Sensibilité génétique aux infections à norovirus

Norovirus (NoV) are the most common cause of acute gastroenteritidis in humans worldwide. They are transmitted through consumption of contaminated food, or mostly by direct person-to-person contact. However, susceptibility to NoV infection is variable. NoVs recognize carbohydrate ligand, including A, B, H and Lewis histoblood group antigen (HBGAs) for attachment to human epithelial cells. Synthesis of these HBGAs requires various glycosyltransferase encoded by the ABO, FUT2, FUT3 genes. The presence of distinct carbohydrates structures dependent upon the combined polymorphism at the FUT2, FUT3 and ABO loci influences susceptibility to NoV infection. NoV–glycan interactions studies show that different strains recognize specific HBGAs. Together with herd immunity, HBGAs play a major role in the epidemiology and evolution of NoVs.     

Diversité génétique d’un génotype rare du virus de l’hépatite A

Purpose of the study

Very few is known on genotype II hepatitis A virus (HAV) since it is rarely isolated. From 2002 to 2007, the French observatory of HAV identified six sub-genotype IIA strains of which one from a patient having travelled to West Africa. To investigate the possible African origin of sub-genotype IIA, we determined its prevalence among French travellers in 2008 and characterised its genetic variability.

Patients and methods

The 2008 mandatory notification records were screened for travel to Africa. Viral genotype was determined on the nucleotide sequencing of the VP1/2A junction region. The P1 region coding for capsid proteins was used to compare the genetic diversity of IIA isolates to those of other genotypes.

Results

In 2008, five out of 54 patients returning from West Africa were infected by IIA strains and an additional “autochthonous” case was identified. Two more African cases were identified in 2009. A total of 14 IIA isolates (eight African and six “autochthonous”) were analysed. Nucleotide and amino-acid variability of IIA sequences was lower than that of the other genotypes. Phylogenetic analysis revealed the clustering of two “autochthonous” cases with African isolates whereas the other ones belonged to a different lineage.

Conclusion

Most IIA strains isolated in France are imported by travellers returning from West Africa. However, the unexplained contamination mode of some “autochthonous” cases suggests another geographical origin to discover or a French reservoir to explore.     

Autisme,génétique et anomalies de la fonction synaptique

Autism is a neurodevelopmental disorder characterized by a deficit of language and communication both associated with a restricted repertoire of activities and interests. The current prevalence of autistic disorder stricto sensu is estimated at 1/500 whereas autism spectrum disorders (ASD) increases up to 1/150 to 1/200. Mental deficiency (MD) and epilepsy are present in numerous autistic individuals. Consequently, autism is as a major public health issue. Autism was first considered as a non biological disease; however various rational approaches for analysing epidemiological data suggested the possibility of the influence of genetic factors. In 2003, this hypothesis was clearly illustrated by the characterization of genetic mutations transmitted through a mendelian manner. Subsequently, the glutamate synapse appeared as a preferential causal target in autism because the identified genes encoded proteins present in this structure. Strikingly, the findings that an identical genetic dysfunction of the synapse might also explain some MD suggested the possibility of a genetic comorbidity between these neurodevelopmental conditions. To date, various identified genes are considered indifferently as “autism” or “MD” genes. The characterization of mutations in the NLGN4X gene in patients with Asperger syndrome, autism without MD, or MD without autism, was the first example. It appears that a genetic continuum between ASD on one hand, and between autism and MD on the other hand, is present. Consequently, it is likely that genes already involved in MD will be found mutated in autistic patients and will represent future target for finding new factors in autism.     

