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Article ; Online: New insights into the mycobacterial PE and PPE proteins provide a framework for future research.

Ates, Louis S

2019 Volume 113, Issue 1, Page(s) 4–21

Abstract: The PE and PPE proteins of Mycobacterium tuberculosis have been studied with great interest since their discovery. Named after the conserved proline (P) and glutamic acid (E) residues in their N-terminal domains, these proteins are postulated to perform ... ...

Abstract	The PE and PPE proteins of Mycobacterium tuberculosis have been studied with great interest since their discovery. Named after the conserved proline (P) and glutamic acid (E) residues in their N-terminal domains, these proteins are postulated to perform wide-ranging roles in virulence and immune modulation. However, technical challenges in studying these proteins and their encoding genes have hampered the elucidation of molecular mechanisms and leave many open questions regarding the biological functions mediated by these proteins. Here, I review the shared and unique characteristics of PE and PPE proteins from a molecular perspective linking this information to their functions in mycobacterial virulence. I discuss how the different subgroups (PE_PGRS, PPE-PPW, PPE-SVP and PPE-MPTR) are defined and why this classification of paramount importance to understand the PE and PPE proteins as individuals and or groups. The goal of this MicroReview is to summarize and structure the existing information on this gene family into a simplified framework of thinking about PE and PPE proteins and genes. Thereby, I hope to provide helpful starting points in studying these genes and proteins for researchers with different backgrounds. This has particular implications for the design and monitoring of novel vaccine candidates and in understanding the evolution of the M. tuberculosis complex.
MeSH term(s)	Antigens, Bacterial/chemistry ; Antigens, Bacterial/immunology ; Bacterial Proteins/chemistry ; Bacterial Proteins/immunology ; Evolution, Molecular ; Humans ; Multigene Family/immunology ; Mycobacterium tuberculosis/immunology ; Mycobacterium tuberculosis/pathogenicity ; Proline-Rich Protein Domains ; Tuberculosis/immunology ; Tuberculosis/microbiology ; Virulence
Chemical Substances	Antigens, Bacterial ; Bacterial Proteins
Language	English
Publishing date	2019-11-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	619315-8
ISSN	1365-2958 ; 0950-382X
ISSN (online)	1365-2958
ISSN	0950-382X
DOI	10.1111/mmi.14409
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Article ; Online: Discovery of the type VII ESX-1 secretion needle?

Ates, Louis S / Brosch, Roland

Molecular microbiology

2017 Volume 103, Issue 1, Page(s) 7–12

Abstract: Mycobacterium tuberculosis, the etiological agent of human tuberculosis, harbours five ESAT-6/type VII secretion (ESX/T7S) systems. The first esx gene clusters were identified during the genome-sequencing project of M. tuberculosis H37Rv. Follow-up ... ...

Abstract	Mycobacterium tuberculosis, the etiological agent of human tuberculosis, harbours five ESAT-6/type VII secretion (ESX/T7S) systems. The first esx gene clusters were identified during the genome-sequencing project of M. tuberculosis H37Rv. Follow-up studies revealed additional genes playing important roles in ESX/T7S systems. Among the latter genes, one can find those that encode Pro-Glu (PE) and Pro-Pro-Glu (PPE) proteins as well as a gene cluster that is encoded >260 kb upstream of the esx-1 locus and encodes ESX-1 secretion-associated proteins EspA (Rv3616c), EspC (Rv3615c) and EspD (Rv3614c). The espACD cluster has been suggested to have an important function in ESX-1 secretion since EspA-EspC and EsxA-EsxB are mutually co-dependent on each other for secretion. However, the molecular mechanism of this co-dependence and interaction between the substrates remained unknown. In this issue of Molecular Microbiology, Lou and colleagues show that EspC forms high-molecular weight polymerization complexes that resemble selected components of type II, III and/or IV secretion systems of Gram-negative bacteria. Indeed, EspC-multimeric complexes form filamentous structures that could well represent a secretion needle of ESX-1 type VII secretion systems. This exciting observation opens new avenues for research to discover and characterize ESX/T7S components and elucidates the co-dependence of EsxA/B secretion with EspA/C.
MeSH term(s)	Antigens, Bacterial/metabolism ; Bacterial Proteins/metabolism ; Bacterial Secretion Systems/genetics ; Bacterial Secretion Systems/metabolism ; Genome, Bacterial ; Multigene Family ; Mycobacterium tuberculosis/genetics ; Protein Transport ; Type VII Secretion Systems/genetics ; Type VII Secretion Systems/metabolism
Chemical Substances	Antigens, Bacterial ; Bacterial Proteins ; Bacterial Secretion Systems ; Type VII Secretion Systems
Language	English
Publishing date	2017
Publishing country	England
Document type	Editorial ; Introductory Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	619315-8
ISSN	1365-2958 ; 0950-382X
ISSN (online)	1365-2958
ISSN	0950-382X
DOI	10.1111/mmi.13579
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Article ; Online: Ectopic expression of cGAS in

