{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T08:09:36Z","timestamp":1762762176546,"version":"3.41.2"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T00:00:00Z","timestamp":1715817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Sepsis remains a major cause of mortality and morbidity in infants. In recent years, several gene marker strategies for the early identification of sepsis have been proposed but only a few have been independently validated for adult cohorts and applicability to infant sepsis remains unclear. Biomarkers to assess disease severity and risks of shock also represent an important unmet need.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To elucidate characteristics driving sepsis in infants, we assembled a multi-transcriptomic dataset from public microarray datasets originating from five independent studies pertaining to bacterial sepsis in infant &amp;lt; 6-months of age (total n=335). We utilized a COmbat co-normalization strategy to enable comparative evaluation across multiple studies while preserving the relationship between cases and controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found good concordance with only two out of seven of the published adult sepsis gene signatures (accuracy &amp;gt; 80%), highlighting the narrow utility of adult-derived signatures for infant diagnosis. Pseudotime analysis of individual subjects\u2019 gene expression profiles showed a continuum of molecular changes forming tight clusters concurrent with disease progression between healthy controls and septic shock cases. In depth gene expression analyses between bacteremia, septic shock, and healthy controls characterized lymphocyte activity, hemostatic processes, and heightened innate immunity during the molecular transition toward a state of shock.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our analysis revealed the presence of multiple significant transcriptomic perturbations that occur during the progression to septic shock in infants that are characterized by late-stage induction of clotting factors, in parallel with a heightened innate immune response and a suppression of adaptive cell functionality.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1281111","type":"journal-article","created":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T04:26:05Z","timestamp":1715833565000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["The molecular landscape of sepsis severity in infants: enhanced coagulation, innate immunity, and T cell repression"],"prefix":"10.3389","volume":"15","author":[{"given":"Susie Shih Yin","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed","family":"Toufiq","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pirooz","family":"Eghtesady","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Van Panhuys","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathieu","family":"Garand","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1186\/s13054-018-2157-z","article-title":"The global burden of sepsis: barriers and potential solutions","volume":"22","author":"Rudd","year":"2018","journal-title":"Crit Care"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901481","article-title":"Neonatal innate TLR-mediated responses are distinct from those of adults","volume":"183","author":"Kollmann","year":"2009","journal-title":"J Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.it.2014.04.007","article-title":"Ontogeny of early life immunity","volume":"35","author":"Dowling","year":"2014","journal-title":"Trends Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"325","DOI":"10.21037\/atm","article-title":"Epidemiologic trends of sepsis in western countries","volume":"4","author":"Suarez de la Rica","year":"2016","journal-title":"Ann Transl Med"},{"key":"B5","first-page":"499","article-title":"[The pathogenesis of the systemic inflammatory response syndrome and compensatory antiinflammatory response syndrome following surgical stress]","volume":"104","author":"Ono","year":"2003","journal-title":"Nihon Geka Gakkai Zasshi"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1097\/01.PCC.0000161946.73305.0A","article-title":"Definitions of bloodstream infection in the newborn","volume":"6","author":"Haque","year":"2005","journal-title":"Pediatr Crit Care Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"895","DOI":"10.2217\/bmm-2020-0016","article-title":"Biomarkers in pediatric sepsis: a review of recent literature","volume":"14","author":"Oikonomakou M","year":"2020","journal-title":"biomark Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s00520-021-06782-w","article-title":"Utility of procalcitonin and C-reactive protein as predictors of Gram-negative bacteremia in febrile hematological outpatients","volume":"30","author":"Jabbour","year":"2022","journal-title":"Support Care Cancer"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1007\/s00134-022-06769-z","article-title":"Presymptomatic diagnosis of postoperative infection and sepsis using gene expression signatures","volume":"48","author":"Lukaszewski","year":"2022","journal-title":"Intensive Care Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201712-2472OC","article-title":"for discriminating sepsis from systemic inflammatory response syndrome in the ICU","volume":"198","author":"Miller","year":"2018","journal-title":"Am J Respir Crit Care Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/jpids\/pix021","article-title":"Validation of the sepsis