The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Erin Khan Melissa - One of the best experts on this subject based on the ideXlab platform.
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TLR9 activation by Leishmania major DNA : role of genomic sequences and implication of DNA cofactor
2014Co-Authors: Erin Khan MelissaAbstract:La plus grande sensibilité des souris TLR9-/- a révélé le rôle de ce récepteur dans l'infection par Leishmania major. Les cellules dendritiques (DCs) sont activées de manière TLR9-dépendante par l'ADN du L. major et d'autres Trypanosomatidae et non par l'ADN de vertébré. La nature de l'ADN capable d'activer le TLR9 reste controversée quant à la séquence/charpente de l'ADN et l'implication de cofacteurs se liant avec le TLR9 ou l'ADN. Nous avons démontré l'importance de la séquence d'ADN. Contrairement aux génomes de parasites, l'ADN de vertébré présente une contre-sélection des motifs activateurs du TLR9 au profit des motifs inhibiteurs. De plus, l'activation du TLR9 par l'ADN du parasite est augmentée en présence de la protéine HMGB1, qui se fixe mieux sur l'ADN de parasite que de vertébré. La maturation du TLR9 requiert un clivage protéolytique par des protéases endosomales, dont les cathepsines (Cat) B, S, L et l'asparagine endopeptidase (AEP) qui interviennent différemment dans les macrophages et les DCs. Après infection par L. major, nous avons montré que les souris AEP-/-, CatS-/- et CatL-/- ont une pathologie identique aux souris WT, ce qui peut être dû à la redondance de leur fonction. Etonnamment, les souris CatB-/- sont plus résistantes. Leurs lésions et la charge parasitaire dans les ganglions se résolvent plus rapidement, reflétant une réponse immune plus précoce et un contrôle plus rapide de la réaction inflammatoire.En conclusion, ces résultats contribuent à une meilleure compréhension des mécanismes permettant au TLR9 de discriminer entre l'ADN de pathogène et de vertébré et soulèvent le rôle non protecteur de la cathepsine B dans l'infection par L. major.As TLR9-deficient mice are more sensitive to Leishmania major infection, we have shown previously that TLR9 receptor mediates this parasite infection. Dendritic cells (DCs) are activated by L. major and other Trypanosomatidae DNA and not by vertebrate DNA. There is an ongoing controversy concerning the properties of DNA required for TLR9 activation, regarding the DNA sequence or backbone or the implication of a cofactor interacting with TLR9 or DNA. We have established the importance of DNA sequences. In contrast to parasite genome, vertebrate genome have counter-selected stimulatory sequences and over-represented inhibitory motifs for TLR9. In addition, host proteins contribute to TLR9-dependent DC activation. HMGB1 enhances TLR9 activation only in the presence of L. major DNA and, surprisingly, HMGB1 binds more abundantly L. major than vertebrate DNA. TLR9 activation requires a proteolytic cleavage by endosomal proteases, as cathepsins (Cat) B, S and L and asparagine endopeptidase (AEP) that have a differential activity in macrophages and DCs. After L. major infection, we have showed that AEP-/-, CatS-/- and CatL-/- mice have a similar pathology than WT mice, likely due to their functionnally redundant activites. In contrast, CatB-/- mice are more resistant to the infection. Their lesion sizes and the parasite burdens in lymph nodes are significantly decreased, reflecting an earlier immune response and a more rapid control of the inflammatory response. In conclusion, our results bring further insights into how TLR9 discriminates between Trypanosomatidae and vertebrate DNA and reveal a non protective role of cathepsin B in L. major infection
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Rôle de l'ADN dans l'activation du TLR9 lors de l'infection par Leishmania major (propriétés des séquences génomiques et implication des facteurs protéiques)