Waanders, Lisette / van der Donk, Lieve E H / Ates, Louis S / Maaskant, Janneke / van Hamme, John L / Eldering, Eric / van Bruggen, Jaco A C / Rietveld, Joanne M / Bitter, Wilbert / Geijtenbeek, Teunis B H / Kuijl, Coenraad P

Journal for immunotherapy of cancer

2023 Volume 11, Issue 4

Abstract: Background: Interferon (IFN)-β induction via activation of the stimulator of interferon genes (STING) pathway has shown promising results in tumor models. STING is activated by cyclic dinucleotides such as cyclic GMP-AMP dinucleotides with ... ...

Abstract	Background: Interferon (IFN)-β induction via activation of the stimulator of interferon genes (STING) pathway has shown promising results in tumor models. STING is activated by cyclic dinucleotides such as cyclic GMP-AMP dinucleotides with phosphodiester linkages 2'-5' and 3'-5' (cGAMPs), that are produced by cyclic GMP-AMP synthetase (cGAS). However, delivery of STING pathway agonists to the tumor site is a challenge. Bacterial vaccine strains have the ability to specifically colonize hypoxic tumor tissues and could therefore be modified to overcome this challenge. Combining high STING-mediated IFN-β levels with the immunostimulatory properties of Methods: We have engineered Results: Expression of cGAS in Conclusion: S. typhimurium
MeSH term(s)	Humans ; Salmonella typhimurium/metabolism ; Ectopic Gene Expression ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism ; Macrophages/metabolism ; Interferon Type I ; Neoplasms/metabolism ; Dendritic Cells/metabolism ; Tumor Microenvironment
Chemical Substances	cyclic guanosine monophosphate-adenosine monophosphate ; Nucleotidyltransferases (EC 2.7.7.-) ; Interferon Type I
Language	English
Publishing date	2023-04-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2022-005839
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Article ; Online: Type VII Secretion: A Highly Versatile Secretion System.

Ates, Louis S / Houben, Edith N G / Bitter, Wilbert

Microbiology spectrum

2016 Volume 4, Issue 1

Abstract: Type VII secretion (T7S) systems of mycobacteria secrete substrates over the unusual diderm cell envelope. Furthermore, T7S gene clusters are present throughout the phylum Actinobacteria, and functional T7S-like systems have been identified in Firmicutes. ...

Abstract	Type VII secretion (T7S) systems of mycobacteria secrete substrates over the unusual diderm cell envelope. Furthermore, T7S gene clusters are present throughout the phylum Actinobacteria, and functional T7S-like systems have been identified in Firmicutes. Most of the T7S substrates can be divided into two families: the Esx proteins, which are found in both Firmicutes and Actinobacteria, and the PE and PPE proteins, which are more mycobacterium-specific. Members of both families have been shown to be secreted as folded heterodimers, suggesting that this is a conserved feature of T7S substrates. Most knowledge of the mechanism of T7S and the roles of T7S systems in virulence comes from studies of pathogenic mycobacteria. These bacteria can contain up to five T7S systems, called ESX-1 to ESX-5, each having its own role in bacterial physiology and virulence. In this article, we discuss the general composition of T7S systems and the role of the individual components in secretion. These conserved components include two membrane proteins with (predicted) enzymatic activities: a predicted ATPase (EccC), likely to be required for energy provision of T7S, and a subtilisin-like protease (MycP) involved in processing of specific substrates. Additionally, we describe the role of a conserved intracellular chaperone in T7S substrate recognition, based on recently published crystal structures and molecular analysis. Finally, we discuss system-specific features of the different T7S systems in mycobacteria and their role in pathogenesis and provide an overview of the role of T7S in virulence of other pathogenic bacteria.
MeSH term(s)	Gene Transfer, Horizontal ; Genes, Bacterial ; Humans ; Mycobacterium/genetics ; Mycobacterium/metabolism ; Mycobacterium/pathogenicity ; Mycobacterium Infections/microbiology ; Type VII Secretion Systems/genetics ; Type VII Secretion Systems/physiology
Chemical Substances	Type VII Secretion Systems
Language	English
Publishing date	2016-03-11
Publishing country	United States
Document type	Journal Article
ISSN	2165-0497
ISSN (online)	2165-0497
DOI	10.1128/microbiolspec.VMBF-0011-2015
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Article ; Online: An optimized retroviral toolbox for overexpression and genetic perturbation of primary lymphocytes.