metaScore for diagnosis of neonatal sepsis","volume":"7","author":"Sweeney","year":"2018","journal-title":"J Pediatr Infect Dis Soc"},{"key":"B12","doi-asserted-by":"publisher","first-page":"6708520","DOI":"10.1155\/2018\/6708520","article-title":"Potential genes and pathways of neonatal sepsis based on functional gene set enrichment analyses","volume":"2018","author":"Meng","year":"2018","journal-title":"Comput Math Methods Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0171689","article-title":"Transcriptomic meta-analysis reveals up-regulation of gene expression functional in osteoclast differentiation in human septic shock","volume":"12","author":"Mukhopadhyay","year":"2017","journal-title":"PloS One"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001916","article-title":"A molecular host response assay to discriminate between sepsis and infection-negative systemic inflammation in critically ill patients: discovery and validation in independent cohorts","volume":"12","author":"McHugh","year":"2015","journal-title":"PloS Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201502-0355OC","article-title":"A molecular biomarker to diagnose community-acquired pneumonia on intensive care unit admission","volume":"192","author":"Scicluna","year":"2015","journal-title":"Am J Respir Crit Care Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2021.05.039","article-title":"Distinguishing septic shock from non-septic shock in postsurgical patients using gene expression","volume":"83","author":"Mart\u00ednez-Paz","year":"2021","journal-title":"J Infect"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0184159","article-title":"Unique transcriptomic response to sepsis is observed among patients of different age groups","volume":"12","author":"Raymond","year":"2017","journal-title":"PloS One"},{"key":"B18","doi-asserted-by":"publisher","first-page":"496","DOI":"10.2119\/molmed.2015.00064","article-title":"Postnatal age is a critical determinant of the neonatal host response to sepsis","volume":"21","author":"Wynn","year":"2015","journal-title":"Mol Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.9207","article-title":"Association of RNA biosignatures with bacterial infections in febrile infants aged 60 days or younger","volume":"316","author":"Mahajan","year":"2016","journal-title":"JAMA"},{"key":"B20","doi-asserted-by":"publisher","first-page":"346ra91","DOI":"10.1126\/scitranslmed.aaf7165","article-title":"Robust classification of bacterial and viral infections via integrated host gene expression diagnostics","volume":"8","author":"Sweeney","year":"2016","journal-title":"Sci Transl Med"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.3390\/biomedicines9101297","article-title":"Reverse engineering of the pediatric sepsis regulatory network and identification of master regulators","volume":"9","author":"Oliveira RA de","year":"2021","journal-title":"Biomedicines"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2100697","article-title":"SysInflam huDB, a web resource for mining human blood cells transcriptomic data associated with systemic inflammatory responses to sepsis","volume":"207","author":"Toufiq","year":"2021","journal-title":"J Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0068294","article-title":"Increased CD4(+) T cell co-inhibitory immune receptor CEACAM1 in neonatal sepsis and soluble-CEACAM1 in meningococcal sepsis: a role in sepsis-associated immune suppression","volume":"8","author":"van der Flier","year":"2013","journal-title":"PloS One"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4402","article-title":"Reversed graph embedding resolves complex single-cell trajectories","volume":"14","author":"Qiu","year":"2017","journal-title":"Nat Methods"},{"key":"B25","doi-asserted-by":"publisher","first-page":"100141","DOI":"10.1016\/j.xinn.2021.100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation (Camb)"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0114-2","article-title":"Determining cell type abundance and expression from bulk tissues with digital cytometry","volume":"37","author":"Newman","year":"2019","journal-title":"Nat Biotechnol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.01.041","article-title":"RNA-seq signatures normalized by mRNA abundance allow absolute deconvolution of human immune cell types","volume":"26","author":"Monaco","year":"2019","journal-title":"Cell Rep"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab382","article-title":"MetaboAnalyst 5.0: narrowing the gap between raw spectra and functional insights","volume":"49","author":"Pang","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.448589","article-title":"Dysferlin regulates cell adhesion in human monocytes","volume":"288","author":"de Morr\u00e9e","year":"2013","journal-title":"J Biol Chem"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-014-9920-3","article-title":"Glyceraldehyde-3-phosphate dehydrogenase is an inappropriate housekeeping gene for normalising gene expression in sepsis","volume":"37","author":"Cummings","year":"2014","journal-title":"Inflammation"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2022.e11634","article-title":"Identification of key biomarkers in neonatal sepsis by integrated bioinformatics analysis and clinical validation","volume":"8","author":"Yan","year":"2022","journal-title":"Heliyon"},{"key":"B32","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1177\/1753425916671018","article-title":"Environment impacts