2014Co-Authors: Erin Khan Melissa, Doyen NoëlleAbstract:La plus grande sensibilité des souris TLR9-/- a révélé le rôle de ce récepteur dans l'infection par Leishmania major. Les cellules dendritiques (DCs) sont activées de manière TLR9-dépendante par l'ADN du L. major et d'autres Trypanosomatidae et non par l'ADN de vertébré. La nature de l'ADN capable d'activer le TLR9 reste controversée quant à la séquence/charpente de l'ADN et l'implication de cofacteurs se liant avec le TLR9 ou l'ADN. Nous avons démontré l'importance de la séquence d'ADN. Contrairement aux génomes de parasites, l'ADN de vertébré présente une contre-sélection des motifs activateurs du TLR9 au profit des motifs inhibiteurs. De plus, l'activation du TLR9 par l'ADN du parasite est augmentée en présence de la protéine HMGB1, qui se fixe mieux sur l'ADN de parasite que de vertébré. La maturation du TLR9 requiert un clivage protéolytique par des protéases endosomales, dont les cathepsines (Cat) B, S, L et l'asparagine endopeptidase (AEP) qui interviennent différemment dans les macrophages et les DCs. Après infection par L. major, nous avons montré que les souris AEP-/-, CatS-/- et CatL-/- ont une pathologie identique aux souris WT, ce qui peut être dû à la redondance de leur fonction. Etonnamment, les souris CatB-/- sont plus résistantes. Leurs lésions et la charge parasitaire dans les ganglions se résolvent plus rapidement, reflétant une réponse immune plus précoce et un contrôle plus rapide de la réaction inflammatoire.En conclusion, ces résultats contribuent à une meilleure compréhension des mécanismes permettant au TLR9 de discriminer entre l'ADN de pathogène et de vertébré et soulèvent le rôle non protecteur de la cathepsine B dans l'infection par L. major.As TLR9-deficient mice are more sensitive to Leishmania major infection, we have shown previously that TLR9 receptor mediates this parasite infection. Dendritic cells (DCs) are activated by L. major and other Trypanosomatidae DNA and not by vertebrate DNA. There is an ongoing controversy concerning the properties of DNA required for TLR9 activation, regarding the DNA sequence or backbone or the implication of a cofactor interacting with TLR9 or DNA. We have established the importance of DNA sequences. In contrast to parasite genome, vertebrate genome have counter-selected stimulatory sequences and over-represented inhibitory motifs for TLR9. In addition, host proteins contribute to TLR9-dependent DC activation. HMGB1 enhances TLR9 activation only in the presence of L. major DNA and, surprisingly, HMGB1 binds more abundantly L. major than vertebrate DNA. TLR9 activation requires a proteolytic cleavage by endosomal proteases, as cathepsins (Cat) B, S and L and asparagine endopeptidase (AEP) that have a differential activity in macrophages and DCs. After L. major infection, we have showed that AEP-/-, CatS-/- and CatL-/- mice have a similar pathology than WT mice, likely due to their functionnally redundant activites. In contrast, CatB-/- mice are more resistant to the infection. Their lesion sizes and the parasite burdens in lymph nodes are significantly decreased, reflecting an earlier immune response and a more rapid control of the inflammatory response. In conclusion, our results bring further insights into how TLR9 discriminates between Trypanosomatidae and vertebrate DNA and reveal a non protective role of cathepsin B in L. major infection.PARIS-JUSSIEU-Bib.électronique (751059901) / SudocSudocFranceF
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Rôle de l'ADN dans l'activation du TLR9 lors de l'infection par Leishmania major : propriétés des séquences génomiques et implication des facteurs protéiques
HAL CCSD, 2014Co-Authors: Erin Khan MelissaAbstract:As TLR9-deficient mice are more sensitive to Leishmania major infection, we have shown previously that TLR9 receptor mediates this parasite infection. Dendritic cells (DCs) are activated by L. major and other Trypanosomatidae DNA and not by vertebrate DNA. There is an ongoing controversy concerning the properties of DNA required for TLR9 activation, regarding the DNA sequence or backbone or the implication of a cofactor interacting with TLR9 or DNA. We have established the importance of DNA sequences. In contrast to parasite genome, vertebrate genome have counter-selected stimulatory sequences and over-represented inhibitory motifs for TLR9. In addition, host proteins contribute to TLR9-dependent DC activation. HMGB1 