{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T04:20:32Z","timestamp":1793420432009,"version":"4.5.0"},"reference-count":46,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T00:00:00Z","timestamp":1631750400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32070133"],"award-info":[{"award-number":["32070133"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81871624"],"award-info":[{"award-number":["81871624"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31800126"],"award-info":[{"award-number":["31800126"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Salmonella enterica serovar Typhi (S. Typhi) is a human-limited intracellular pathogen and the cause of typhoid fever, a severe systemic disease. Pathogen\u2013host interaction at the metabolic level affects the pathogenicity of intracellular pathogens, but it remains unclear how S. Typhi infection influences host metabolism for its own benefit. Herein, using metabolomics and transcriptomics analyses, combined with in vitro and in vivo infection assays, we investigated metabolic responses in human macrophages during S. Typhi infection, and the impact of these responses on S. Typhi intracellular replication and systemic pathogenicity. We observed increased glucose content, higher rates of glucose uptake and glycolysis, and decreased oxidative phosphorylation in S. Typhi-infected human primary macrophages. Replication in human macrophages and the bacterial burden in systemic organs of humanized mice were reduced by either the inhibition of host glucose uptake or a mutation of the bacterial glucose uptake system, indicating that S. Typhi utilizes host-derived glucose to enhance intracellular replication and virulence. Thus, S. Typhi promotes its pathogenicity by inducing metabolic changes in host macrophages and utilizing the glucose that subsequently accumulates as a nutrient for intracellular replication. Our findings provide the first metabolic signature of S. Typhi-infected host cells and identifies a new strategy utilized by S. Typhi for intracellular replication.<\/jats:p>","DOI":"10.3390\/ijms221810003","type":"journal-article","created":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T21:38:12Z","timestamp":1631828292000},"page":"10003","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Salmonella enterica Serovar Typhi Induces Host Metabolic Reprogramming to Increase Glucose Availability for Intracellular Replication"],"prefix":"10.3390","volume":"22","author":[{"given":"Jingting","family":"Wang","sequence":"first","affiliation":[{"name":"The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300457, China"},{"name":"Tianjin Key Laboratory of Microbial Functional Genomics, TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin 300457, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Ma","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300457, China"},{"name":"Tianjin Key Laboratory of Microbial Functional Genomics, TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin 300457, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanwu","family":"Li","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300457, China"},{"name":"Tianjin Key Laboratory of Microbial Functional Genomics, TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin 300457, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Wang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300457, China"},{"name":"Tianjin Key Laboratory of Microbial Functional Genomics, TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin 300457, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Huang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300457, China"},{"name":"Tianjin Key Laboratory of Microbial Functional Genomics, TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin 300457, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8580-606X","authenticated-orcid":false,"given":"Lingyan","family":"Jiang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300457, China"},{"name":"Tianjin Key Laboratory of Microbial Functional Genomics, TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin 300457, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Feng","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Nankai University, Tianjin 300457, China"},{"name":"Tianjin Key Laboratory of Microbial Functional Genomics, TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin 300457, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1016\/j.tim.2019.05.002","article-title":"Salmonella\u00a0enterica","volume":"27","author":"Knodler","year":"2019","journal-title":"Trends Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.chom.2019.08.001","article-title":"Genome-wide Analysis of Salmonella enterica serovar Typhi in Humanized Mice Reveals Key Virulence Features","volume":"26","author":"Karlinsey","year":"2019","journal-title":"Cell Host Microbe"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/S1473-3099(18)30685-6","article-title":"The global burden of typhoid and paratyphoid fevers: A systematic analysis for the Global Burden of Disease Study 2017","volume":"19","author":"Stanaway","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Yang, S.M., Kim, E., Kim, D., Baek, J., Yoon, H., and Kim, H.Y. (2021). Rapid detection of Salmonella enteritidis, typhimurium, and thompson by specific peak analysis using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Foods, 10.","DOI":"10.3390\/foods10050933"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Nguyen, T., Lee, S., Yang, Y.A., Ahn, C., Sim, J.H., Kei, T.G., Barnard, K.N., Yu, H., Millano, S.K., and Chen, X. (2020). The role of 9-O-acetylated glycan receptor moieties in the typhoid toxin binding and intoxication. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008336"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9589208","DOI":"10.1155\/2018\/9589208","article-title":"Estimating Typhoid Fever Risk Associated with Lack of Access to Safe Water: A Systematic Literature Review","volume":"2018","author":"Mogasale","year":"2018","journal-title":"J. Environ. Public Health"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Gaviria-Cantin, T., El Mouali, Y., Le Guyon, S., R\u00f6mling, U., and Balsalobre, C. (2017). Gre factors-mediated control of hilD transcription is essential for the invasion of epithelial cells by Salmonella enterica serovar Typhimurium. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006312"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1128\/IAI.66.5.2310-2318.1998","article-title":"Differential early interactions between Salmonella enterica serovar Typhi and two other pathogenic Salmonella serovars with intestinal epithelial cells","volume":"66","author":"Weinstein","year":"1998","journal-title":"Infect. Immun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.1099\/mic.0.041624-0","article-title":"Intracellular survival of Salmonella enterica serovar Typhi in human macrophages is independent of Salmonella pathogenicity island (SPI)-2","volume":"156","author":"Forest","year":"2010","journal-title":"Microbiology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1046\/j.1365-2958.1998.01047.x","article-title":"Genes encoding putative effector proteins of the type III secretion system of Salmonella pathogenicity island 2 are required for bacterial virulence and proliferation in macrophages","volume":"30","author":"Hensel","year":"1998","journal-title":"Mol. Microbiol"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"17492","DOI":"10.1073\/pnas.0407536101","article-title":"Vi polysaccharide of Salmonella typhi targets the prohibitin family of molecules in intestinal epithelial cells and suppresses early inflammatory responses","volume":"101","author":"Sharma","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Winter, S.E., Winter, M.G., Godinez, I., Yang, H.J., R\u00fcssmann, H., Andrews-Polymenis, H.L., and B\u00e4umler, A.J. (2010). A rapid change in virulence gene expression during the transition from the intestinal lumen into tissue promotes systemic dissemination of Salmonella. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001060"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1080\/1040841X.2016.1249335","article-title":"Vi capsular polysaccharide: Synthesis, virulence, and application","volume":"43","author":"Hu","year":"2017","journal-title":"Crit. Rev. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1128\/IAI.74.3.1555-1564.2006","article-title":"The outer core lipopolysaccharide of Salmonella enterica serovar Typhi is required for bacterial entry into epithelial cells","volume":"74","author":"Hoare","year":"2006","journal-title":"Infect. Immun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3677","DOI":"10.1073\/pnas.0737682100","article-title":"Salmochelins, siderophores of Salmonella enterica and uropathogenic Escherichia coli strains, are recognized by the outer membrane receptor IroN","volume":"100","author":"Hantke","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1111\/febs.14446","article-title":"Metabolic reprogramming of host cells upon bacterial infection: Why shift to a Warburg-like metabolism?","volume":"285","author":"Escoll","year":"2018","journal-title":"FEBS J."},{"key":"ref_17","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":"Russell","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.chom.2017.07.020","article-title":"Legionella pneumophila Modulates Mitochondrial Dynamics to Trigger Metabolic Repurposing of Infected Macrophages","volume":"22","author":"Escoll","year":"2017","journal-title":"Cell Host Microbe"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.celrep.2014.10.004","article-title":"Tumor suppressor p53 alters host cell metabolism to limit Chlamydia trachomatis infection","volume":"9","author":"Siegl","year":"2014","journal-title":"Cell Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4227","DOI":"10.4049\/jimmunol.1502456","article-title":"Metabolic reprogramming of host cells by virulent Francisella tularensis for optimal replication and modulation of inflammation","volume":"196","author":"Wyatt","year":"2016","journal-title":"J. Immunol."