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      Comparative Proteomic Analysis of Mycobacterium tuberculosis Lineage 7 and Lineage 4 Strains Reveals Differentially Abundant Proteins Linked to Slow Growth and Virulence

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          Abstract

          In order to decipher the nature of the slowly growing Mycobacterium tuberculosis (M.tuberculosis) lineage 7, the differentially abundant proteins in strains of M. tuberculosis lineage 7 and lineage 4 were defined. Comparative proteomic analysis by mass spectrometry was employed to identify, quantitate and compare the protein profiles of strains from the two M. tuberculosis lineages. Label-free peptide quantification of whole cells from M. tuberculosis lineage 7 and 4 yielded the identification of 2825 and 2541 proteins, respectively. A combined total of 2867 protein groups covering 71% of the predicted M. tuberculosis proteome were identified. The abundance of 125 proteins in M. tuberculosis lineage 7 and 4 strains was significantly altered. Notably, the analysis showed that a number of M. tuberculosis proteins involved in growth and virulence were less abundant in lineage 7 strains compared to lineage 4. Five ABC transporter proteins, three phosphate binding proteins essential for inorganic phosphate uptake, and six components of the type 7 secretion system ESX-3 involved in iron acquisition were less abundant in M. tuberculosis lineage 7. This proteogenomic analysis provided an insight into the lineage 7-specific protein profile which may provide clues to understanding the differential properties of lineage 7 strains in terms of slow growth, survival fitness, and pathogenesis.

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          Most cited references26

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          In silico prediction of protein-protein interactions in human macrophages

          Background: Protein-protein interaction (PPI) network analyses are highly valuable in deciphering and understanding the intricate organisation of cellular functions. Nevertheless, the majority of available protein-protein interaction networks are context-less, i.e. without any reference to the spatial, temporal or physiological conditions in which the interactions may occur. In this work, we are proposing a protocol to infer the most likely protein-protein interaction (PPI) network in human macrophages. Results: We integrated the PPI dataset from the Agile Protein Interaction DataAnalyzer (APID) with different meta-data to infer a contextualized macrophage-specific interactome using a combination of statistical methods. The obtained interactome is enriched in experimentally verified interactions and in proteins involved in macrophage-related biological processes (i.e. immune response activation, regulation of apoptosis). As a case study, we used the contextualized interactome to highlight the cellular processes induced upon Mycobacterium tuberculosis infection. Conclusion: Our work confirms that contextualizing interactomes improves the biological significance of bioinformatic analyses. More specifically, studying such inferred network rather than focusing at the gene expression level only, is informative on the processes involved in the host response. Indeed, important immune features such as apoptosis are solely highlighted when the spotlight is on the protein interaction level.
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            Genes required for mycobacterial growth defined by high density mutagenesis.

            Despite over a century of research, tuberculosis remains a leading cause of infectious death worldwide. Faced with increasing rates of drug resistance, the identification of genes that are required for the growth of this organism should provide new targets for the design of antimycobacterial agents. Here, we describe the use of transposon site hybridization (TraSH) to comprehensively identify the genes required by the causative agent, Mycobacterium tuberculosis, for optimal growth. These genes include those that can be assigned to essential pathways as well as many of unknown function. The genes important for the growth of M. tuberculosis are largely conserved in the degenerate genome of the leprosy bacillus, Mycobacterium leprae, indicating that non-essential functions have been selectively lost since this bacterium diverged from other mycobacteria. In contrast, a surprisingly high proportion of these genes lack identifiable orthologues in other bacteria, suggesting that the minimal gene set required for survival varies greatly between organisms with different evolutionary histories.
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              A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity.

              Copper is an essential micronutrient that is necessary for healthy immune function. This requirement is underscored by an increased susceptibility to bacterial infection in copper-deficient animals; however, a molecular understanding of its importance in immune defense is unknown. In this study, we investigated the effect of proinflammatory agents on copper homeostasis in RAW264.7 macrophages. Interferon-gamma was found to increase expression of the high affinity copper importer, CTR1, and stimulate copper uptake. This was accompanied by copper-stimulated trafficking of the ATP7A copper exporter from the Golgi to vesicles that partially overlapped with phagosomal compartments. Silencing of ATP7A expression attenuated bacterial killing, suggesting a role for ATP7A-dependent copper transport in the bactericidal activity of macrophages. Significantly, a copper-sensitive mutant of Escherichia coli lacking the CopA copper-transporting ATPase was hypersensitive to killing by RAW264.7 macrophages, and this phenotype was dependent on ATP7A expression. Collectively, these data suggest that copper-transporting ATPases, CopA and ATP7A, in both bacteria and macrophage are unique determinants of bacteria survival and identify an unexpected role for copper at the host-pathogen interface.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                09 May 2017
                2017
                : 8
                : 795
                Affiliations
                [1] 1Department of Microbiology, Oslo University Hospital Oslo, Norway
                [2] 2Department of Microbiology, University of Oslo Oslo, Norway
                [3] 3Department of Medical Biotechnology, Institute of Biotechnology, Addis Ababa University Addis Ababa, Ethiopia
                [4] 4Centre for Applied Biotechnology, Uni Research Environment Bergen, Norway
                [5] 5Infection Control and Environmental Health, Norwegian Institute of Public Health Oslo, Norway
                [6] 6Department of Research and Innovation, Armauer Hansen Research Institute Addis Ababa, Ethiopia
                Author notes

                Edited by: Biswarup Mukhopadhyay, Virginia Tech, USA

                Reviewed by: Thomas Dick, Rutgers University, USA; Nomakorinte Gcebe, Agricultural Research Council, South Africa; Jonathan M. Blackburn, University of Cape Town, South Africa

                *Correspondence: Solomon A. Yimer s.a.yimer@ 123456medisin.uio.no

                This article was submitted to Microbial Physiology and Metabolism, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2017.00795
                5423352
                28536560
                e2357910-570e-4a01-8e4a-258d19759b04
                Copyright © 2017 Yimer, Birhanu, Kalayou, Riaz, Zegeye, Beyene, Holm-Hansen, Norheim, Abebe, Aseffa and Tønjum.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 December 2016
                : 18 April 2017
                Page count
                Figures: 6, Tables: 6, Equations: 0, References: 56, Pages: 14, Words: 9143
                Funding
                Funded by: Norges Forskningsråd 10.13039/501100005416
                Award ID: 204747
                Award ID: 234506
                Award ID: 192468
                Funded by: Helse Sør-Øst RHF 10.13039/501100006095
                Award ID: 39591
                Categories
                Microbiology
                Original Research

                Microbiology & Virology
                mycobacterium tuberculosis,tuberculosis,lineage 7,proteomics,ethiopia,mass spectrometry,type 7 secretion

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