van der Donk, Lieve E H / van der Spek, Jet / van Duivenvoorde, Tom / Ten Brink, Marieke S / Geijtenbeek, Teunis B H / Kuijl, Coenraad P / van Heijst, Jeroen W J / Ates, Louis S

Biology open

2022 Volume 11, Issue 2

Abstract: Genetic manipulation of primary lymphocytes is crucial for both clinical purposes and fundamental research. Despite their broad use, we encountered a paucity of data on systematic comparison and optimization of retroviral vectors, the workhorses of ... ...

Abstract	Genetic manipulation of primary lymphocytes is crucial for both clinical purposes and fundamental research. Despite their broad use, we encountered a paucity of data on systematic comparison and optimization of retroviral vectors, the workhorses of genetic modification of primary lymphocytes. Here, we report the construction and validation of a versatile range of retroviral expression vectors. These vectors can be used for the knockdown or overexpression of genes of interest in primary human and murine lymphocytes, in combination with a wide choice of selection and reporter strategies. By streamlining the vector backbone and insert design, these publicly available vectors allow easy interchangeability of the independent building blocks, such as different promoters, fluorescent proteins, surface markers and antibiotic resistance cassettes. We validated these vectors and tested the optimal promoters for in vitro and in vivo overexpression and knockdown of the murine T cell antigen receptor. By publicly sharing these vectors and the data on their optimization, we aim to facilitate genetic modification of primary lymphocytes for researchers entering this field.
MeSH term(s)	Animals ; Genetic Vectors/genetics ; Humans ; Lymphocytes ; Mice ; Promoter Regions, Genetic ; Retroviridae/genetics
Language	English
Publishing date	2022-03-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2632264-X
ISSN	2046-6390 ; 2046-6390
ISSN (online)	2046-6390
ISSN	2046-6390
DOI	10.1242/bio.059032
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Article ; Online: Optimization of secretion and surface localization of heterologous OVA protein in mycobacteria by using LipY as a carrier.

Burggraaf, Maroeska J / Ates, Louis S / Speer, Alexander / van der Kuij, Kim / Kuijl, Coen / Bitter, Wilbert

Microbial cell factories

2019 Volume 18, Issue 1, Page(s) 44

Abstract: Background: Mycobacterium bovis Bacille Calmette-Guérin (BCG) is not only used as a vaccine against tuberculosis but also protects against leprosy and is used as part of bladder cancer treatment to induce a protective immune response. However, ... ...

