Variable-number tandem-repeat markers for typing Mycobacterium intracellulare strains isolated in humans

<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium intracellulare</it>, a species of the <it>Mycobacterium avium complex</it>, may be the cause of severe lung, lymphatic node, skin and bone/joint infections, as well as bacteriemia. The goal of this work was to identify Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeat (MIRU-VNTR) markers and to study their variability in a collection of isolates of <it>M. intracellulare </it>collected in humans. We studied 61 isolates collected in humans between 2001 and 2008, as well as the reference strain, <it>M. intracellulare </it>ATCC 13950.</p> <p>Results</p> <p>We identified 45 MIRU-VNTR candidates, of which 17 corresponded to the MIRU-VNTR identified in the genome of <it>M. intracellulare </it>ATCC 13950. Among the 45 potential MIRU-VNTR, seven were selected for use in a MIRU-VNTR assay applied to our collection of isolates. Forty-four patterns were found by MIRU-VNTR typing and the discriminatory power of the assay was high with a Hunter-Gaston diversity index of 0.98. We do not have evidence of a particular distribution of MIRU-VNTR polymorphism according to clinical situation.</p> <p>Conclusions</p> <p>Our results suggest that MIRU-VNTR typing could be used for molecular epidemiological studies applied to <it>M. intracellulare</it>.</p

Association between psoas abscess and prosthetic hip infection: a case-control study

Background and purpose The relationship between prosthetic hip infection and a psoas abscess is poorly documented. We determined the frequency of prosthetic hip infections associated with psoas abscesses and identified their determinants

Rates and Predictors of Treatment Failure in Staphylococcus aureus Prosthetic Joint Infections According to Different Management Strategies: A Multinational Cohort Study—The ARTHR-IS Study Group

Introduction: Guidelines have improved the management of prosthetic joint infections (PJI). However, it is necessary to reassess the incidence and risk factors for treatment failure (TF) of Staphylococcus aureus PJI (SA-PJI) including functional loss, which has so far been neglected as an outcome. Methods: A retrospective cohort study of SA-PJI was performed in 19 European hospitals between 2014 and 2016. The outcome variable was TF, including related mortality, clinical failure and functional loss both after the initial surgical procedure and after all procedures at 18 months. Predictors of TF were identified by logistic regression. Landmark analysis was used to avoid immortal time bias with rifampicin when debridement, antibiotics and implant retention (DAIR) was performed. Results: One hundred twenty cases of SA-PJI were included. TF rates after the first and all surgical procedures performed were 32.8% and 24.2%, respectively. After all procedures, functional loss was 6.0% for DAIR and 17.2% for prosthesis removal. Variables independently associated with TF for the first procedure were Charlson >= 2, haemoglobin 30 kg/m(2) and delay of DAIR, while rifampicin use was protective. For all procedures, the variables associated with TF were haemoglobin < 10 g/dL, hip fracture and additional joint surgery not related to persistent infection. Conclusions: TF remains common in SA-PJI. Functional loss accounted for a substantial proportion of treatment failures, particularly after prosthesis removal. Use of rifampicin after DAIR was associated with a protective effect. Among the risk factors identified, anaemia and obesity have not frequently been reported in previous studies. [GRAPHICS]