enhances TLR9 activation only in the presence of L. major DNA and, surprisingly, HMGB1 binds more abundantly L. major than vertebrate DNA. TLR9 activation requires a proteolytic cleavage by endosomal proteases, as cathepsins (Cat) B, S and L and asparagine endopeptidase (AEP) that have a differential activity in macrophages and DCs. After L. major infection, we have showed that AEP-/-, CatS-/- and CatL-/- mice have a similar pathology than WT mice, likely due to their functionnally redundant activites. In contrast, CatB-/- mice are more resistant to the infection. Their lesion sizes and the parasite burdens in lymph nodes are significantly decreased, reflecting an earlier immune response and a more rapid control of the inflammatory response. In conclusion, our results bring further insights into how TLR9 discriminates between Trypanosomatidae and vertebrate DNA and reveal a non protective role of cathepsin B in L. major infection.La plus grande sensibilité des souris TLR9-/- a révélé le rôle de ce récepteur dans l'infection par Leishmania major. Les cellules dendritiques (DCs) sont activées de manière TLR9-dépendante par l'ADN du L. major et d'autres Trypanosomatidae et non par l'ADN de vertébré. La nature de l'ADN capable d'activer le TLR9 reste controversée quant à la séquence/charpente de l'ADN et l'implication de cofacteurs se liant avec le TLR9 ou l'ADN. Nous avons démontré l'importance de la séquence d'ADN. Contrairement aux génomes de parasites, l'ADN de vertébré présente une contre-sélection des motifs activateurs du TLR9 au profit des motifs inhibiteurs. De plus, l'activation du TLR9 par l'ADN du parasite est augmentée en présence de la protéine HMGB1, qui se fixe mieux sur l'ADN de parasite que de vertébré. La maturation du TLR9 requiert un clivage protéolytique par des protéases endosomales, dont les cathepsines (Cat) B, S, L et l'asparagine endopeptidase (AEP) qui interviennent différemment dans les macrophages et les DCs. Après infection par L. major, nous avons montré que les souris AEP-/-, CatS-/- et CatL-/- ont une pathologie identique aux souris WT, ce qui peut être dû à la redondance de leur fonction. Etonnamment, les souris CatB-/- sont plus résistantes. Leurs lésions et la charge parasitaire dans les ganglions se résolvent plus rapidement, reflétant une réponse immune plus précoce et un contrôle plus rapide de la réaction inflammatoire.En conclusion, ces résultats contribuent à une meilleure compréhension des mécanismes permettant au TLR9 de discriminer entre l'ADN de pathogène et de vertébré et soulèvent le rôle non protecteur de la cathepsine B dans l'infection par L. major
Craig W. Lindsley - One of the best experts on this subject based on the ideXlab platform.
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sterol 14α demethylase structure based optimization of drug candidates for human infections with the protozoan Trypanosomatidae
Journal of Medicinal Chemistry, 2018Co-Authors: Laura Friggeri, Tatiana Y. Hargrove, Girish Rachakonda, Anna L. Blobaum, Gabriel Melo De Oliveira, David W. Nes, Paxtyn M Fisher, Cristiane Franca Da Silva, Maria De Nazare Correia Soeiro, Craig W. LindsleyAbstract:Sterol 14α-demethylases (CYP51) are cytochrome P450 enzymes essential for sterol biosynthesis in eukaryotes and therapeutic targets for antifungal azoles. Multiple attempts to repurpose antifungals for treatment of human infections with protozoa (Trypanosomatidae) have been undertaken, yet so far none of them have revealed sufficient efficacy. VNI and its derivative VFV are two potent experimental inhibitors of Trypanosomatidae CYP51, effective in vivo against Chagas disease, visceral leishmaniasis, and sleeping sickness and currently under consideration as antiprotozoal drug candidates. However, VNI is less potent against Leishmania and drug-resistant strains of Trypanosoma cruzi and VFV, while displaying a broader spectrum of antiprotozoal activity, and is metabolically less stable. In this work we have designed, synthesized, and characterized a set of close analogues and identified two new compounds (7 and 9) that exceed VNI/VFV in their spectra of antiprotozoal activity, microsomal stability, and phar...
