{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T09:03:03Z","timestamp":1782550983010,"version":"3.54.5"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T00:00:00Z","timestamp":1737936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21AI146397"],"award-info":[{"award-number":["R21AI146397"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI150797"],"award-info":[{"award-number":["R01AI150797"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Missouri Metabolomics Center"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p><jats:italic>Brucella<\/jats:italic> is a gram negative, facultative intracellular bacterial pathogen that constitutes a substantial threat to human and animal health. <jats:italic>Brucella<\/jats:italic> can replicate in a variety of tissues and can induce immune responses that alter host metabolite availability. Here, mice were infected with <jats:italic>B<\/jats:italic>. <jats:italic>melitensis<\/jats:italic> and murine spleens, livers, and female reproductive tracts were analyzed by GC-MS to determine tissue-specific metabolic changes at one-, two- and four- weeks post infection. The most remarkable changes were observed at two-weeks post-infection when relative to uninfected tissues, 42 of 329 detected metabolites in reproductive tracts were significantly altered by <jats:italic>Brucella<\/jats:italic> infection, while in spleens and livers, 68\/205 and 139\/330 metabolites were significantly changed, respectively. Several of the altered metabolites in host tissues were linked to the GABA shunt and glutaminolysis. Treatment of macrophages with GABA did not alter control of <jats:italic>B<\/jats:italic>. <jats:italic>melitensis<\/jats:italic> infection, and deletion of the putative GABA transporter BMEI0265 did not alter <jats:italic>B<\/jats:italic>. <jats:italic>melitensis<\/jats:italic> virulence. While glutaminolysis inhibition did not affect control of <jats:italic>B<\/jats:italic>. <jats:italic>melitensis<\/jats:italic> in macrophages, glutaminolysis was required for macrophage IL-1\u03b2 production in response to <jats:italic>B<\/jats:italic>. <jats:italic>melitensis<\/jats:italic>. In summary, these results indicate that <jats:italic>Brucella<\/jats:italic> infection alters host tissue metabolism and that these changes could have effects on inflammation and the outcome of infection.<\/jats:p>","DOI":"10.1371\/journal.pone.0314672","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T18:28:47Z","timestamp":1738002527000},"page":"e0314672","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Metabolomic analysis of murine tissues infected with Brucella melitensis"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5679-5242","authenticated-orcid":true,"given":"B\u00e1rbara","family":"Ponzilacqua-Silva","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis S.","family":"Dadelahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles R.","family":"Moley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa F. N.","family":"Abushahba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2337-908X","authenticated-orcid":true,"given":"Jerod A.","family":"Skyberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,1,27]]},"reference":[{"issue":"1\u20134","key":"pone.0314672.ref001","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0378-1135(02)00214-6","article-title":"Brucella intracellular life: from invasion to intracellular replication","volume":"90","author":"JP Gorvel","year":"2002","journal-title":"Vet Microbiol"},{"issue":"2","key":"pone.0314672.ref002","doi-asserted-by":"crossref","first-page":"213","DOI":"10.3201\/eid0302.970219","article-title":"Brucellosis: an overview","volume":"3","author":"MJ Corbel","year":"1997","journal-title":"Emerg Infect Dis"},{"issue":"1","key":"pone.0314672.ref003","doi-asserted-by":"crossref","first-page":"2544","DOI":"10.1080\/22221751.2022.2130099","article-title":"Outbreak of occupational Brucella infection caused by live attenuated Brucella vaccine in a biological products company in Chongqing, China, 2020","volume":"11","author":"C Zhou","year":"2020","journal-title":"Emerg Microbes Infect"},{"issue":"12","key":"pone.0314672.ref004","doi-asserted-by":"crossref","first-page":"33","DOI":"10.2807\/esm.09.12.00506-en","article-title":"Bichat guidelines for the clinical management of brucellosis and bioterrorism-related brucellosis","volume":"9","author":"P Bossi","year":"2004","journal-title":"Euro Surveill"},{"issue":"1\u20132","key":"pone.0314672.ref005","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.prevetmed.2005.01.017","article-title":"A model of animal-human brucellosis transmission in Mongolia","volume":"69","author":"J Zinsstag","year":"2005","journal-title":"Prev Vet Med"},{"issue":"2","key":"pone.0314672.ref006","doi-asserted-by":"crossref","first-page":"224926","DOI":"10.1080\/22221751.2023.2249126","article-title":"The emergence of Brucella canis as a public health threat in Europe: what