Abstract	Background: Mycobacterium bovis Bacille Calmette-Guérin (BCG) is not only used as a vaccine against tuberculosis but also protects against leprosy and is used as part of bladder cancer treatment to induce a protective immune response. However, protection by BCG vaccination is not optimal. To improve vaccine efficacy, recombinant BCG expressing heterologous antigens has been put forward to elicit antigen-specific cellular and humoral responses. Cell surface localized or secreted antigens induce better immune responses than their cytosolic counterparts. Optimizing secretion of heterologous proteins or protein fragments holds therefore unexplored potential for improving the efficacy of recombinant BCG vaccine candidates. Secretion of heterologous antigens requires crossing the mycobacterial inner and outer membrane. Mycobacteria have specialized ESX or type VII secretion systems that enable translocation of proteins across both membranes. Probing this secretion system could therefore be a valid approach to surface localize heterologous antigens. Results: We show that ESX-5 substrate LipY, a lipase, can be used as a carrier for heterologous secretion of an ovalbumin fragment (OVA). LipY contains a PE domain and a lipase domain, separated by a linker region. This linker domain is processed upon secretion. Fusion of the PE and linker domains of LipY to OVA enabled ESX-5-dependent secretion of the fusion construct LipY-OVA in M. marinum, albeit with low efficiency. Subsequent random mutagenesis of LipY-OVA and screening for increased secretion resulted in mutants with improved heterologous secretion. Detailed analysis identified two mutations in OVA that improved secretion, i.e. an L280P mutation and a protein-extending frameshift mutation. Finally, deletion of the linker domain of LipY enhanced secretion of LipY-OVA, although this mutation also reduced surface association. Further analysis in wild type LipY showed that the linker domain is required for surface association. Conclusion: We show that the ESX-5 system can be used for heterologous secretion. Furthermore, minor mutations in the substrate can enhance secretion. Especially the C-terminal region seems to be important for this. The linker domain of LipY is involved in surface association. These findings show that non-biased screening approaches aid in optimization of heterologous secretion, which can contribute to heterologous vaccine development.
MeSH term(s)	Antigens, Bacterial/genetics ; Bacterial Proteins/genetics ; Carboxylic Ester Hydrolases/genetics ; Carrier Proteins/genetics ; Membrane Proteins/genetics ; Mutagenesis ; Mutation ; Mycobacterium marinum/genetics ; Ovalbumin/genetics ; Ovalbumin/metabolism ; Type VII Secretion Systems/genetics ; Type VII Secretion Systems/metabolism ; Virulence Factors/genetics
Chemical Substances	Antigens, Bacterial ; Bacterial Proteins ; Carrier Proteins ; Membrane Proteins ; Type VII Secretion Systems ; Virulence Factors ; Ovalbumin (9006-59-1) ; Carboxylic Ester Hydrolases (EC 3.1.1.-) ; LipY protein, Mycobacterium tuberculosis (EC 3.1.1.-)
Language	English
Publishing date	2019-03-06
Publishing country	England
Document type	Journal Article
ISSN	1475-2859
ISSN (online)	1475-2859
DOI	10.1186/s12934-019-1093-1
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Article ; Online: Pathogenomic analyses of

Orgeur, Mickael / Frigui, Wafa / Pawlik, Alexandre / Clark, Simon / Williams, Ann / Ates, Louis S / Ma, Laurence / Bouchier, Christiane / Parkhill, Julian / Brodin, Priscille / Brosch, Roland

Microbial genomics

2021 Volume 7, Issue 2

Abstract: Mycobacterium ... ...

Abstract	Mycobacterium microti
MeSH term(s)	Animals ; Antigens, Bacterial/genetics ; Arvicolinae/microbiology ; Bacterial Proteins/genetics ; Bacterial Vaccines/administration & dosage ; Bacterial Vaccines/genetics ; Disease Models, Animal ; Gene Deletion ; Guinea Pigs ; High-Throughput Nucleotide Sequencing ; Humans ; Mice ; Mice, SCID ; Mycobacterium tuberculosis/classification ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/pathogenicity ; Phylogeny ; Tuberculosis/prevention & control ; Whole Genome Sequencing/methods
Chemical Substances	Antigens, Bacterial ; Bacterial Proteins ; Bacterial Vaccines ; ESAT-6 protein, Mycobacterium tuberculosis
Language	English
Publishing date	2021-02-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2835258-0
ISSN	2057-5858 ; 2057-5858
ISSN (online)	2057-5858
ISSN	2057-5858
DOI	10.1099/mgen.0.000505
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Article ; Online: Separate signaling events control TCR downregulation and T cell activation in primary human T cells.

van der Donk, Lieve E H / Ates, Louis S / van der Spek, Jet / Tukker, Laura M / Geijtenbeek, Teunis B H / van Heijst, Jeroen W J

Immunity, inflammation and disease

2020 Volume 9, Issue 1, Page(s) 223–238

Abstract: Introduction: T-cell antigen receptor (TCR) interaction with cognate peptide:MHC complexes trigger clustering of TCR:CD3 complexes and signal transduction. Triggered TCR:CD3 complexes are rapidly internalized and degraded in a process called ligand- ... ...