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Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae
2018Co-Authors: Laura Friggeri, Tatiana Y. Hargrove, Girish Rachakonda, Anna L. Blobaum, Paxtyn Fisher, Gabriel Melo De Oliveira, Cristiane França Da Silva, Maria De Nazaré C. Soeiro, David W. Nes, Craig W. LindsleyAbstract:Sterol 14α-demethylases (CYP51) are cytochrome P450 enzymes essential for sterol biosynthesis in eukaryotes and therapeutic targets for antifungal azoles. Multiple attempts to repurpose antifungals for treatment of human infections with protozoa (Trypanosomatidae) have been undertaken, yet so far none of them have revealed sufficient efficacy. VNI and its derivative VFV are two potent experimental inhibitors of Trypanosomatidae CYP51, effective in vivo against Chagas disease, visceral leishmaniasis, and sleeping sickness and currently under consideration as antiprotozoal drug candidates. However, VNI is less potent against Leishmania and drug-resistant strains of Trypanosoma cruzi and VFV, while displaying a broader spectrum of antiprotozoal activity, and is metabolically less stable. In this work we have designed, synthesized, and characterized a set of close analogues and identified two new compounds (7 and 9) that exceed VNI/VFV in their spectra of antiprotozoal activity, microsomal stability, and pharmacokinetics (tissue distribution in particular) and, like VNI/VFV, reveal no acute toxicity
Helen Piontkivska - One of the best experts on this subject based on the ideXlab platform.
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environmental kinetoplastid like 18s rrna sequences and phylogenetic relationships among Trypanosomatidae paraphyly of the genus trypanosoma
Molecular and Biochemical Parasitology, 2005Co-Authors: Helen Piontkivska, Austin L. HughesAbstract:Using kinetoplastid-like sequences from deep-sea environmental samples as an outgroup, we applied phylogenetic analysis to 18S rRNA sequences of the families Trypanosomatidae and Bodonidae (Eugelenozoa: Kinetoplastida). The monophyly of the genus Trypanosoma was not supported by a number of different methods. Rather, the results indicate that the American and African trypanosomes constitute distinct clades, therefore, implying that the major human disease agents T. cruzi (cause of Chagas’ disease) and T. brucei (cause of African sleeping sickness) are not as closely related to each other as they were previously thought to be. Likewise, the results did not support monophyly of the genera Leishmania, Leptomonas, Bodo and Cryptobia.
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Molecular phylogenetics of Trypanosomatidae: contrasting results from 18S rRNA and protein phylogenies
Kinetoplastid Biology and Disease, 2003Co-Authors: Austin L. Hughes, Helen PiontkivskaAbstract:Phylogenetic analyses of the family Trypanosomatidae have been conducted using both 18S rRNA gene sequences and a variety of protein sequences. Using a variety of phylogenetic methods, 18S rRNA phylogenies indicate that the genus Trypanosoma is not monophyletic. Rather, they suggest that the American and African trypanosomes constitute distinct clades. By contrast, phylogenetic analyses of available sequences in 42 protein families gene generally supported monophyly of the genus Trypanosoma . One possible explanation for these conflicting results is poor taxon sampling in the case of protein coding genes, most of which have been sequenced for only a few species of Trypanosomatidae.
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Phylogeny of Trypanosomatidae and Bodonidae (Kinetoplastida) Based on 18S rRNA: Evidence for Paraphyly of Trypanosoma and Six Other Genera
Molecular biology and evolution, 2003Co-Authors: Austin L. Hughes, Helen PiontkivskaAbstract:Phylogenetic analysis of 18S rRNA sequences from the families Trypanosomatidae and Bodonidae (Eugelenozoa: Kinetoplastida) was conducted using a variety of methods. Unlike previous analyses using unrooted trees and/or smaller numbers of sequences, the analysis did not support monophyly of the genus Trypanosoma, which includes the major human parasites T. cruzi (cause of Chagas' disease) and T. brucei (cause of African sleeping sickness). The section Salivaria of the genus Trypanosoma fell outside a cluster that includes the section Stercoraria of the genus Trypanosoma, along with members of the genera Leishmania, Endotrypanum, Leptomonas, Herpetomonas, Phytomonas, Crithidia, and Blastochrithidia. The phylogenetic analysis also indicated that the genera Bodo, Cryptobia, Leptomonas, Herpetomonas, Crithidia, and Blastocrithidia are polyphyletic. The results suggested that parasitism of vertebrates has probably arisen independently a number of times within the Trypanosomatidae.