we know and what we need to learn","volume":"12","author":"V Djokic","year":"2023","journal-title":"Emerg Microbes Infect"},{"issue":"1","key":"pone.0314672.ref007","doi-asserted-by":"crossref","first-page":"e00073","DOI":"10.1128\/CMR.00073-19","article-title":"Laboratory diagnosis of human brucellosis","volume":"33","author":"P Yagupsky","year":"2019","journal-title":"Clin Microbiol Rev"},{"issue":"2","key":"pone.0314672.ref008","doi-asserted-by":"crossref","first-page":"186","DOI":"10.3390\/pathogens10020186","article-title":"Brucella: reservoirs and niches in animals and humans","volume":"10","author":"G Gonz\u00e1lez-Espinoza","year":"2021","journal-title":"Pathogens"},{"issue":"3","key":"pone.0314672.ref009","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1111\/j.1365-2958.2004.04017.x","article-title":"Adaptation of the brucellae to their intracellular niche","volume":"52","author":"RM Roop","year":"2004","journal-title":"Mol Microbiol"},{"key":"pone.0314672.ref010","doi-asserted-by":"crossref","first-page":"115875","DOI":"10.1016\/j.biopha.2023.115875","article-title":"Biomedicine & Pharmacotherapy Nano and microparticle drug delivery systems for the treatment of Brucella infections","volume":"169","author":"A Razei","year":"2023","journal-title":"Biomed Pharmacother"},{"key":"pone.0314672.ref011","doi-asserted-by":"crossref","first-page":"106958","DOI":"10.1016\/j.bpc.2023.106958","article-title":"Interaction of gentamicin and gentamicin-AOT with poly-(lactide-co-glycolate) in a drug delivery system\u2014density functional theory calculations and molecular dynamics simulation","volume":"294","author":"S Duran","year":"2023","journal-title":"Biophys Chem"},{"issue":"6","key":"pone.0314672.ref012","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.4049\/jimmunol.1501612","article-title":"Cutting Edge: Mycobacterium tuberculosis Induces aerobic glycolysis in human alveolar macrophages that Is required for control of intracellular bacillary replication","volume":"196","author":"LE Gleeson","year":"2016","journal-title":"J Immunol"},{"issue":"1","key":"pone.0314672.ref013","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.cell.2019.05.003","article-title":"Lactate is a natural suppressor of RLR signaling by targeting MAVS","volume":"178","author":"W Zhang","year":"2019","journal-title":"Cell"},{"issue":"5","key":"pone.0314672.ref014","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s41577-019-0128-5","article-title":"Itaconate: the poster child of metabolic reprogramming in macrophage function","volume":"19","author":"LAJ O\u2019Neill","year":"2019","journal-title":"Nat Rev Immunol"},{"issue":"2","key":"pone.0314672.ref015","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1080\/1040841X.2017.1332002","article-title":"Brucella central carbon metabolism: an update","volume":"44","author":"T Barbier","year":"2018","journal-title":"Crit Rev Microbiol"},{"issue":"1","key":"pone.0314672.ref016","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40364-020-00251-y","article-title":"Metabolic reprogramming in macrophage responses","volume":"9","author":"Y Liu","year":"2021","journal-title":"Biomark Res"},{"issue":"3","key":"pone.0314672.ref017","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.immuni.2015.02.005","article-title":"Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization","volume":"42","author":"AK Jha","year":"2015","journal-title":"Immunity"},{"issue":"10","key":"pone.0314672.ref018","doi-asserted-by":"crossref","first-page":"e0015621","DOI":"10.1128\/IAI.00156-21","article-title":"MyD88-dependent glucose restriction and itaconate production control Brucella Infection","volume":"89","author":"CA Lacey","year":"2021","journal-title":"Infect Immun"},{"issue":"5","key":"pone.0314672.ref019","doi-asserted-by":"crossref","first-page":"e1009597","DOI":"10.1371\/journal.ppat.1009597","article-title":"STING regulates metabolic reprogramming in macrophages via HIF-1\u03b1 during Brucella infection","volume":"17","author":"MTR Gomes","year":"2021","journal-title":"PLoS Pathog"},{"issue":"2","key":"pone.0314672.ref020","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.chom.2013.07.009","article-title":"PPAR\u03b3-mediated increase in glucose availability sustains chronic Brucella abortus infection in alternatively activated macrophages","volume":"14","author":"MN Xavier","year":"2013","journal-title":"Cell Host Microbe"},{"issue":"5","key":"pone.0314672.ref021","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/s41577-019-0124-9","article-title":"Immunometabolism at the interface between macrophages and pathogens","volume":"19","author":"DG Russell","year":"2019","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"pone.0314672.ref022","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1297-9716-43-29","article-title":"What have we learned from brucellosis in the mouse model?","volume":"43","author":"MJ Grillo","year":"2012","journal-title":"Vet