},{"key":"ref_21","first-page":"e00227-17","article-title":"Brucella abortus induces a Warburg shift in host metabolism that is linked to enhanced intracellular survival of the pathogen","volume":"199","author":"Willett","year":"2017","journal-title":"J. Bacteriol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1038\/s41467-021-21186-4","article-title":"Salmonella Typhimurium reprograms macrophage metabolism via T3SS effector SopE2 to promote intracellular replication and virulence","volume":"12","author":"Jiang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/s41419-020-2481-5","article-title":"Role of pyruvate kinase M2-mediated metabolic reprogramming during podocyte differentiation","volume":"11","author":"Yuan","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"38067","DOI":"10.1038\/srep38067","article-title":"p53 coordinates DNA repair with nucleotide synthesis by suppressing PFKFB3 expression and promoting the pentose phosphate pathway","volume":"6","author":"Franklin","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1038\/ncb3231","article-title":"AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest","volume":"17","author":"Maestre","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_26","first-page":"945","article-title":"PFKFB3 is involved in breast cancer proliferation, migration, invasion and angiogenesis","volume":"52","author":"Peng","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.molcel.2014.09.025","article-title":"Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport","volume":"56","author":"Yang","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"19611","DOI":"10.1073\/pnas.1117773108","article-title":"Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability","volume":"108","author":"Wise","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5039","DOI":"10.1038\/s41598-018-23436-w","article-title":"Loss of IDH2 accelerates age-related hearing loss in male mice","volume":"8","author":"White","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6484","DOI":"10.1038\/s41598-017-05916-7","article-title":"Lactate oxidation facilitates growth of Mycobacterium tuberculosis in human macrophages","volume":"7","author":"Billig","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Abu Kwaik, Y., and Bumann, D. (2015). Host delivery of favorite meals for intracellular pathogens. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004866"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1128\/IAI.00093-09","article-title":"Glucose and glycolysis are required for the successful infection of macrophages and mice by Salmonella enterica serovar typhimurium","volume":"77","author":"Bowden","year":"2009","journal-title":"Infect. Immun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1099\/mic.0.034744-0","article-title":"Glucose and glucose 6-phosphate as carbon sources in extra- and intracellular growth of enteroinvasive Escherichia coli and Salmonella enterica","volume":"156","author":"Goebel","year":"2010","journal-title":"Microbiology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"14543","DOI":"10.1016\/S0021-9258(19)45412-4","article-title":"Sugar transport by the bacterial phosphotransferase system. The glucose receptors of the Salmonella typhimurium phosphotransferase system","volume":"257","author":"Stock","year":"1982","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1128\/mr.57.3.543-594.1993","article-title":"Phosphoenolpyruvate:carbohydrate phosphotransferase systems of bacteria","volume":"57","author":"Postma","year":"1993","journal-title":"Microbiol. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1128\/jb.179.4.1298-1306.1997","article-title":"Molecular characterization of glucokinase from Escherichia coli K-12","volume":"179","author":"Meyer","year":"1997","journal-title":"J. Bacteriol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Yu, C., Du, F., Zhang, C., Li, Y., Liao, C., He, L., Cheng, X., and Zhang, X. (2020). Salmonella enterica serovar Typhimurium sseK3 induces apoptosis and enhances glycolysis in macrophages. BMC Microbiol., 20.","DOI":"10.1186\/s12866-020-01838-z"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"155424","DOI":"10.1016\/j.cyto.2021.155424","article-title":"Effects of Salmonella enterica serovar typhimurium sseK1 on macrophage inflammation-related cytokines and glycolysis","volume":"140","author":"Lu","year":"2021","journal-title":"Cytokine"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Jiang, L., Feng, L., Yang, B., Zhang, W., Wang, P., Jiang, X., and Wang, L. (2017). Signal transduction pathway mediated by the novel regulator LoiA for low oxygen tension induced Salmonella Typhimurium invasion. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006429"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt removes adapter sequences from high-throughput sequencing reads","volume":"17","author":"Martin","year":"2011","journal-title":"EMBnet J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: A fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq\u2014A Python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/s41589-018-0038-z","article-title":"The cyanobacterial ornithine-ammonia cycle involves an arginine dihydrolase","volume":"14","author":"Zhang","year":"2018","journal-title":"Nat. Chem. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e13663","DOI":"10.7554\/eLife.13663","article-title":"Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death","volume":"5","author":"Sanman","year":"2016","journal-title":"eLife"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Gal-Mor, O., Gibson, D.L., Baluta, D., Vallance, B.A., and Finlay, B.B. (2008). A novel secretion pathway of Salmonella enterica acts as an antivirulence modulator during salmonellosis. PLoS Pathog., 4.","DOI":"10.1371\/journal.ppat.1000036"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10003\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:00:38Z","timestamp":1760166038000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10003"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,16]]},"references-count":46,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms221810003"],"URL":"https:\/\/doi.org\/10.3390\/ijms221810003","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,16]]}}}