Génétique humaine de la tuberculose

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major public health problem worldwide, resulting in 8.7 million new cases and 1.4 million deaths each year. One third of the world's population is exposed to M. tuberculosis and, after exposure, most, but not all, individuals become infected. Among infected subjects, only a minority (∼10%) will eventually develop clinical disease, which is typically either a primary, often extra-pulmonary, TB in children, or a reactivation, pulmonary TB in adults. Considerable genetic epidemiological evidence has accumulated to support a major role for human genetic factors in the development of TB. Numerous association studies with various candidate genes have been conducted in pulmonary TB, with very few consistent results. Recent genome-wide association studies revealed only a modest role for two inter-genic polymorphisms. However, a first major locus for pulmonary TB was mapped to chromosome 8q12-q13 in a Moroccan population after a genome-wide linkage screen. Using a similar strategy, two other major loci controlling TB infection were recently identified. While the precise identification of these major genes is ongoing, the other fascinating observation of these last years was the demonstration that TB can also reflect a Mendelian predisposition. Following the findings obtained in the syndrome of Mendelian susceptibility to mycobacterial diseases, several children with complete IL-12Rβ1 deficiency, were found to have severe TB as their sole phenotype. Overall, these recent findings provide the proof of concept that the human genetics of TB involves a continuous spectrum from Mendelian to complex predisposition with intermediate major gene involvement. The understanding of the molecular genetic basis of TB will have fundamental immunological and medical implications, in particular for the development of new vaccines and treatments.     

L’apport de la génétique de l’hôte dans la maladie VIH

In the 1990s, the variability of responses to human immunodeficiency virus (HIV) could only be tracked by phenotypic criteria such as the number of CD4 T lymphocytes, the occurrence of opportunistic infection, the disease free survival without treatment. In 1996, the viral load is the leading phenotype for genetic studies. Ever since, thanks to a better understanding of the HIV infection pathophysiology, numerous studies helped to highlight the influence of genetic variability on inter-individual response to this virus. Among the genes having an impact, we can quote the following examples: CCR5, HLA-B and HLA-C genes. Practical applications of genetics in clinical medicine include search for HLA-B*57:01 before abacavir introduction. Recently, an eradicating treatment for HIV disease after bone marrow transplantation with a donor homozygote for a CCR5 gene non-functional variant (CCR5Δ32) has been reported. Interest in genetics of chronic viral infection is not specific to HIV. It has also been used on other viral diseases and it has gained a major place on the management of diseases.     

Le psoriasis : physiopathologie et immunogénétique

Psoriasis is a multifactorial disease that involves genetic, immunological and environmental factors. During the last decade, several studies by genome scan on families or cases/controls helped to highlight more than ten loci “PSORS” located on different chromosomes and containing several candidate genes. Psoriasis appears as a genetic disease that follows the mixed model with the involvement of a major gene (PSORS1) and a set of minor genes with a variable penetrance depending on the locus. Genetic data have focused on the involvement of the immune system in the pathogenesis of psoriasis. It is now accepted that psoriasis is an immunological disease involving the response profiles TH1 and TH17. Much remains to be done to better elucidate the mechanisms involved in the genesis of psoriatic lesions to find new therapeutic targets.     

Génétique des cardiomyopathies héréditaires

Hereditary cardiomyopathy is a primitive disorder in which the heart muscle is structurally and functionally abnormal in the absence of any other cause of cardiomyopathy. They are separated into four phenotypic groups, hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy and arrhythmogenic cardiomyopathy of the right ventricle. Hypertrophic cardiomyopathy was the first identified at the molecular level and then the first to benefit of molecular testing. The molecular analyses were then extended the following years to the dilated cardiomyopathy and restrictive cardiomyopathy. The arythmogenic right ventricular cardiomyopathy was the latest to be analyzed at the molecular level because the identification of genes involved in that phenotype was published only in 2002 to 2006. The genetics analysis of these diseases has developed over the past decade and, although still complex, is now available in current hospital practice. The objectives of these tests are to confirm a diagnosis difficult to achieve by classic clinical approach and to perform predictive and presymptomatic diagnosis in families when the mutation was identified. This allows for appropriate care of patients at risk, and may respond to a request for prenatal diagnosis in particularly serious forms. These tests are framed in the context of genetic counselling consultation and patients are the subjects of a multidisciplinary care in reference centres.     

Les tests génétiques à l’heure de la deuxième révision des lois de bioéthique

This article focuses on six questions raised by genetic testing in human: (1) the use of genetic tests, (2) information given to relatives of patients affected with genetic disorders, (3) prenatal and preimplantatory diagnosis for late onset genetic diseases and the use of pangenomic tests in prenatal diagnosis, (4) direct-to-consumer genetic testing, (5) population screening in the age of genomic medicine and (6) incidental findings when genetic testing are used.     

