Résumé : La tuberculose (TB), maladie infectieuse contagieuse, est causée par une mycobactérie appartenant au complexe Mycobacterium tuberculosis (MTBC). Malgré de nombreuses campagnes de vaccination par le BCG (Bacilles de Calmette et Guérin) et les traitements antituberculeux, on observe une réémergence de la maladie depuis les années 80. Ce bouleversement s’explique par la coïnfection avec le virus du VIH/SIDA, la désorganisation des systèmes de santé et par l’apparition des bactéries résistantes aux principaux antibiotiques antituberculeux. Dans ce contexte une meilleure connaissance des mouvements et de l’évolution des clones circulants du bacille tuberculeux permettrait de détecter plus rapidement et de façon plus pertinente l’émergence d’épidémies. Le contrôle et la surveillance de la maladie représentent des moyens essentiels pour lutter contre l’expansion mondiale de la tuberculose. C’est ainsi que l’unité de la Tuberculose et des Mycobactéries de l’Institut Pasteur de la Guadeloupe (IPG) a mis en place une base de données de profils génotypiques pour l’étude de l’épidémiologie globale de la tuberculose. Dans le cadre de cette thèse, nous décrirons les méthodes de bioinformatique qui ont été utilisées pour la gestion et l’exploitation de la 6ème version (SITVIT2) de cette base de données des génotypes pour mieux comprendre l’évolution et la dissémination mondiale du bacille tuberculeux. Cette base intègre aussi plusieurs marqueurs moléculaires tels que les MIRU-VNTRs (« mycobacterial interspersed repetitive units-variable number of tandem repeats ») et le Spoligotype43 servant à mieux décrire et identifier les familles de profils génotypiques du MTBC. La banque de données SITVIT2 ne cesse d’évoluer, et elle contient actuellement des informations épidémiologiques sur 111 635 isolats cliniques. Cette base de données est consultable en ligne à l’adresse suivante : http://www.pasteur-guadeloupe.fr:8081/SITVIT2/. Nous avons également réalisé une base de données nommée SITVITBovis qui est dédiée à la tuberculose bovine. Cette base de données sera accessible à l’adresse : http://www.pasteur-guadeloupe.fr:8081/SITVIT_Bovis/. Parallèlement au développement et à la gestion des bases de données, ce travail de thèse s’est appuyé sur plusieurs études épidémiologiques et phylogéographiques mettant en corrélation les données disponibles sur la résistance aux médicaments ou les caractéristiques démographiques (dont le sexe, l’âge, le statut VIH, et l’origine du patient). Notre initiative de recherche permet ainsi d’améliorer la caractérisation phylogénétique détaillée des lignées du MTBC, ainsi que l’épidémiologie des clones en circulation, afin d’élaborer une cartographie géographique des isolats cliniques prédominants pour les bacilles tuberculeux principalement impliqués dans la maladie, à l’échelle nationale, régionale et mondiale. La superposition ultérieure de ces cartes avec des données sociopolitiques, économiques et démographiques obtenues auprès de Systèmes d’information géographique (SIG) ont permis de dresser un portrait précis des disparités actuelles par pays ou sous-région. Cette thèse représente une importante collaboration avec plusieurs équipes de chercheurs travaillant également dans le domaine de l’épidémiologie moléculaire de la tuberculose. L’objectif à long terme de ce travail, est d’optimiser la structure de la base, et de pérenniser l’enrichissement de celle-ci (notamment par l’automatisation et la facilité de la saisie de données). Une représentation optimale et une meilleure accessibilité des données de la base conforteraient les efforts faits pour le contrôle et la surveillance de la TB dans monde.
Tuberculosis (TB) is a contagious infectious disease caused by mycobacteria belonging to the Mycobacterium tuberculosis complex (MTBC). Despite numerous campaigns of vaccination by the BCG (Bacillus Calmette-Guérin) vaccine, and TB treatments, there was a resurgence of the disease since the 80s. This disruption is due to coinfection with HIV/AIDS, disorganization of health systems and the emergence of bacteria resistant to anti-TB drugs. In this context, a better understanding of the movements and changes of circulating clones of tubercle bacilli would detect faster and more relevant emerging epidemics. The control and monitoring of the disease are essential means to fight against the worldwide spread of tuberculosis. Thus the TB and Mycobacteria unit of the Pasteur Institute of Guadeloupe (IPG) has developed a database of genotypic profiles for the study of global epidemiology of tuberculosis.In this thesis, we discuss the Bioinformatical methods that have been used for the management and development of the 6th version (SITVIT2) of this database of genotypes to better understand the evolution and global dissemination of the tubercle bacillus. The database also includes several molecular markers such as MIRU-VNTRs (mycobacterial interspersed repetitive units- variable number of tandem repeats) and Spoligotype43 allowing a better description and identification of the families of genotypic profiles of Mycobacterium tuberculosis complex. SITVIT2 database is constantly evolving, and it currently contains epidemiological information on 111,635 clinical isolates. This database is available online at the following address: http://www.pasteur-guadeloupe.fr:8081/SITVIT2/. We also developed a database named "SITVITBovis", which is dedicated to bovine tuberculosis. This database will be accessible at: http://www.pasteur-guadeloupe.fr:8081/SITVIT_Bovis/.Alongside the development and management of databases, this work was based on several epidemiological and phylogeographic studies correlating data on drug resistance or demographic characteristics (including sex, age, HIV status, and the origin of the patient). Our research initiative is thus focused to further improve in depth phylogenetic characterization of MTBC lineages, as well as the epidemiological analysis of circulating clones to generate evidence-based geographical mapping of predominant clinical isolates of tubercle bacilli causing the bulk of the disease both at country and regional level. Further superposition of these maps with socio-political, economical and demographical available through Geographic Information Systems (GIS) allows to have a precise view of prevailing disparities at the level of country or sub-region. This thesis represents an important collaboration with several researchers teams also working in the field of molecular epidemiology of tuberculosis.The long-term goal of this work is to further optimize the database structure, and sustain enriching it (including automation and ease of data entry). Optimum performance and accessibility of data in the database would reinforce efforts to control and surveillance of TB in the world.

