Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background

The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom been clarified whether drug-resistance mechanisms vary with the pathogen's genotype. Nevertheless this is of critical importance in gaining an understanding of the complexity of this global threat and in underpinning epidemiological surveillance of pathogen drug resistance in the field. This study aimed to assess the molecular and phenotypic heterogeneity that emerges in natural parasite populations under drug treatment pressure. We studied lines of the protozoan parasite Leishmania (L.) donovani with differential susceptibility to antimonial drugs; the lines being derived from clinical isolates belonging to two distinct genetic populations that circulate in the leishmaniasis endemic region of Nepal. Parasite pathways known to be affected by antimonial drugs were characterised on five experimental levels in the lines of the two populations. Characterisation of DNA sequence, gene expression, protein expression and thiol levels revealed a number of molecular features that mark antimonial-resistant parasites in only one of the two populations studied. A final series of in vitro stress phenotyping experiments confirmed this heterogeneity amongst drug-resistant parasites from the two populations. These data provide evidence that the molecular changes associated with antimonial-resistance in natural Leishmania populations depend on the genetic background of the Leishmania population, which has resulted in a divergent set of resistance markers in the Leishmania populations. This heterogeneity of parasite adaptations provides severe challenges for the control of drug resistance in the field and the design of molecular surveillance tools for widespread applicability

Accelerated Blood Clearance (ABC) phenomenon favors the accumulation of tartar emetic in pegylated liposomes in BALB/c mice liver.

Tartar emetic (TE) was the first drug used to treat leishmaniasis.However, its use was discontinued due to high toxicity. Association of TE with liposomes is a strategy to reduce its side effects. Pegylated liposomes (Lpeg) present lower rates of uptake by macrophages and prolonged circulation compared to their nonpegylated counterparts. However, repeated administration of Lpeg can cause an Accelerated Blood Clearance (ABC) phenomenon, whereby recognition of liposomes by antibodies results in faster phagocytosis. Thiswork evaluated the effect of TE administration on histopathological aspects and the effect of the ABC phenomenon on targeting and toxicity in mice. Our results show that treatment with free or liposomal TE had no effect on the erythrocyte count, on liver and spleen weight, and on hepatic, splenic, and cardiac histology in mice. Severe lesions were observed on the kidneys of animals treated with a single dose of free TE. Treatment with TE in Lpeg after induction of ABC phenomenon caused a significant increase in Sb level in the liver without toxicity. Furthermore, mice treated with TE in liposomes showed normal renal histopathology. These results suggest site-specific targeting of Sb to the liver after induction of ABC phenomenon with no toxicity to other organs

Gene Expression Profiling and Molecular Characterization of Antimony Resistance in Leishmania amazonensis

Leishmania are unicellular microorganisms that can be transmitted to humans by the bite of sandflies. They cause a spectrum of diseases called leishmaniasis, which are classified as neglected tropical diseases by the World Health Organization. The treatment of leishmaniasis is based on the administration of antimony-containing drugs. These drugs have been used since 1947 and still constitute the mainstay for leishmaniasis treatment in several countries. One of the problems with these compounds is the emergence of resistance. Our work seeks to understand how these parasites become resistant to the drug. We studied antimony-resistant Leishmania amazonensis mutants. We analyzed gene expression at the whole genome level in antimony-resistant parasites and identified mechanisms used by Leishmania for resistance. This work could help us in developing new strategies for treatment in endemic countries where people are unresponsive to antimony-based chemotherapy. The identification of common mechanisms among different species of resistant parasites may also contribute to the development of diagnostic kits to identify and monitor the spread of resistance

Nouvelle methode d'analyse du transport des anthracyclines dans les cellules. Application a l'etude du mecanisme du transport de ces composes dans les cellules tumorales resistantes a plusieurs drogues

SIGLEINIST T 76862 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Le loup (canis lupus lupus) captif (de la connaissance du monde propre à l'amélioration des conditions de captivité)

Cette étude porte sur le comportement du loup d'Europe captif et comporte deux phases : la comparaison de six meutes élevées dans des enclos différents et une étude fine d'une meute menée à différentes saisons. Les résultats obtenus montrent que la meute est caractérisée par une certaine instabilité des liens entre les individus. La comparaison des meutes montre que plus la qualité de l'enclos est importante, plus la proportion du temps passé au repos augmente. Quelle que soit la taille de l'enclos, les animaux utilisent seulement une partie de la surface disponible. Le type d'élevage et la gestion du groupe caractérisent la diversité comportementale. L'utilisation habituelle des indices de bien-être généralement utilisés est discutée. Ce travail souligne l'importance du choix du lieu et de la composition du groupe au niveau du bien-être. Il permet d'améliorer les connaissances sur l'animal et son monde propre afin de proposer des suggestions en terme d'élevage.TOURS-BU Sciences Pharmacie (372612104) / SudocPARIS-Museum Hist.Naturelle (751052304) / SudocSudocFranceF