work both in HeI and in HeII. Local and semi-local instrumentation was developed specifically for the purpose of this experiment(e.g. sub-micrometer anemometer, total head pressure tube and second sound tweezer). The difficulties encountered with this local and fragile instrumentation are discussed. Global characterization of the flow is presented including velocity, pressure, temperature stability and turbulence intensity. Finally, first results obtained with semi local measurements (total head pressure tube and second sound tweezer) both in the two phases of helium are presented

Development of an innovative adenovirus-inspired self-assembling vaccine platform rapidly adaptable to coronaviruses and other emergent viruses

The COVID-19 pandemic clearly shows how emergent diseases can cause severe global health and economic problems. We must be prepared to react swiftly against new pathogenic agents and this requires the development of vaccines that are safe, efficient in the long-term and easily adaptable with a short revision time. To this end, the COVID-19 mRNA and adenoviral vector vaccines have been spectacular successes, permitting rapid vaccination across the world in an unprecedented manner. Here we report the design of a new adenovirus-derived vaccine technology based on non-infectious pseudo-viral nanoparticles from the serotype 3 human adenovirus. Each nanoparticle comprises sixty identical proteins that assemble to form a 30 nm diameter spherical particle. A sequence has been engineered into the surface of this protein that enables the display of a covalently-bound target antigens. To demonstrate the efficiency of this approach, we added the SARS-CoV 2 spike protein receptor binding domain (RBD), that interacts with host cell ACE2 receptors, to the surface of the nanoparticles. We first showed that the glycosylated RBD retained its ACE2-binding function when displayed on nanoparticles. We then measured the in vivo humoral response of our vaccine candidate in mice and observed a strong antibody response after the prime injection; further levels were achieved following a second booster injection. In mice preimmunized with underivatized adenoviral nanoparticles, we tested if adenovirus seroprevalence, as frequently observed in humans, was detrimental to the RBD-mediated protection provided by our vaccine candidate. Interestingly, a strong anti-coronaviral response was still observed suggesting that existing circulating anti-adenovirus antibodies are not deleterious to our vaccine platform. We then performed pseudo-CoV 2 neutralization assays and obtained higher ID50 values than observed with COVID-19 convalescent sera, thus showing the high potential efficacy of our vaccine platform. This new vaccine technology is a tool that is easily adaptable to future SARS-CoV 2 variants and, more generally, to future emergent viruses and pathogens

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

Disease Tolerance and Pathogen Resistance Genes May Underlie Trypanosoma cruzi Persistence and Differential Progression to Chagas Disease Cardiomyopathy

Chagas disease is caused by infection with the protozoan Trypanosoma cruzi and affects over 8 million people worldwide. In spite of a powerful innate and adaptive immune response in acute infection, the parasite evades eradication, leading to a chronic persistent infection with low parasitism. Chronically infected subjects display differential patterns of disease progression. While 30% develop chronic Chagas disease cardiomyopathy (CCC)—a severe inflammatory dilated cardiomyopathy—decades after infection, 60% of the patients remain disease-free, in the asymptomatic/indeterminate (ASY) form, and 10% develop gastrointestinal disease. Infection of genetically deficient mice provided a map of genes relevant for resistance to T. cruzi infection, leading to the identification of multiple genes linked to survival to infection. These include pathogen resistance genes (PRG) needed for intracellular parasite destruction, and genes involved in disease tolerance (protection against tissue damage and acute phase death—DTG). All identified DTGs were found to directly or indirectly inhibit IFN-γ production or Th1 differentiation. We hypothesize that the absolute need for DTG to control potentially lethal IFN-γ PRG activity leads to T. cruzi persistence and establishment of chronic infection. IFN-γ production is higher in CCC than ASY patients, and is the most highly expressed cytokine in CCC hearts. Key DTGs that downmodulate IFN-γ, like IL-10, and Ebi3/IL27p28, are higher in ASY patients. Polymorphisms in PRG and DTG are associated with differential disease progression. We thus hypothesize that ASY patients are disease tolerant, while an imbalance of DTG and IFN-γ PRG activity leads to the inflammatory heart damage of CCC

Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways

Abstract\ud \ud Background\ud Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage.\ud \ud \ud Methods\ud Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects.\ud \ud \ud Results\ud The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%.\ud \ud \ud Conclusions\ud Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.FAPES