http://www.theses.fr/2014AGUY0791/document

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : National audience
Les leishmanioses sont des maladies parasitaires à transmission vectorielle observées sur tous les continents, à l’exception de l’Amérique du Nord et de l’Australie. Nous focaliserons ici sur la leishmaniose viscérale méditerranéenne due à Leishmania infantum et dont l’incidence annuelle est estimée entre 1200 et 2000 cas. Son cycle biologique est zoonotique avec un réservoir animal essentiellement canin. Les récentes observations épidémiologiques sont rapportées ici, notamment la mise en évidence du portage humain asymptomatique et l’extension de la zone endémique de la leishmaniose canine. La prise en charge thérapeutique de la leishmaniose viscérale méditerranéenne du patient immunocompétent fait essentiellement appel à l’amphotéricine B liposomale. Le débat existe toujours sur la pertinence d’une prophylaxie secondaire ou des traitements itératifs à chaque rechute chez le patient co-infecté par le VIH. Summary Leishmaniasis are protozoan infections transmitted by the bite of the sandflies, widely reported except in North-America and Australia. Here, we focus on mediterranean visceral leishmaniasis due to Leishmania infantum, with an estimated annual incidence of 1200–2000 cases. Its biological cycle is zoonotic and mainly involves the canine reservoir. The recent epidemiological observations are reported here, particularly the asymptomatic carriage but also the extension of the canine enzooty. Regarding treatment of immunocompetent patients, the drug of choice for mediterranean visceral leishmaniasis is liposomal amphotericin B. In case of HIV-Leishmania co-infection, the interest of secondary prophylaxis is still in debate
ISSN: 2210-6545

hal-01225489
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01225489
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01225489/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01225489/file/Mise%20au%20point%20et%20actualit%C3%A9s%20sur%20la%20leishmaniose%20visc%C3%A9rale%20m%C3%A9diterran%C3%A9enne.pdf
DOI : 10.1016/j.antinf.2014.12.005

