{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T01:17:10Z","timestamp":1768526230837,"version":"3.49.0"},"posted":{"date-parts":[[2025,7,14]]},"group-title":"Microbiology","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T00:00:00Z","timestamp":1752451200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                  is a leading cause of pneumonia. Importantly, the extent and impact of changes in the infected airway on bacterial nutrient availability and gene expression are not known. Utilizing untargeted UPLC-ESI-MS\/MS metabolomics, we comprehensively characterized the metabolic landscape in the airway across early, mid, and severe stages of pneumococcal pneumonia. This revealed that dynamic shifts in metabolites occurred during pneumonia, with an initial influx of metabolites at the early stage, followed by declines as the disease progressed. Specific host metabolic perturbations were indicative of purine dysregulation, cellular stress, and outright tissue injury. Levels of glucose, a known modulator of pneumococcal capsule production, were highest at early disease stage, and then declined as the disease progressed, overlaying general metabolite trends. Concurrent bacterial transcriptome profiling was performed using a NanoString nCounter custom panel of 66 genes selected for their importance to metabolism, virulence, and stress response; 9% of which had disease-stage significant differences in gene expression. This analysis revealed remarkably high expression of\n                  <jats:italic>spxB<\/jats:italic>\n                  , the gene encoding pyruvate oxidase, at the severe stage of pneumonia compared to the mid-stage pneumonia, consistent with a drop in glucose levels and indicative of a shift towards mixed fermentation and the increased production of hydrogen peroxide. Our study improves our understanding of how pneumococcal infection alters the lung environment, driving profound metabolic shifts that, in turn, influence bacterial phenotypes. This detailed understanding of host-pathogen metabolic interactions offers valuable insights into novel therapeutic strategies.\n                <\/jats:p>","DOI":"10.1101\/2025.07.14.664699","type":"posted-content","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T05:50:31Z","timestamp":1752558631000},"source":"Crossref","is-referenced-by-count":1,"title":["Alterations in Nutrient Availability in the Lungs During\n                  <i>Streptococcus pneumoniae<\/i>\n                  -Induced Pneumonia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0629-7461","authenticated-orcid":false,"given":"Hansol","family":"Im","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vipin","family":"Chembilikandy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adonis","family":"D\u2019Mello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madison","family":"Pearson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0615-3257","authenticated-orcid":false,"given":"Herv\u00e9","family":"Tettelin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8542-4069","authenticated-orcid":false,"given":"Carlos J.","family":"Orihuela","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025071614410371000_2025.07.14.664699v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-018-0001-8"},{"key":"2025071614410371000_2025.07.14.664699v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(94)90060-4"},{"key":"2025071614410371000_2025.07.14.664699v1.3","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14133"},{"key":"2025071614410371000_2025.07.14.664699v1.4","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00451-21"},{"key":"2025071614410371000_2025.07.14.664699v1.5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2010428117"},{"key":"2025071614410371000_2025.07.14.664699v1.6","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00277-16"},{"key":"2025071614410371000_2025.07.14.664699v1.7","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00881-09"},{"key":"2025071614410371000_2025.07.14.664699v1.8","doi-asserted-by":"crossref","first-page":"e3002020","DOI":"10.1371\/journal.pbio.3002020","article-title":"Targeting NAD+ regeneration enhances antibiotic susceptibility of Streptococcus pneumoniae during invasive disease","volume":"21","year":"2023","journal-title":"PLoS Biol"},{"key":"2025071614410371000_2025.07.14.664699v1.9","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.02005-14"},{"key":"2025071614410371000_2025.07.14.664699v1.10","doi-asserted-by":"publisher","DOI":"10.1086\/424596"},{"key":"2025071614410371000_2025.07.14.664699v1.11","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00178-09"},{"key":"2025071614410371000_2025.07.14.664699v1.12","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.02434-14"},{"issue":"10","key":"2025071614410371000_2025.07.14.664699v1.13","doi-asserted-by":"crossref","first-page":"593","DOI":"10.3390\/toxins15100593","article-title":"Impact of Endogenous Pneumococcal Hydrogen Peroxide on the Activity and Release of Pneumolysin","volume":"15","year":"2023","journal-title":"Toxins (Basel"},{"key":"2025071614410371000_2025.07.14.664699v1.14","doi-asserted-by":"crossref","unstructured":"Mandell LA , Zhanel GG , Rotstein C , Muscedere J , Loeb M , Johnstone J . 