Immunopathology and therapeutic approach in African Trypanosomiasis

La Trypanosomose Humaine Africaine (THA) ou maladie du sommeil est une infection provoquée par un protozoaire du genre Trypanosoma. La recherche de nouvelles cibles thérapeutiques est nécessaire afin d’améliorer l’efficacité et la tolérance des traitements. Dans un premier travail, nous avons étudié l’importance de CYP51 (stérol 14α-déméthylase), une cible potentielle, par la technique d’interférence à ARN (RNAi). Nous avons démontré le caractère essentiel de cette enzyme pour le parasite, ainsi que les conséquences de sa déplétion sur la cytodiérèse. De plus, la survie de souris infectées par la souche CYP51RNAi induite était prolongée, montrant l’implication de CYP51 dans la virulence. La combinaison du posaconazole, un dérivé triazolé inhibant CYP51, à l’éflornithine a montré un effet similaire à la combinaison nifurtimox-éflornithine dans un modèle murin. Nos résultats soulignent l’intérêt potentiel d’un traitement ciblant CYP51 dans la trypanosomose. Du fait de l’importance de l’immunodépression dans la THA et de la capacité du trypanosome à échapper au système immunitaire de l’hôte, nous avons étudié, dans un deuxième travail, l’effet de T. gambiense et de son sécrétome (protéines excrétées/sécrétées) sur des cellules dendritiques humaines (DCs) in vitro. Nous avons ainsi montré une altération de la maturation des DCs induite par le LPS en présence du sécrétome. Nous avons également montré qu’une des protéines de ce sécrétome, TbKHC1, est exprimée par différentes espèces de trypanosomes. Elle est impliquée dans l’induction de l’arginase macrophagique chez la souris, un mécanisme d’échappement au système immunitaire. Ces travaux apportent des éléments pour une meilleure compréhension des phénomènes immunopathologiques rencontrés, dans la perspective de thérapeutiques ciblées et d’une approche vaccinale.Trypanosoma brucei gambiense, an extracellular eukaryotic flagellate parasite, is the main causative agent of Human African Trypanosomiasis (HAT), also known as sleeping sickness. Trypanosomes have developped efficient mechanisms to escape the host immune response. New therapeutic options are needed for patients with HAT. Sterol 14α-demethylase (CYP51) is a potential drug target but its essentiality has not been studied in T. brucei. In a first study, we demonstrated its essentiality by RNA interference (CYP51RNAi) in vitro. CYP51RNAi induction caused morphological defects with multiflagellated cells, suggesting cytokinesis dysfunction. Additionally, the survival of CYP51RNAi infected-mice was improved, showing CYP51 RNAi effect on trypanosomal virulence. During infection with virulent strains, posaconazole-eflornithine and nifurtimox-eflornithine combinations showed similar improvement in mice survival. Thus, our results provide support for a CYP51 targeting based treatment in HAT. In a second work, we studied the innate host immune system characteristics in trypanosomiasis, as a severe immune dysregulation is present in HAT. To analyse the potential immunomodulatory activity of T. gambiense in human settings, we assess the effect of its secretome on dendritic cells (DCs) in vitro, using human monocyte-derived DCs. A significant inhibition of the LPS-induced maturation of DCs was observed with secretome. In line with this impairment, secretome down regulated cytokines production by LPS-activated DCs. TbKHC1, a kinesin heavy chain, is a component of the parasite secretome. We confirmed its role in parasitic escape to immune system by inducing arginase activity, in a murine model. Our results provide new information about the immune system characteristics during trypanosomiasis, which may help to uncover new therapeutic approachs in HAT

Immunopathologie et approche thérapeutique dans la Trypanosomose Africaine

Trypanosoma brucei gambiense, an extracellular eukaryotic flagellate parasite, is the main causative agent of Human African Trypanosomiasis (HAT), also known as sleeping sickness. Trypanosomes have developped efficient mechanisms to escape the host immune response. New therapeutic options are needed for patients with HAT. Sterol 14α-demethylase (CYP51) is a potential drug target but its essentiality has not been studied in T. brucei. In a first study, we demonstrated its essentiality by RNA interference (CYP51RNAi) in vitro. CYP51RNAi induction caused morphological defects with multiflagellated cells, suggesting cytokinesis dysfunction. Additionally, the survival of CYP51RNAi infected-mice was improved, showing CYP51 RNAi effect on trypanosomal virulence. During infection with virulent strains, posaconazole-eflornithine and nifurtimox-eflornithine combinations showed similar improvement in mice survival. Thus, our results provide support for a CYP51 targeting based treatment in HAT. In a second work, we studied the innate host immune system characteristics in trypanosomiasis, as a severe immune dysregulation is present in HAT. To analyse the potential immunomodulatory activity of T. gambiense in human settings, we assess the effect of its secretome on dendritic cells (DCs) in vitro, using human monocyte-derived DCs. A significant inhibition of the LPS-induced maturation of DCs was observed with secretome. In line with this impairment, secretome down regulated cytokines production by LPS-activated DCs. TbKHC1, a kinesin heavy chain, is a component of the parasite secretome. We confirmed its role in parasitic escape to immune system by inducing arginase activity, in a murine model. Our results provide new information about the immune system characteristics during trypanosomiasis, which may help to uncover new therapeutic approachs in HAT.La Trypanosomose Humaine Africaine (THA) ou maladie du sommeil est une infection provoquée par un protozoaire du genre Trypanosoma. La recherche de nouvelles cibles thérapeutiques est nécessaire afin d’améliorer l’efficacité et la tolérance des traitements. Dans un premier travail, nous avons étudié l’importance de CYP51 (stérol 14α-déméthylase), une cible potentielle, par la technique d’interférence à ARN (RNAi). Nous avons démontré le caractère essentiel de cette enzyme pour le parasite, ainsi que les conséquences de sa déplétion sur la cytodiérèse. De plus, la survie de souris infectées par la souche CYP51RNAi induite était prolongée, montrant l’implication de CYP51 dans la virulence. La combinaison du posaconazole, un dérivé triazolé inhibant CYP51, à l’éflornithine a montré un effet similaire à la combinaison nifurtimox-éflornithine dans un modèle murin. Nos résultats soulignent l’intérêt potentiel d’un traitement ciblant CYP51 dans la trypanosomose. Du fait de l’importance de l’immunodépression dans la THA et de la capacité du trypanosome à échapper au système immunitaire de l’hôte, nous avons étudié, dans un deuxième travail, l’effet de T. gambiense et de son sécrétome (protéines excrétées/sécrétées) sur des cellules dendritiques humaines (DCs) in vitro. Nous avons ainsi montré une altération de la maturation des DCs induite par le LPS en présence du sécrétome. Nous avons également montré qu’une des protéines de ce sécrétome, TbKHC1, est exprimée par différentes espèces de trypanosomes. Elle est impliquée dans l’induction de l’arginase macrophagique chez la souris, un mécanisme d’échappement au système immunitaire. Ces travaux apportent des éléments pour une meilleure compréhension des phénomènes immunopathologiques rencontrés, dans la perspective de thérapeutiques ciblées et d’une approche vaccinale