Génotype HLA-B*5701 et hypersensibilité à l’abacavir

A potentially life-threatening hypersensitive reaction occurs in association with initiation of HIV nucleoside analogue abacavir therapy in 4 to 8% of patients. Preliminary studies appear to confirm the role of the immune system in abacavir hypersensitivity. The reaction is possibly the result of presentation of drug peptides onto HLA, that may induce a pathogenic T-cell response. Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele and prospective HLA-B*5701 genetic screening has now been instituted in clinical practice to reduce the risk of hypersensitivity reaction.     

Méningo-encéphalite à Bartonella quintana chez un sujet immunocompétent : une observation rare

Introduction

Bartonella quintana (Bq) is responsible of various clinical pictures. Neuromeningeal complications are rarely reported.

Case

A 20-year-old woman was admitted for fever, headache lasting for 5 days. On admission, she was febrile at 39.3 °C and had a stiff neck. Symptoms, contact with animals, biological tests and lumbar puncture (PL) rendered viral meningitis a likely diagnosis. She had received symptomatic treatment and the outcome was favorable. Three days later, the patient had headache, agitation and confusion with fever. The PL noted 130/mm³ whites, 90% lymphocytes. The albuminorachie was 0.98 g/L, glucorachie was normal. The patient was treated with 400 mg of ofloxacine/day, seven days. Serologic tests for B. quintana were reactive. The outcome was favorable.

Conclusion

B. quintana infection should be considered in neurological symptoms of unknown etiology.     

Évolution de la résistance des entérobactéries aux céphalosporines de troisième génération de 2000 à 2008 au centre hospitalier de Perpignan

The aim of this work was to evaluate the evolution of Enterobacteriaceae resistance to third generation cephalosporin (3CG) from 2000 to 2008 at Perpignan hospital. Were observed: the percentage of strains isolated from short stay wards, intensive care unit and medium and long-term care facility. The percentage of strains isolated from: urine, suppuration, tracheal aspiration, and blood have been evaluated. The proportion of Escherichia coli (E. coli) strains among the Enterobacteriaceae strains intermediate (I) or resistant (R) to 3GC was also evaluated.The number of Enterobacteriaceae intermediated (I) or resistant (R) to 3GC increased (402 %).The distribution of species I or R to 3GC has changed, decrease of Klebsielle pneumoniae and Enterobacter aeorogenes species, Escherichia.coli and Enterobacter cloacae became dominant in 2008. We noted the change of isolated species distribution, urines represent the main source of multiresistant Enterobacteriaceae (MRE), 72 % of strains. The profile of patients colonised or infected by MRE has changed. Patients mainly infected with hospital acquirred MRE changed to MRE colonised patients carrying the strain into the hospital. The association of fluorinated quinolone resistance and Extended-Spectrum Beta-Lactamase Enterobacteriaceae represented 51 % in 2000, became stable at 73 % from 2002. The association of fluorinated quinolone resistance and high-level Enterobacteriaceae cephalosporinase has increased from 21 % in 2000 to be stable at 50 % since 2006. The mesures to contain the spread of MRE strains remained inefficient because of outpatients circulation, multiresistant E. coli being community species.     

Recombinaison génétique chez le poliovirus vaccinal : étude comparative chez les souches excrétées en cours de vaccination par le vaccin poliomyélitique oral et les souches circulantes

Aim of study

Recombination is one of the major mechanisms of evolution in poliovirus. In this work, recombination was assessed in children during vaccination with OPV and among circulating vaccine strains isolated in Tunisia during the last 15 years in order to identify a possible role of recombination in the response to the vaccine or the acquisition of an increased transmissibility.

Material and methods

This study included 250 poliovirus isolates: 137 vaccine isolates, excreted by children during primary vaccination with OPV and 113 isolates obtained from acute flaccid paralytic (AFP) cases and healthy contacts. Recombination was first assessed using a double PCR-RFLP, and sequencing.