Abstract	Introduction: T-cell antigen receptor (TCR) interaction with cognate peptide:MHC complexes trigger clustering of TCR:CD3 complexes and signal transduction. Triggered TCR:CD3 complexes are rapidly internalized and degraded in a process called ligand-induced TCR downregulation. Classic studies in immortalized T-cell lines have revealed a major role for the Src family kinase Lck in TCR downregulation. However, to what extent a similar mechanism operates in primary human T cells remains unclear. Methods: Here, we developed an anti-CD3-mediated TCR downregulation assay, in which T-cell gene expression in primary human T cells can be knocked down by microRNA constructs. In parallel, we used CRISPR/Cas9-mediated knockout in Jurkat cells for validation experiments. Results: We efficiently knocked down the expression of tyrosine kinases Lck, Fyn, and ZAP70, and found that, whereas this impaired T cell activation and effector function, TCR downregulation was not affected. Although TCR downregulation was marginally inhibited by the simultaneous knockdown of Lck and Fyn, its full abrogation required broad-acting tyrosine kinase inhibitors. Conclusions: These data suggest that there is substantial redundancy in the contribution of individual tyrosine kinases to TCR downregulation in primary human T cells. Our results highlight that TCR downregulation and T cell activation are controlled by different signaling events and illustrate the need for further research to untangle these processes.
MeSH term(s)	Down-Regulation ; Humans ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism ; Phosphorylation ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-fyn/genetics ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Signal Transduction
Chemical Substances	Proto-Oncogene Proteins ; Receptors, Antigen, T-Cell ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (EC 2.7.10.2) ; Proto-Oncogene Proteins c-fyn (EC 2.7.10.2)
Language	English
Publishing date	2020-12-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2050-4527
ISSN (online)	2050-4527
DOI	10.1002/iid3.383
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Article ; Online: RD5-mediated lack of PE_PGRS and PPE-MPTR export in BCG vaccine strains results in strong reduction of antigenic repertoire but little impact on protection.

Ates, Louis S / Sayes, Fadel / Frigui, Wafa / Ummels, Roy / Damen, Merel P M / Bottai, Daria / Behr, Marcel A / van Heijst, Jeroen W J / Bitter, Wilbert / Majlessi, Laleh / Brosch, Roland

PLoS pathogens

2018 Volume 14, Issue 6, Page(s) e1007139

Abstract: Tuberculosis is the deadliest infectious disease worldwide. Although the BCG vaccine is widely used, it does not efficiently protect against pulmonary tuberculosis and an improved tuberculosis vaccine is therefore urgently needed. Mycobacterium ... ...

Abstract	Tuberculosis is the deadliest infectious disease worldwide. Although the BCG vaccine is widely used, it does not efficiently protect against pulmonary tuberculosis and an improved tuberculosis vaccine is therefore urgently needed. Mycobacterium tuberculosis uses different ESX/Type VII secretion (T7S) systems to transport proteins important for virulence and host immune responses. We recently reported that secretion of T7S substrates belonging to the mycobacteria-specific Pro-Glu (PE) and Pro-Pro-Glu (PPE) proteins of the PGRS (polymorphic GC-rich sequences) and MPTR (major polymorphic tandem repeat) subfamilies required both a functional ESX-5 system and a functional PPE38/71 protein for secretion. Inactivation of ppe38/71 and the resulting loss of PE_PGRS/PPE-MPTR secretion were linked to increased virulence of M. tuberculosis strains. Here, we show that a predicted total of 89 PE_PGRS/PPE-MPTR surface proteins are not exported by certain animal-adapted strains of the M. tuberculosis complex including M. bovis. This Δppe38/71-associated secretion defect therefore also occurs in the M. bovis-derived tuberculosis vaccine BCG and could be partially restored by introduction of the M. tuberculosis ppe38-locus. Epitope mapping of the PPE-MPTR protein PPE10, further allowed us to monitor T-cell responses in splenocytes from BCG/M. tuberculosis immunized mice, confirming the dependence of PPE10-specific immune-induction on ESX-5/PPE38-mediated secretion. Restoration of PE_PGRS/PPE-MPTR secretion in recombinant BCG neither altered global antigenic presentation or activation of innate immune cells, nor protective efficacy in two different mouse vaccination-infection models. This unexpected finding stimulates a reassessment of the immunomodulatory properties of PE_PGRS/PPE-MPTR proteins, some of which are contained in vaccine formulations currently in clinical evaluation.
MeSH term(s)	Animals ; Antigens, Bacterial/immunology ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Bacterial Secretion Systems/immunology ; Female ; Genome, Bacterial ; Membrane Proteins/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Multigene Family ; Mycobacterium tuberculosis/immunology ; Tuberculosis/immunology ; Tuberculosis/prevention & control ; Tuberculosis Vaccines/immunology ; Virulence
Chemical Substances	Antigens, Bacterial ; Bacterial Proteins ; Bacterial Secretion Systems ; Membrane Proteins ; Tuberculosis Vaccines
Language	English
Publishing date	2018-06-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1007139
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Article ; Online: Unexpected Genomic and Phenotypic Diversity of Mycobacterium africanum Lineage 5 Affects Drug Resistance, Protein Secretion, and Immunogenicity.

