{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T12:14:11Z","timestamp":1767183251739,"version":"build-2238731810"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012165","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T00:00:00Z","timestamp":1728950400000}}],"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T00:00:00Z","timestamp":1727913600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32GM131994"],"award-info":[{"award-number":["T32GM131994"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM118157"],"award-info":[{"award-number":["R35GM118157"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM131767"],"award-info":[{"award-number":["R35GM131767"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21AI171771"],"award-info":[{"award-number":["R21AI171771"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Zinc is a vital transition metal for all bacteria; however, elevated intracellular free Zn levels can result in mis-metalation of Mn-dependent enzymes. For Mn-centric bacteria such as\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    that primarily use Mn instead of Fe as an enzyme cofactor, Zn is particularly toxic at high concentrations. Here, we report our identification and characterization of the function of the five homologous, CiaRH-regulated Ccn sRNAs in controlling\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>pneumoniae<\/jats:italic>\n                    virulence and metal homeostasis. We show that deletion of all five\n                    <jats:italic>ccn<\/jats:italic>\n                    genes (\n                    <jats:italic>ccnA<\/jats:italic>\n                    ,\n                    <jats:italic>ccnB<\/jats:italic>\n                    ,\n                    <jats:italic>ccnC<\/jats:italic>\n                    ,\n                    <jats:italic>ccnD<\/jats:italic>\n                    , and\n                    <jats:italic>ccnE<\/jats:italic>\n                    ) from\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>pneumoniae<\/jats:italic>\n                    strains D39 (serotype 2) and TIGR4 (serotype 4) causes Zn hypersensitivity and an attenuation of virulence in a murine invasive pneumonia model. We provide evidence that bioavailable Zn disproportionately increases in\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>pneumoniae<\/jats:italic>\n                    strains lacking the five\n                    <jats:italic>ccn<\/jats:italic>\n                    genes. Consistent with a response to Zn intoxication or relatively high intracellular free Zn levels, expression of genes encoding the CzcD Zn exporter and the Mn-independent ribonucleotide reductase, NrdD-NrdG, were increased in the \u0394\n                    <jats:italic>ccnABCDE<\/jats:italic>\n                    mutant relative to its isogenic\n                    <jats:italic>ccn<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    parent strain. The growth inhibition by Zn that occurs as the result of loss of the\n                    <jats:italic>ccn<\/jats:italic>\n                    genes is rescued by supplementation with Mn or Oxyrase, a reagent that removes dissolved oxygen. Lastly, we found that the Zn-dependent growth inhibition of the \u0394\n                    <jats:italic>ccnABCDE<\/jats:italic>\n                    strain was not altered by deletion of\n                    <jats:italic>sodA<\/jats:italic>\n                    , whereas the\n                    <jats:italic>ccn<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+<\/jats:italic>\n                    <\/jats:sup>\n                    \u0394\n                    <jats:italic>sodA<\/jats:italic>\n                    strain phenocopied the \u0394\n                    <jats:italic>ccnABCDE<\/jats:italic>\n                    strain. Overall, our results indicate that the Ccn sRNAs have a crucial role in preventing Zn intoxication in\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>pneumoniae<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1012165","type":"journal-article","created":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T13:43:38Z","timestamp":1727963018000},"page":"e1012165","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["The five homologous CiaR-controlled Ccn sRNAs of Streptococcus pneumoniae modulate Zn-resistance"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2249-7073","authenticated-orcid":true,"given":"Nicholas R.","family":"De Lay","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nidhi","family":"Verma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dhriti","family":"Sinha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abigail","family":"Garrett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maximillian K.","family":"Osterberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisy","family":"Porter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Spencer","family":"Reiling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David P.","family":"Giedroc","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malcolm E.","family":"Winkler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,10,3]]},"reference":[{"issue":"1","key":"ppat.1012165.ref001","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.tig.2020.08.016","article-title":"Networks of Resistance: Small RNA Control of Antibiotic Resistance","volume":"37","author":"DG Mediati","year":"2021","journal-title":"Trends Genet"},{"key":"ppat.1012165.ref002","doi-asserted-by":"crossref","first-page":"uqad030","DOI":"10.1093\/femsml\/uqad030","article-title":"Small regulatory RNAs in Vibrio cholerae","volume":"4","author":"R Ghandour","year":"2023","journal-title":"Microlife"},{"key":"ppat.1012165.ref003","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1146\/annurev-micro-041320-025836","article-title":"Small RNAs, Large Networks: Posttranscriptional Regulons in Gram-Negative Bacteria","volume":"77","author":"K Papenfort","year":"2023","journal-title":"Annual Review of Microbiology"},{"issue":"1","key":"ppat.1012165.ref004","article-title":"Trans-Acting Small RNAs and Their Effects on Gene Expression in Escherichia coli and Salmonella enterica","volume":"9","author":"J Hor","year":"2020","journal-title":"EcoSal Plus"},{"key":"ppat.1012165.ref005","doi-asserted-by":"crossref","first-page":"601352","DOI":"10.3389\/fmicb.2020.601352","article-title":"Diverse Mechanisms and Circuitry for Global Regulation by the RNA-Binding Protein CsrA","volume":"11","author":"C Pourciau","year":"2020","journal-title":"Frontiers in Microbiology"},{"issue":"5","key":"ppat.1012165.ref006","doi-asserted-by":"crossref","first-page":"194504","DOI":"10.1016\/j.bbagrm.2020.194504","article-title":"sRNA-mediated control in bacteria: An increasing diversity of regulatory mechanisms","volume":"1863","author":"MG J\u00f8rgensen","year":"2020","journal-title":"Biochim Biophys Acta Gene Regul Mech"},{"issue":"7","key":"ppat.1012165.ref007","doi-asserted-by":"crossref","first-page":"194546","DOI":"10.1016\/j.bbagrm.2020.194546","article-title":"Regulatory interplay between small RNAs and transcription termination factor Rho","volume":"1863","author":"L Bossi","year":"2020","journal-title":"Biochim Biophys Acta Gene Regul Mech"},{"issue":"5","key":"ppat.1012165.ref008","doi-asserted-by":"crossref","first-page":"fuac017","DOI":"10.1093\/femsre\/fuac017","article-title":"An overview of gene regulation in bacteria by small RNAs derived from mRNA 3\u2019 ends","volume":"46","author":"F Ponath","year":"2022","journal-title":"FEMS Microbiology Reviews"},{"issue":"11","key":"ppat.1012165.ref009","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/S1473-3099(18)30310-4","article-title":"Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990\u20132016: a systematic analysis for the Global Burden of Disease Study 2016","volume":"18","author":"G. 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