Res"},{"issue":"12","key":"pone.0314672.ref023","doi-asserted-by":"crossref","first-page":"6640","DOI":"10.1073\/pnas.120163297","article-title":"One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products","volume":"97","author":"KA Datsenko","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"pone.0314672.ref024","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1128\/JB.01240-09","article-title":"Global regulation of gene expression and cell differentiation in Caulobacter crescentus in response to nutrient availability","volume":"192","author":"JC England","year":"2009","journal-title":"J Bacteriol"},{"issue":"3","key":"pone.0314672.ref025","doi-asserted-by":"crossref","first-page":"e00961","DOI":"10.1128\/IAI.00961-16","article-title":"Temporal role for MyD88 in a model of Brucella-induced arthritis and musculoskeletal inflammation","volume":"85","author":"CA Lacey","year":"2017","journal-title":"Infect Immun"},{"issue":"4","key":"pone.0314672.ref026","first-page":"e818","article-title":"Vaccine-elicited antibodies restrict glucose availability to control Brucella infection","volume":"230","author":"B Ponzilacqua-Silva","year":"2024","journal-title":"J Infect Dis"},{"key":"pone.0314672.ref027","doi-asserted-by":"crossref","first-page":"W652","DOI":"10.1093\/nar\/gkp356","article-title":"Metaboanalyst: A web server for metabolomic data analysis and interpretation","volume":"37","author":"J Xia","year":"2009","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"pone.0314672.ref028","doi-asserted-by":"crossref","first-page":"e0127422","DOI":"10.1128\/mbio.01274-22","article-title":"Glutamine Is required for M1-like polarization of macrophages in response to Mycobacterium tuberculosis infection","volume":"13","author":"Q Jiang","year":"2022","journal-title":"mBio"},{"issue":"9","key":"pone.0314672.ref029","doi-asserted-by":"crossref","first-page":"e0185092","DOI":"10.1371\/journal.pone.0185092","article-title":"Glutaminase is essential for the growth of triple-negative breast cancer cells with a deregulated glutamine metabolism pathway and its suppression synergizes with mTOR inhibition","volume":"12","author":"M Lampa","year":"2017","journal-title":"PLoS One"},{"issue":"5","key":"pone.0314672.ref030","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.celrep.2019.09.056","article-title":"Glutamine anabolism plays a critical role in pancreatic cancer by coupling carbon and nitrogen metabolism","volume":"29","author":"AJ Bott","year":"2019","journal-title":"Cell Rep"},{"key":"pone.0314672.ref031","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3389\/fnins.2015.00022","article-title":"Lactate is always the end product of glycolysis","volume":"9","author":"MJ Rogatzki","year":"2015","journal-title":"Front Neurosci"},{"issue":"15","key":"pone.0314672.ref032","first-page":"e00227","article-title":"Brucella abortus induces a Warburg shift in host metabolism that is linked to enhanced intracellular survival of the pathogen","volume":"199","author":"DM Czyz","year":"2017","journal-title":"J Bacteriol"},{"issue":"7346","key":"pone.0314672.ref033","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/nature10074","article-title":"Evolution and metabolic significance of the urea cycle in photosynthetic diatoms","volume":"473","author":"AE Allen","year":"2011","journal-title":"Nature"},{"issue":"4","key":"pone.0314672.ref034","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/S0934-8840(11)80165-9","article-title":"Minimal requirements for growth of Brucella suis and other Brucella species","volume":"275","author":"M. Plommet","year":"1991","journal-title":"Zentralbl Bakteriol"},{"issue":"7444","key":"pone.0314672.ref035","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nature11986","article-title":"Succinate is an inflammatory signal that induces IL-1\u03b2 through HIF-1\u03b1","volume":"496","author":"GM Tannahill","year":"2013","journal-title":"Nature"},{"key":"pone.0314672.ref036","first-page":"17","volume-title":"Advances in Experimental Medicine and Biology","author":"T Li","year":"2021"},{"issue":"9","key":"pone.0314672.ref037","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/S0753-3322(02)00285-8","article-title":"II. Glutamine and glutamate","volume":"56","author":"H Tapiero","year":"2002","journal-title":"Biomed Pharmacother"},{"issue":"15","key":"pone.0314672.ref038","doi-asserted-by":"crossref","first-page":"5667","DOI":"10.1007\/s00018-021-03881-z","article-title":"GABAergic signaling by cells of the immune system: more the rule than the exception","volume":"78","author":"AK Bhandage","year":"2021","journal-title":"Cellular and Molecular Life Sciences"},{"issue":"15","key":"pone.0314672.ref039","doi-asserted-by":"crossref","first-page":"eabe9274","DOI":"10.1126\/sciadv.abe9274","article-title":"GABA transporter sustains IL-1\u03b2 production in macrophages","volume":"7","author":"Y Xia","year":"2021","journal-title":"Sci