Ates, Louis S / Dippenaar, Anzaan / Sayes, Fadel / Pawlik, Alexandre / Bouchier, Christiane / Ma, Laurence / Warren, Robin M / Sougakoff, Wladimir / Majlessi, Laleh / van Heijst, Jeroen W J / Brossier, Florence / Brosch, Roland

Genome biology and evolution

2018 Volume 10, Issue 8, Page(s) 1858–1874

Abstract: Mycobacterium africanum consists of Lineages L5 and L6 of the Mycobacterium tuberculosis complex (MTBC) and causes human tuberculosis in specific regions of Western Africa, but is generally not transmitted in other parts of the world. Since M. africanum ... ...

Abstract	Mycobacterium africanum consists of Lineages L5 and L6 of the Mycobacterium tuberculosis complex (MTBC) and causes human tuberculosis in specific regions of Western Africa, but is generally not transmitted in other parts of the world. Since M. africanum is evolutionarily closely placed between the globally dispersed Mycobacterium tuberculosis and animal-adapted MTBC-members, these lineages provide valuable insight into M. tuberculosis evolution. Here, we have collected 15 M. africanum L5 strains isolated in France over 4 decades. Illumina sequencing and phylogenomic analysis revealed a previously underappreciated diversity within L5, which consists of distinct sublineages. L5 strains caused relatively high levels of extrapulmonary tuberculosis and included multi- and extensively drug-resistant isolates, especially in the newly defined sublineage L5.2. The specific L5 sublineages also exhibit distinct phenotypic characteristics related to in vitro growth, protein secretion and in vivo immunogenicity. In particular, we identified a PE_PGRS and PPE-MPTR secretion defect specific for sublineage L5.2, which was independent of PPE38. Furthermore, L5 isolates were able to efficiently secrete and induce immune responses against ESX-1 substrates contrary to previous predictions. These phenotypes of Type VII protein secretion and immunogenicity provide valuable information to better link genome sequences to phenotypic traits and thereby understand the evolution of the MTBC.
MeSH term(s)	Adult ; Animals ; Bacterial Proteins/metabolism ; Base Pairing/genetics ; Computational Biology ; Drug Resistance, Bacterial/drug effects ; Drug Resistance, Bacterial/genetics ; Female ; Genetic Markers ; Genomics ; Genotype ; Humans ; Isoniazid/pharmacology ; Male ; Mice, Inbred C57BL ; Middle Aged ; Mycobacterium/drug effects ; Mycobacterium/genetics ; Mycobacterium/immunology ; Mycobacterium/isolation & purification ; Phenotype ; Phylogeny ; Sequence Deletion/genetics ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology
Chemical Substances	Bacterial Proteins ; Genetic Markers ; Isoniazid (V83O1VOZ8L)
Language	English
Publishing date	2018-07-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2495328-3
ISSN	1759-6653 ; 1759-6653
ISSN (online)	1759-6653
ISSN	1759-6653
DOI	10.1093/gbe/evy145
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