{"doi":"10.1128/mbio.00876-13","title":"The Copper-Responsive RicR Regulon Contributes to Mycobacterium tuberculosis Virulence","abstract":"<jats:title>ABSTRACT</jats:title>\n          <jats:p>\n            As with most life on Earth, the transition metal copper (Cu) is essential for the viability of the human pathogen\n            <jats:named-content content-type=\"genus-species\">Mycobacterium tuberculosis</jats:named-content>\n            . However, infected hosts can also use Cu to control microbial growth. Several Cu-responsive pathways are present in\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis</jats:named-content>\n            , including the regulated in copper repressor (RicR) regulon, which is unique to pathogenic mycobacteria. In this work, we describe the contribution of each RicR-regulated gene to Cu resistance\n            <jats:italic>in vitro</jats:italic>\n            and to virulence in animals. We found that the deletion or disruption of individual RicR-regulated genes had no impact on virulence in mice, although several mutants had Cu hypersensitivity. In contrast, a mutant unable to activate the RicR regulon was not only highly susceptible to Cu but also attenuated in mice. Thus, these data suggest that several genes of the RicR regulon are required simultaneously to combat Cu toxicity\n            <jats:italic>in vivo</jats:italic>\n            or that this regulon is also important for resistance against Cu-independent mechanisms of host defense.\n          </jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE</jats:bold>\n            <jats:named-content content-type=\"genus-species\">Mycobacterium tuberculosis</jats:named-content>\n            is the causative agent of tuberculosis, killing millions of people every year. Therefore, understanding the biology of\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis</jats:named-content>\n            is crucial for the development of new therapies to treat this devastating disease. Our studies reveal that although host-supplied Cu can suppress bacterial growth,\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis</jats:named-content>\n            has a unique pathway, the RicR regulon, to defend against Cu toxicity. These findings suggest that Cu homeostasis pathways in both the host and the pathogen could be exploited for the treatment of tuberculosis.\n          </jats:p>","journal":"mBio","year":2014,"id":610715,"datarank":0.6782682865573562,"base_score":4.5217885770490405,"endowment":4.5217885770490405,"self_citation_contribution":0.6782682865573562,"citation_network_contribution":0.0,"self_endowment_contribution":0.6782682865573562,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":91,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1570297,"name":"Richard A. Festa","orcid":null,"position":1,"is_corresponding":false},{"id":281182,"name":"Thomas R. Ioerger","orcid":"0000-0001-8702-9102","position":2,"is_corresponding":false},{"id":1570299,"name":"Susan Butler-Wu","orcid":null,"position":3,"is_corresponding":false},{"id":248998,"name":"James C. Sacchettini","orcid":"0000-0001-5767-2367","position":4,"is_corresponding":false},{"id":498111,"name":"K. Heran Darwin","orcid":"0000-0002-5043-7548","position":5,"is_corresponding":false},{"id":550603,"name":"Marie I. Samanovic","orcid":"0000-0002-6987-2232","position":6,"is_corresponding":false},{"id":281832,"name":"Xiaoshan Shi","orcid":"0000-0001-7931-8684","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"The Copper-Responsive RicR Regulon Contributes to Mycobacterium tuberculosis Virulence","abstract":"<jats:title>ABSTRACT</jats:title>\n          <jats:p>\n            As with most life on Earth, the transition metal copper (Cu) is essential for the viability of the human pathogen\n            <jats:named-content content-type=\"genus-species\">Mycobacterium tuberculosis</jats:named-content>\n            . However, infected hosts can also use Cu to control microbial growth. Several Cu-responsive pathways are present in\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis</jats:named-content>\n            , including the regulated in copper repressor (RicR) regulon, which is unique to pathogenic mycobacteria. In this work, we describe the contribution of each RicR-regulated gene to Cu resistance\n            <jats:italic>in vitro</jats:italic>\n            and to virulence in animals. We found that the deletion or disruption of individual RicR-regulated genes had no impact on virulence in mice, although several mutants had Cu hypersensitivity. In contrast, a mutant unable to activate the RicR regulon was not only highly susceptible to Cu but also attenuated in mice. Thus, these data suggest that several genes of the RicR regulon are required simultaneously to combat Cu toxicity\n            <jats:italic>in vivo</jats:italic>\n            or that this regulon is also important for resistance against Cu-independent mechanisms of host defense.