Facteurs pronostiques dans la prise en charge initiale des méningites bactériennes communautaires de l'adulte (étude sur 4 ans au CHU de Bordeaux)

BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Trypanosomatid Infections: How Do Parasites and Their Excreted–Secreted Factors Modulate the Inducible Metabolism of l-Arginine in Macrophages?

Mononuclear phagocytes (monocytes, dendritic cells, and macrophages) are among the first host cells to face intra- and extracellular protozoan parasites such as trypanosomatids, and significant expansion of macrophages has been observed in infected hosts. They play essential roles in the outcome of infections caused by trypanosomatids, as they can not only exert a powerful antimicrobial activity but also promote parasite proliferation. These varied functions, linked to their phenotypic and metabolic plasticity, are exerted via distinct activation states, in which l-arginine metabolism plays a pivotal role. Depending on the environmental factors and immune response elements, l-arginine metabolites contribute to parasite elimination, mainly through nitric oxide (NO) synthesis, or to parasite proliferation, through l-ornithine and polyamine production. To survive and adapt to their hosts, parasites such as trypanosomatids developed mechanisms of interaction to modulate macrophage activation in their favor, by manipulating several cellular metabolic pathways. Recent reports emphasize that some excreted–secreted (ES) molecules from parasites and sugar-binding host receptors play a major role in this dialog, particularly in the modulation of the macrophage’s inducible l-arginine metabolism. Preventing l-arginine dysregulation by drugs or by immunization against trypanosomatid ES molecules or by blocking partner host molecules may control early infection and is a promising way to tackle neglected diseases including Chagas disease, leishmaniases, and African trypanosomiases. The present review summarizes recent knowledge on trypanosomatids and their ES factors with regard to their influence on macrophage activation pathways, mainly the NO synthase/arginase balance. The review ends with prospects for the use of biological knowledge to develop new strategies of interference in the infectious processes used by trypanosomatids, in particular for the development of vaccines or immunotherapeutic approaches

Med Mal Infect

INTRODUCTION: Periprosthetic knee infection is a severe complication. Confirmed criteria are lacking to choose between one-stage or two-stage prosthesis replacement to treat the infection. The one-stage replacement could lead to a satisfactory control of the infection and to better functional results. METHOD: Retrospective study conducted between January 1, 2009 and December 31, 2014. The objectives of this study were to compare the infection outcome and functional results between the one-stage and two-stage replacement procedures. Functional results were evaluated using the IKS score, KOOS score, and SF-12 quality of life score. RESULTS: Forty-one patients underwent a two-stage replacement procedure and 21 patients a one-stage replacement. The average follow-up was 22 months after surgery. The infection was cured in 78% of patients who underwent a two-stage replacement and 90% of patients who underwent a one-stage replacement (P=0.3). The flexion range of motion was significantly better in the one-stage group than in the two-stage group (P=0.04). Results of the IKS score and of the KOOS score were better in the one-stage group. No difference was observed for the SF-12 score. CONCLUSION: The one-stage replacement procedure for periprosthetic knee infection was associated with a similar healing frequency as the two-stage replacement procedure, and with better knee function