2022. Community-Acquired Pneumonia in Canada During Coronavirus Disease 2019. Open Forum Infect Dis 9:ofac043.","DOI":"10.1093\/ofid\/ofac043"},{"issue":"2","key":"2025071614410371000_2025.07.14.664699v1.15","first-page":"10","article-title":"Streptococcus pneumoniae: Invasion and Inflammation","volume":"7","year":"2019","journal-title":"Microbiol Spectr"},{"key":"2025071614410371000_2025.07.14.664699v1.16","doi-asserted-by":"crossref","first-page":"878244","DOI":"10.3389\/fimmu.2022.878244","article-title":"The Yin and Yang of Pneumolysin During Pneumococcal Infection","volume":"13","year":"2022","journal-title":"Front Immunol"},{"key":"2025071614410371000_2025.07.14.664699v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.12.005"},{"key":"2025071614410371000_2025.07.14.664699v1.18","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.mib.2016.11.008","article-title":"Bacteria and endothelial cells: a toxic relationship","volume":"35","year":"2017","journal-title":"Curr Opin Microbiol"},{"key":"2025071614410371000_2025.07.14.664699v1.19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011630"},{"key":"2025071614410371000_2025.07.14.664699v1.20","doi-asserted-by":"crossref","first-page":"109267","DOI":"10.1016\/j.celrep.2021.109267","article-title":"Streptococcus pneumoniae binds to host GAPDH on dying lung epithelial cells worsening secondary infection following influenza","volume":"35","year":"2021","journal-title":"Cell Rep"},{"issue":"3","key":"2025071614410371000_2025.07.14.664699v1.21","first-page":"e00673","article-title":"Streptococcus pneumoniae Binds to Host Lactate Dehydrogenase via PspA and PspC To Enhance Virulence","volume":"12","year":"2021","journal-title":"mBio"},{"key":"2025071614410371000_2025.07.14.664699v1.22","first-page":"71","article-title":"Lung abscess caused by Streptococcus pneumoniae serotype 6B","volume":"23","year":"2018","journal-title":"Respir Med Case Rep"},{"key":"2025071614410371000_2025.07.14.664699v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/srep38013"},{"key":"2025071614410371000_2025.07.14.664699v1.24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1843.2006.00942.x"},{"key":"2025071614410371000_2025.07.14.664699v1.25","first-page":"1","article-title":"Inflammatory mechanisms in the lung","volume":"2","year":"2009","journal-title":"J Inflamm Res"},{"key":"2025071614410371000_2025.07.14.664699v1.26","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s40635-018-0184-3","article-title":"Body temperature and mouse scoring systems as surrogate markers of death in cecal ligation and puncture sepsis","volume":"6","year":"2018","journal-title":"Intensive Care Med Exp"},{"key":"2025071614410371000_2025.07.14.664699v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-24210-8"},{"key":"2025071614410371000_2025.07.14.664699v1.28","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKAB382"},{"key":"2025071614410371000_2025.07.14.664699v1.29","unstructured":"Council. NR. 2011. Guide for the care and use of laboratory animals, 8th ed. National Academies Press, Washington, DC."},{"key":"2025071614410371000_2025.07.14.664699v1.30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2012265117"},{"key":"2025071614410371000_2025.07.14.664699v1.31","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2012-0246OC"},{"key":"2025071614410371000_2025.07.14.664699v1.32","doi-asserted-by":"crossref","first-page":"102238","DOI":"10.1016\/j.coph.2022.102238","article-title":"Metabolomics of airways disease in cystic fibrosis","volume":"65","year":"2022","journal-title":"Curr Opin Pharmacol"},{"key":"2025071614410371000_2025.07.14.664699v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccc.2021.05.003"},{"key":"2025071614410371000_2025.07.14.664699v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.rcl.2005.10.009"},{"key":"2025071614410371000_2025.07.14.664699v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.10.017"},{"key":"2025071614410371000_2025.07.14.664699v1.36","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200718"},{"key":"2025071614410371000_2025.07.14.664699v1.37","first-page":"1653392","article-title":"Xanthine Oxidase-Induced Inflammatory Responses in Respiratory Epithelial Cells: A Review in Immunopathology of COVID-19","volume":"2021","year":"2021","journal-title":"Int J Inflam"},{"key":"2025071614410371000_2025.07.14.664699v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2015.08.109"},{"key":"2025071614410371000_2025.07.14.664699v1.39","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.3389\/fimmu.2017.01172","article-title":"Poly(ADP-Ribose)Polymerase-1 in Lung Inflammatory Disorders: A Review","volume":"8","year":"2017","journal-title":"Front Immunol"},{"key":"2025071614410371000_2025.07.14.664699v1.40","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00089807"},{"key":"2025071614410371000_2025.07.14.664699v1.41","first-page":"e21935","article-title":"Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis","volume":"35","year":"2021","journal-title":"FASEB J"},{"key":"2025071614410371000_2025.07.14.664699v1.42","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/s42255-019-0115-y","article-title":"Succinate accumulation drives ischaemia-reperfusion injury during organ transplantation","volume":"1","year":"2019","journal-title":"Nat Metab"},{"key":"2025071614410371000_2025.07.14.664699v1.43","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PPAT.1009941"},{"key":"2025071614410371000_2025.07.14.664699v1.44","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00941"},{"key":"2025071614410371000_2025.07.14.664699v1.45","doi-asserted-by":"publisher","DOI":"10.3390\/nu10111564"},{"key":"2025071614410371000_2025.07.14.664699v1.46","doi-asserted-by":"crossref","first-page":"1109449","DOI":"10.3389\/fcimb.2023.1109449","article-title":"Role of Streptococcus pneumoniae extracellular glycosidases in immune evasion","volume":"13","year":"2023","journal-title":"Front Cell Infect Microbiol"},{"key":"2025071614410371000_2025.07.14.664699v1.47","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0121042"},{"key":"2025071614410371000_2025.07.14.664699v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10015-4"},{"key":"2025071614410371000_2025.07.14.664699v1.49","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2025.2532685:2532685"},{"key":"2025071614410371000_2025.07.14.664699v1.50","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.13045"},{"key":"2025071614410371000_2025.07.14.664699v1.51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005887"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.07.14.664699","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:07:10Z","timestamp":1768468030000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.07.14.664699"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,14]]},"references-count":51,"URL":"https:\/\/doi.org\/10.1101\/2025.07.14.664699","relation":{},"subject":[],"published":{"date-parts":[[2025,7,14]]},"subtype":"preprint"}}