\n          </jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE</jats:bold>\n            <jats:named-content content-type=\"genus-species\">Mycobacterium tuberculosis</jats:named-content>\n            is the causative agent of tuberculosis, killing millions of people every year. Therefore, understanding the biology of\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis</jats:named-content>\n            is crucial for the development of new therapies to treat this devastating disease. Our studies reveal that although host-supplied Cu can suppress bacterial growth,\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis</jats:named-content>\n            has a unique pathway, the RicR regulon, to defend against Cu toxicity. These findings suggest that Cu homeostasis pathways in both the host and the pathogen could be exploited for the treatment of tuberculosis.\n          </jats:p>","is_dataset_classified":null,"base_score":4.5217885770490405,"endowment":4.5217885770490405,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"24549843","pmcid":"PMC3944814","openalex_id":"https://openalex.org/W2049085442","authors":[],"funders":[{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL092774","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL92774","title":null},{"funder_name":"National Institutes of Health","grant_id":"5R01HL092774-07","title":"Virulence Regulation by the Mycobacterium tuberculosis Proteasome"}],"total_grants":3,"fwci":6.8539,"citation_percentile":0.97658716,"influential_citations":0,"citation_trend":[{"year":2014,"count":2},{"year":2015,"count":17},{"year":2016,"count":2},{"year":2017,"count":10},{"year":2018,"count":3},{"year":2019,"count":7},{"year":2020,"count":3},{"year":2021,"count":12},{"year":2022,"count":7},{"year":2023,"count":5},{"year":2024,"count":8},{"year":2025,"count":11},{"year":2026,"count":3}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1128/mbio.00876-13","host_type":"journal"},{"url":"https://doi.org/10.1128/mbio.00876-13","host_type":"publisher"},{"url":"https://journals.asm.org/doi/pdf/10.1128/mBio.00876-13","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/24549843","host_type":"repository"},{"url":"https://doaj.org/article/aa7d1669284643a8868f17587bd8a794","host_type":"repository"},{"url":"https://doaj.org/article/c732046e99e1428eb8b6fb82c13d818f","host_type":"repository"},{"url":"http://europepmc.org/articles/PMC3944814","host_type":"repository"},{"url":"https://hdl.handle.net/1969.1/183958","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3944814","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC3944814","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC3944814?pdf=render","host_type":"Europe_PMC"},{"url":"https://mbio.asm.org/content/5/1/e00876-13.full.pdf","host_type":""},{"url":"http://dx.doi.org/10.1128/mBio.00876-13","host_type":""},{"url":"https://dx.doi.org/10.1128/mbio.00876-13","host_type":""}],"fields_of_study":["Trace Elements in Health","Tuberculosis Research and Epidemiology","Diagnosis and treatment of tuberculosis","0301 basic medicine","03 medical and health sciences","Animals","Copper","Disease Models, Animal","Female","Gene Expression Regulation, Bacterial","Gene Knockout Techniques","Mice","Mice, Inbred C57BL","Mycobacterium tuberculosis","Regulon","Tuberculosis","Virulence","Virulence Factors"],"mesh_terms":["Animals","Copper","Disease Models, Animal","Female","Mice, Inbred C57BL","Mycobacterium tuberculosis","Tuberculosis","Virulence","Gene Expression Regulation, Bacterial","Regulon","Virulence Factors","Mice","Gene Knockout Techniques"],"keywords":["Regulon","Mycobacterium tuberculosis","Virulence","Tuberculosis","Microbiology","Pathogen","Biology","Efflux","Copper toxicity","Human pathogen","Mutant","Gene","Genetics","Chemistry","Copper","Medicine","Virulence Factors","Gene Expression Regulation, Bacterial","QR1-502","Mice, Inbred C57BL","Disease Models, Animal","Gene Knockout Techniques","Mice","Animals","Female","Research Article"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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