Silvia A. Justi - One of the best experts on this subject based on the ideXlab platform.
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An overview on the ecology of Triatominae (Hemiptera:Reduviidae)
Acta tropica, 2015Co-Authors: Cleber Galvão, Silvia A. JustiAbstract:Chagas disease, the American trypanosomiasis, is an important neglected tropical illness caused by the flagellate protozoan Trypanosoma cruzi (Kinetoplastida, Trypanosomatidae) and transmitted by insects of the subfamily Triatominae (Hemiptera: Reduviidae). Here we provide an overview on the current knowledge about Triatominae ecology, its association with human, T. cruzi infection and the immediate consequences of habitat fragmentation. We also discuss the geographic distribution of the species and the importance of predicting their distributions to control programs.
Laura Friggeri - One of the best experts on this subject based on the ideXlab platform.
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sterol 14α demethylase structure based optimization of drug candidates for human infections with the protozoan Trypanosomatidae
Journal of Medicinal Chemistry, 2018Co-Authors: Laura Friggeri, Tatiana Y. Hargrove, Girish Rachakonda, Anna L. Blobaum, Gabriel Melo De Oliveira, David W. Nes, Paxtyn M Fisher, Cristiane Franca Da Silva, Maria De Nazare Correia Soeiro, Craig W. LindsleyAbstract:Sterol 14α-demethylases (CYP51) are cytochrome P450 enzymes essential for sterol biosynthesis in eukaryotes and therapeutic targets for antifungal azoles. Multiple attempts to repurpose antifungals for treatment of human infections with protozoa (Trypanosomatidae) have been undertaken, yet so far none of them have revealed sufficient efficacy. VNI and its derivative VFV are two potent experimental inhibitors of Trypanosomatidae CYP51, effective in vivo against Chagas disease, visceral leishmaniasis, and sleeping sickness and currently under consideration as antiprotozoal drug candidates. However, VNI is less potent against Leishmania and drug-resistant strains of Trypanosoma cruzi and VFV, while displaying a broader spectrum of antiprotozoal activity, and is metabolically less stable. In this work we have designed, synthesized, and characterized a set of close analogues and identified two new compounds (7 and 9) that exceed VNI/VFV in their spectra of antiprotozoal activity, microsomal stability, and phar...
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Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae
2018Co-Authors: Laura Friggeri, Tatiana Y. Hargrove, Girish Rachakonda, Anna L. Blobaum, Paxtyn Fisher, Gabriel Melo De Oliveira, Cristiane França Da Silva, Maria De Nazaré C. Soeiro, David W. Nes, Craig W. LindsleyAbstract:Sterol 14α-demethylases (CYP51) are cytochrome P450 enzymes essential for sterol biosynthesis in eukaryotes and therapeutic targets for antifungal azoles. Multiple attempts to repurpose antifungals for treatment of human infections with protozoa (Trypanosomatidae) have been undertaken, yet so far none of them have revealed sufficient efficacy. VNI and its derivative VFV are two potent experimental inhibitors of Trypanosomatidae CYP51, effective in vivo against Chagas disease, visceral leishmaniasis, and sleeping sickness and currently under consideration as antiprotozoal drug candidates. However, VNI is less potent against Leishmania and drug-resistant strains of Trypanosoma cruzi and VFV, while displaying a broader spectrum of antiprotozoal activity, and is metabolically less stable. In this work we have designed, synthesized, and characterized a set of close analogues and identified two new compounds (7 and 9) that exceed VNI/VFV in their spectra of antiprotozoal activity, microsomal stability, and pharmacokinetics (tissue distribution in particular) and, like VNI/VFV, reveal no acute toxicity