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The mucosal events of HIV transmission have been extensively studied, but the role of infected cells present in the genital and rectal secretions, and in the semen, in particular, remains a matter of debate. As a prerequisite to a thorough in vivo investigation of the early transmission events through infected cells, we characterized in detail by multi-parameter flow cytometry the changes in macaque seminal leukocytes during SIVmac251 infection, focusing on T cells, macrophages and dendritic cells. Using immunocytofluorescence targeting SIV proteins and real-time quantitative PCR targeting SIV DNA, we investigated the nature of the infected cells on sorted semen leukocytes from macaques at different stages of infection. Finally, we cocultured semen CD4(+) T cells and macrophages with a cell line permissive to SIV infection to assess their infectivity in vitro. We found that primary infection induced strong local inflammation, which was associated with an increase in the number of leukocytes in semen, both factors having the potential to favor cell-associated virus transmission. Semen CD4(+) T cells and macrophages were productively infected at all stages of infection and were infectious in vitro. Lymphocytes had a mucosal phenotype and expressed activation (CD69 & HLA-DR) and migration (CCR5, CXCR4, LFA-1) markers. CD69 expression was increased in semen T cells by SIV infection, at all stages of infection. Macrophages predominated at all stages and expressed CD4, CCR5, MAC-1 and LFA-1. Altogether, we demonstrated that semen contains the two major SIV-target cells (CD4+ T cells and macrophages). Both cell types can be productively infected at all stages of SIV infection and are endowed with markers that may facilitate transmission of infection during sexual exposure.
ISSN: 1553-7366

hal-00955292
https://hal-univ-rennes1.archives-ouvertes.fr/hal-00955292
https://hal-univ-rennes1.archives-ouvertes.fr/hal-00955292/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-00955292/file/Semen_CD4_T-accepted.pdf
PUBMED : 24348253

Éditeur(s) : HAL CCSD Elsevier
Résumé : Field isolates of Toxoplasma gondii in Europe and North America have been grouped into three clonal lineages that display different virulence in mice. Whether the genetic structure of the parasite is related to clinical expression in humans has not yet been demonstrated. We developed an enzyme-linked immunosorbent assay which uses lineage-specific, polymorphic polypeptides derived from the dense granule antigens, GRA5 and GRA6. Our goal was to compare serotypical patterns observed in asymptomatic versus symptomatic (ocular disease and severe infection in human immunodeficiency virus (HIV)-positive patients) infections among patients from Europe and South America. Independent of the clinical presentation of the disease, serotypes differed according to geographical origin, with a homogeneous distribution of serotype II in Europe and of serotypes I and III in South America. We conclude that GRA5-GRA6 serotyping is an interesting tool to study serotype prevalence in populations but it is not an accurate marker of pathogenicity of Toxoplasma infection in humans.
ISSN: 1286-4579

hal-00306841
https://hal.archives-ouvertes.fr/hal-00306841
DOI : 10.1016/j.micinf.2008.04.001
PUBMED : 18539501

Éditeur(s) : HAL CCSD International Medical Press
Résumé : International audience
Background: Although the role of clinical/biological factors associated with mortality has already been explored in HIV-infected patients on antiretroviral therapy (ART), to date little attention has been given to the potential role of social vulnerability. This study aimed to construct an appropriate measure of social vulnerability and to evaluate whether this measure is predictive of increased mortality risk in ART-treated patients followed up in the ANRS CO8 APROCO-COPILOTE cohort.Methods: The cohort enrolled 1,281 patients initiating a protease inhibitor-based regimen in 1997–1999. Clinical/laboratory data were collected every 4 months. Self-administered questionnaires collected psycho-social/behavioural characteristics at enrolment (month [M] 0), M4 and every 8–12 months thereafter. A multiple correspondence analysis using education, employment and housing indicators helped construct a composite indicator measuring social vulnerability. The outcome studied was all-cause deaths occurring after M4. The relationship between social vulnerability and mortality, after adjustment for other predictors, was studied using a shared-frailty Cox model, taking into account informative study dropout.Results: Over a median (IQR) follow-up of 7.9 (3.0–11.2) years, 121 deaths occurred among 1,057 eligible patients, corresponding to a mortality rate (95% CI) of 1.64 (1.37, 1.96)/100 person-years. Leading causes of death were non-AIDS defining cancers (n=26), AIDS (n=23) and cardiovascular diseases (n=12). Social vulnerability (HR [95% CI] =1.2 [1.0, 1.5]) was associated with increased mortality risk, after adjustment for other known behavioural and bio-medical predictors.Conclusions: Social vulnerability remains a major mortality predictor in ART-treated patients. A real need exists for innovative interventions targeting individuals cumulating several sources of social vulnerability, to ensure that social inequalities do not continue to lead to higher mortality.
ISSN: 1359-6535

hal-01299300
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01299300
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01299300/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01299300/file/Twelve-year%20mortality%20in%20HIV-infected%20patients_accepted.pdf
DOI : 10.3851/IMP2960