Adv"},{"issue":"8","key":"pone.0314672.ref040","doi-asserted-by":"crossref","first-page":"e0237371","DOI":"10.1371\/journal.pone.0237371","article-title":"Characterizing the transport and utilization of the neurotransmitter GABA in the bacterial pathogen Brucella abortus","volume":"15","author":"JA Budnick","year":"2020","journal-title":"PLoS One"},{"issue":"1","key":"pone.0314672.ref041","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1084\/jem.20151570","article-title":"Immunometabolism governs dendritic cell and macrophage function","volume":"213","author":"LAJ O\u2019Neill","year":"2016","journal-title":"J Exp Med"},{"key":"pone.0314672.ref042","doi-asserted-by":"crossref","first-page":"995219","DOI":"10.3389\/fmicb.2022.995219","article-title":"How the crosstalk between innate immune sensors and metabolic pathways affect the outcome of Brucella abortus infection?","volume":"13","author":"SC Oliveira","year":"2022","journal-title":"Front Microbiol"},{"issue":"10","key":"pone.0314672.ref043","doi-asserted-by":"crossref","first-page":"e00257","DOI":"10.1128\/IAI.00257-20","article-title":"Brucella abortus and pregnancy in mice: Impact of chronic infection on fertility and the role of regulatory T cells in tissue colonization","volume":"88","author":"SA Adetunji","year":"2020","journal-title":"Infect Immun"},{"issue":"2","key":"pone.0314672.ref044","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1177\/030098589303000204","article-title":"Placental pathology of the pregnant mouse infected with Brucella abortus stain 2308","volume":"30","author":"L Tobias","journal-title":"Vet Pathol."},{"issue":"4","key":"pone.0314672.ref045","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1007\/s40475-016-0092-0","article-title":"Human Brucellosis and Adverse Pregnancy Outcomes","volume":"3","author":"AM Arenas-Gamboa","year":"2016","journal-title":"Curr Trop Med Rep"},{"issue":"10","key":"pone.0314672.ref046","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1038\/nri.2017.66","article-title":"Mitochondrial control of immunity: beyond ATP","volume":"17","author":"MM Mehta","year":"2017","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"pone.0314672.ref047","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.immuni.2020.09.014","article-title":"Modification of Proteins by Metabolites in Immunity","volume":"54","author":"C Diskin","year":"2021","journal-title":"Immunity"},{"issue":"11","key":"pone.0314672.ref048","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.3390\/nu10111564","article-title":"Glutamine: Metabolism and immune function, supplementation and clinical translation","volume":"10","author":"V Cruzat","year":"2018","journal-title":"Nutrients. MDPI AG"},{"issue":"2","key":"pone.0314672.ref049","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1189\/jlb.1211626","article-title":"IFN-\u03b3-deficient mice develop IL-1-dependent cutaneous and musculoskeletal inflammation during experimental brucellosis","volume":"92","author":"JA Skyberg","year":"2012","journal-title":"J Leukoc Biol"},{"key":"pone.0314672.ref050","doi-asserted-by":"crossref","first-page":"391","DOI":"10.3389\/fcimb.2018.00391","article-title":"IL-1R and inflammasomes mediate early pulmonary protective mechanisms in respiratory Brucella abortus infection","volume":"8","author":"MS Hielpos","year":"2018","journal-title":"Front Cell Infect Microbiol"},{"key":"pone.0314672.ref051","doi-asserted-by":"crossref","first-page":"1180837","DOI":"10.3389\/fimmu.2023.1180837","article-title":"Brucella abortus modulates macrophage polarization and inflammatory response by targeting glutaminases through the NF-\u03baB signaling pathway","volume":"14","author":"T Zhao","year":"2023","journal-title":"Front Immunol"},{"issue":"6","key":"pone.0314672.ref052","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1073\/pnas.0915139107","article-title":"Inhibitory role for GABA in autoimmune inflammation","volume":"107","author":"R Bhat","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pone.0314672.ref053","doi-asserted-by":"crossref","first-page":"4184","DOI":"10.1038\/s41467-018-06487-5","article-title":"GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections","volume":"9","author":"JK Kim","year":"2018","journal-title":"Nat Commun"},{"key":"pone.0314672.ref054","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0065-2164(08)00603-5","article-title":"Acid stress responses in Listeria monocytogenes","volume":"65","author":"S Ryan","year":"2008","journal-title":"Adv Appl Microbiol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0314672","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T18:29:13Z","timestamp":1738002553000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0314672"}},"subtitle":[],"editor":[{"given":"Roy Martin","family":"Roop","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,1,27]]},"references-count":54,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0314672","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,27]]}}}