Results

Nineteen per cent of recombinant strains were identified: 20% of strains excreted by vaccinees among 18% of circulating strains. The proportion of recombinant in isolates of serotype1 was very low in the two groups while the proportions of recombinants in serotypes 2 and 3 were different. In vaccinees, the frequency of recombinants in serotype3 decreased during the course of vaccination: 54% after the first dose, 32% after the second and 14% after the third dose.

Conclusion

These results suggest that recombination enhances the ability of serotype3 vaccine strains to induce an immune response. Apart from recent vaccination, it may contribute to a more effective transmissibility of vaccine strains among human population.     

Les aspects génétiques de la maladie d’Alzheimer (Revue)

Alzheimer's disease is a degenerative brain disorder, which concerns memory, cognition and behavior pattern. Its etiology is unknown, it is characterized by typical histological lesions: senile plaques and neuro-fibrillary tangles. Alzheimer's disease is a multifactorial pathology, characterized by interactions between genetic and environmental factors. Genetic factors concern first of all the exceptional monogenic forms, characterized by early onset (< 60 years), autosomal dominant forms. Mutations of the genes coding for amyloid-ß precursor protein or preselinins 1 and 2 are involved. The much more frequent sporadic forms also have genetic factors, the best studied being the apolipoprotein E4 coding allele and some more recent genotypes which will be mentioned. No causal, only symptomatic treatments are available.     

La voie IL-2/IL-2R chez la cellule dendritique module à la fois leur synthèse de cytokines et leur capacité à activer des lymphocytes T CD4 allogéniques

The results provide new insights into the role of IL-2/IL-2R pathway in DC. We report that stimulation of human monocyte-derived DC with LPS strongly upregulated CD25 (α chain of the IL-2R) expression. In addition, by using a humanized monoclonal antibody against CD25, we demonstrated that the IL-2 signalling in DC upregulated both IL-12 and γIFN production but decreased IL-10 synthesis. Anti-CD25 treatment reduced the ability of LPS-DC to induce allogeneic CD4⁺ T cell proliferation as compared to LPS-matured DC. In addition, LPS-matured DC treated with IL-2 had a higher allostimulatory capacity compared to LPS-DC. We also found that LPS-matured DC produced IL-2. Thus, IL-2 seems to contribute actively to DC activation through an autocrine pathway. Moreover, IL-2 pathway in DC is involved in T helper priming. These findings might be useful for protocols in cellular therapy and a valuable tool to understand graft rejection versus the acquisition of peripheral tolerance.     

Actualité de la résistance aux antibiotiques chez les bacilles à Gram négatif en Algérie

Antibiotic resistance has become a major public health problem in Algeria. Indeed the past decade, we have seen a significant increase in resistance to antibiotics especially in Gram-negative bacilli. Resistance to β-lactams in enterobacteria is dominated by the production of ESBL CTX-M-3 and CTX-M-15. The strains producing these enzymes are often the cause of potentially serious infections in both hospital and community settings. Identified plasmid cephalosporinases are CMY-2, CMY-12 and DHA-1. The isolation of strains of Enterobacteriaceae and Pseudomonas aeruginosa producing carbapenemases is rare in Algeria. Some Enterobacteriaceae producing OXA-48 or VIM-19 have been reported; so far, only VIM-2 has been identified in P. aeruginosa. However, the situation regarding the strains of Acinetobacter baumannii resistant to carbapenemases seems to be more disturbing. The carbapenemase OXA-23 is the most common and seems to be endemic in the north. The carbapenemase NDM-1 has also been identified. Resistance to aminoglycosides is marked by the identification armA gene associated with bla_CTX-M genes in strains of Salmonella sp. Several other resistance genes have been identified sporadically in strains of Enterobacteriaceae, P. aeruginosa and A. baumannii. Resistance genes to fluoroquinolones are more recent identification in Algeria. The most common are the Qnr determinants followed by the bifunctional enzyme AAC[6’]-Ib-cr. Resistance to sulfonamides and trimethoprim was also reported in Enterobacteriaceae strains in the west of the country.