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
Varicella zoster virus (VZV) is a leading cause of acute viral encephalitis but little is known about its clinical, biological and imaging features. Furthermore, the most favourable treatment regimen has not been determined. We studied a prospective cohort of 20 HIV-negative patients presenting with acute VZV encephalitis caused by primary infection or reactivation. VZV was identified in 16 of 20 cases by PCR detection of the DNA in the cerebrospinal fluid. The four remaining cases occurred during or soon after a VZV rash. The median age of the 17 adults was 76 (19-86) years; the three other patients were children (0.5-5 years). Three patients were immunocompromised. Nine adult patients presented with a rash. Eighteen patients presented with fever and an acute encephalitic syndrome: diffuse brain dysfunction, focal neurological signs, seizures and cranial nerve palsies. Three patients presented with either ventricular or subdural haemorrhage, one with myelitis, and one with asymptomatic stenosis of the middle cerebral artery. The imaging was either normal or revealed non-specific abnormalities such as cortical atrophy but no evidence of stroke. All patients were given acyclovir at various dosages and durations but the case fatality rate remained high (15%) and sequelae were frequently observed either at discharge or at follow-up 3 years later.
ISSN: 1198-743X

hal-00875232
https://hal.archives-ouvertes.fr/hal-00875232
PUBMED : 22085160
DOI : 10.1111/j.1469-0691.2011.03705.x

Éditeur(s) : HAL CCSD American Society for Microbiology
Résumé : International audience
Summary: The apicomplexan parasite Toxoplasma gondii was discovered a little over 100 years ago, but knowledge of its biological life cycle and its medical importance has grown in the last 40 years. This obligate intracellular parasite was identified early as a pathogen responsible for congenital infection, but its clinical expression and the importance of reactivations of infections in immunocompromised patients were recognized later, in the era of organ transplantation and HIV infection. Recent knowledge of host cell-parasite interactions and of parasite virulence has brought new insights into the comprehension of the pathophysiology of infection. In this review, we focus on epidemiological and diagnostic aspects, putting them in perspective with current knowledge of parasite genotypes. In particular, we provide critical information on diagnostic methods according to the patient's background and discuss the implementation of screening tools for congenital toxoplasmosis according to health policies.
ISSN: 0893-8512

hal-00696903
https://hal.archives-ouvertes.fr/hal-00696903
https://hal.archives-ouvertes.fr/hal-00696903/document
https://hal.archives-ouvertes.fr/hal-00696903/file/Epidemiologysur and_Diagnostic-accepted.pdf
DOI : 10.1128/CMR.05013-11

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
: In South America, disseminated histoplasmosis due to Histoplasma capsulatum var. capsulatum (H. capsulatum), is a severe and frequent opportunistic infection in AIDS patients. In areas outside the USA where specific-Histoplasma antigen detection is not available, the diagnosis is difficult. With the galactomannan antigen (GM) detection, a test commonly used for invasive aspergillosis diagnosis, there is a cross-reactivity with H. capsulatum that can be helpful for the diagnosis of histoplasmosis. The aim of this study was to evaluate the GM detection for the diagnosis of disseminated histoplasmosis in AIDS patients. The performance of the GM detection was evaluated with serum collected in French Guiana where H. capsulatum is highly endemic. Sera from AIDS patients with disseminated histoplasmosis occurring from 2002 to 2009 and from control HIV-positive patients without histoplasmosis were tested with the GM detection and Histoplasma-specific antibody detection (IEP). In 39 AIDS patients with proven disseminated histoplasmosis, the sensitivity of the Histoplasma IEP was only 35.9% and was linked to the TCD4+ lymphocyte level. For the GM detection, the sensitivity (Se) was 76.9% and specificity (Sp) was 100% with the recommended threshold for aspergillosis diagnosis (0.5). The test was more efficient with a threshold of 0.4 (Se: 0.82 [95% CI: 0.66-0.92], Sp: 1.00 [95% CI: 0.86-1.00], LR+: >10, LR-: 0.18). This study confirms that the GM detection can be a surrogate marker for the diagnosis of disseminated histoplasmosis in AIDS patients in endemic areas where Histoplasma EIA is not available.
ISSN: 1438-4221

inserm-01065096
http://www.hal.inserm.fr/inserm-01065096
http://www.hal.inserm.fr/inserm-01065096/document
http://www.hal.inserm.fr/inserm-01065096/file/2014_Iriart_-_Complementary_tool_for_managementsur histo_infections_in_AID.pdf
DOI : 10.1016/j.ijmm.2014.07.016