{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T12:08:28Z","timestamp":1778069308940,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011188","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,3,15]],"date-time":"2024-03-15T00:00:00Z","timestamp":1710460800000}}],"reference-count":97,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T00:00:00Z","timestamp":1709596800000},"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":["R01GM115931"],"award-info":[{"award-number":["R01GM115931"]}],"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":["R01GM134259"],"award-info":[{"award-number":["R01GM134259"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Bacteria have evolved complex transcriptional regulatory networks, as well as many diverse regulatory strategies at the RNA level, to enable more efficient use of metabolic resources and a rapid response to changing conditions. However, most RNA-based regulatory mechanisms are not well conserved across different bacterial species despite controlling genes important for virulence or essential biosynthetic processes. Here, we characterize the activity of, and assess the fitness benefit conferred by, twelve cis-acting regulatory RNAs (including several riboswitches and a T-box), in the opportunistic pathogen\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    TIGR4. By evaluating native locus mutants of each regulator that result in constitutively active or repressed expression, we establish that growth defects in planktonic culture are associated with constitutive repression of gene expression, while constitutive activation of gene expression is rarely deleterious. In contrast, in mouse nasal carriage and pneumonia models, strains with either constitutively active and repressed gene expression are significantly less fit than matched control strains. Furthermore, two RNA-regulated pathways, FMN synthesis\/transport and pyrimidine synthesis\/transport display exceptional sensitivity to mis-regulation or constitutive gene repression in both planktonic culture and\n                    <jats:italic>in vivo<\/jats:italic>\n                    environments. Thus, despite lack of obvious phenotypes associated with constitutive gene expression\n                    <jats:italic>in vitro<\/jats:italic>\n                    , the fitness benefit conferred on bacteria via fine-tuned metabolic regulation through cis-acting regulatory RNAs is substantial\n                    <jats:italic>in vivo<\/jats:italic>\n                    , and therefore easily sufficient to drive the evolution and maintenance of diverse RNA regulatory mechanisms.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011188","type":"journal-article","created":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T13:31:55Z","timestamp":1709645515000},"page":"e1011188","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["RNA cis-regulators are important for Streptococcus pneumoniae in vivo success"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6225-7149","authenticated-orcid":true,"given":"Indu","family":"Warrier","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2940-7106","authenticated-orcid":true,"given":"Ariana","family":"Perry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3176-0278","authenticated-orcid":true,"given":"Sara M.","family":"Hubbell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Eichelman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"van Opijnen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7014-9271","authenticated-orcid":true,"given":"Michelle M.","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,3,5]]},"reference":[{"issue":"1","key":"pgen.1011188.ref001","doi-asserted-by":"crossref","first-page":"3282","DOI":"10.1038\/s41467-021-23588-w","article-title":"RNA atlas of human bacterial pathogens uncovers stress dynamics linked to infection","volume":"12","author":"K Avican","year":"2021","journal-title":"Nat Commun"},{"issue":"6","key":"pgen.1011188.ref002","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/s41576-021-00326-y","article-title":"Cross-species RNA-seq for deciphering host\u2013microbe interactions","volume":"22","author":"AJ Westermann","year":"2021","journal-title":"Nat Rev Genet"},{"issue":"10","key":"pgen.1011188.ref003","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.tim.2022.03.007","article-title":"The emerging role of bacterial regulatory RNAs in disease","volume":"30","author":"H Eichner","year":"2022","journal-title":"Trends in Microbiology"},{"issue":"1","key":"pgen.1011188.ref004","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1146\/annurev-micro-030117-020335","article-title":"Regulating Bacterial Virulence with RNA","volume":"71","author":"JJ Quereda","year":"2017","journal-title":"Annual Review of Microbiology"},{"key":"pgen.1011188.ref005","doi-asserted-by":"crossref","first-page":"337","DOI":"10.3389\/fcimb.2019.00337","article-title":"RNA-Dependent Regulation of Virulence in Pathogenic Bacteria.","volume":"9","author":"S Chakravarty","year":"2019","journal-title":"Front Cell Infect Microbiol"},{"issue":"31","key":"pgen.1011188.ref006","doi-asserted-by":"crossref","first-page":"11685","DOI":"10.1074\/jbc.REV119.005593","article-title":"Trouble is coming: Signaling pathways that regulate general stress responses in bacteria","volume":"294","author":"S. Gottesman","year":"2019","journal-title":"J Biol Chem"},{"issue":"6282","key":"pgen.1011188.ref007","doi-asserted-by":"crossref","first-page":"aad9822","DOI":"10.1126\/science.aad9822","article-title":"Term-seq reveals abundant ribo-regulation of antibiotics resistance in bacteria","volume":"352","author":"D Dar","year":"2016","journal-title":"Science"},{"issue":"5","key":"pgen.1011188.ref008","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.02503-17","article-title":"Bacterial Adaptation to Antibiotics through Regulatory RNAs","volume":"62","author":"B Felden","year":"2018","journal-title":"Antimicrobial Agents and Chemotherapy"},{"issue":"2","key":"pgen.1011188.ref009","article-title":"RNA Thermometers in Bacterial Pathogens.","volume":"6","author":"E Loh","year":"2018","journal-title":"Microbiol Spectr"},{"issue":"3","key":"pgen.1011188.ref010","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1021\/acs.biochem.1c00765","article-title":"The Biochemical Landscape of 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