innate immune ontogeny","volume":"23","author":"Garand","year":"2017","journal-title":"Innate Immun"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.7.3195","article-title":"IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking","volume":"168","author":"Dufour","year":"2002","journal-title":"J Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7493-1_12","article-title":"Profiling tumor infiltrating immune cells with CIBERSORT","volume":"1711","author":"Chen","year":"2018","journal-title":"Methods Mol Biol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.704633","article-title":"Integrative transcriptomics reveals activation of innate immune responses and inhibition of inflammation during oral immunotherapy for egg allergy in children","volume":"12","author":"Karisola","year":"2021","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3909","article-title":"The prognostic landscape of genes and infiltrating immune cells across human cancers","volume":"21","author":"Gentles","year":"2015","journal-title":"Nat Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-021-01918-4","article-title":"Paediatric and neonatal sepsis and inflammation","volume":"91","author":"Molloy","year":"2022","journal-title":"Pediatr Res"},{"key":"B38","doi-asserted-by":"publisher","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":"B39","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1186\/s13059-022-02648-4","article-title":"Exaggerated false positives by popular differential expression methods when analyzing human population samples","volume":"23","author":"Li","year":"2022","journal-title":"Genome Biol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.10.014","article-title":"Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly","volume":"37","author":"Kollmann","year":"2012","journal-title":"Immunity"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2005.02799.x","article-title":"T cell-mediated immune responses in human newborns: ready to learn","volume":"141","author":"Marchant","year":"2005","journal-title":"Clin Exp Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0071-9","article-title":"A comparison of single-cell trajectory inference methods","volume":"37","author":"Saelens","year":"2019","journal-title":"Nat Biotechnol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1038\/s41586-019-0969-x","article-title":"The single-cell transcriptional landscape of mammalian organogenesis","volume":"566","author":"Cao","year":"2019","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/nri3552","article-title":"Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy","volume":"13","author":"Hotchkiss","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2011.1829","article-title":"Immunosuppression in patients who die of sepsis and multiple organ failure","volume":"306","author":"Boomer","year":"2011","journal-title":"JAMA"},{"key":"B46","doi-asserted-by":"publisher","first-page":"R105","DOI":"10.1186\/cc12750","article-title":"Early alterations of B cells in patients with septic shock","volume":"17","author":"Monserrat","year":"2013","journal-title":"Crit Care"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.11.6952","article-title":"Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans","volume":"166","author":"Hotchkiss","year":"2001","journal-title":"J Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.07.009","article-title":"Bacterial stress responses during host infection","volume":"20","author":"Fang","year":"2016","journal-title":"Cell Host Microbe"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2014.05.004","article-title":"Infection mobilizes hematopoietic stem cells through cooperative NOD-like receptor and Toll-like receptor signaling","volume":"15","author":"Burberry","year":"2014","journal-title":"Cell Host Microbe"},{"key":"B50","doi-asserted-by":"publisher","first-page":"2412","DOI":"10.3390\/jcm10112412","article-title":"Metabolic alterations in sepsis","volume":"10","author":"Wasyluk","year":"2021","journal-title":"J Clin Med"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12499","article-title":"The immune system\u2019s role in sepsis progression, resolution, and long-term outcome","volume":"274","author":"Delano","year":"2016","journal-title":"Immunol Rev"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.11.025","article-title":"Synergism of TNF-\u03b1 and IFN-\u03b3 Triggers inflammatory cell death, tissue damage, and mortality in SARS-coV-2 infection and cytokine shock syndromes","volume":"184","author":"Karki","year":"2021","journal-title":"Cell"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/ni1582","article-title":"Functions of natural killer cells","volume":"9","author":"Vivier","year":"2008","journal-title":"Nat Immunol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2011.06.001","article-title":"CXCL10\/IP-10 in infectious diseases pathogenesis and potential therapeutic implications","volume":"22","author":"Liu","year":"2011","journal-title":"Cytokine Growth Factor Rev"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1281111\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T04:26:09Z","timestamp":1715833569000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1281111\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,16]]},"references-count":54,"alternative-id":["10.3389\/fimmu.2024.1281111"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1281111","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2024,5,16]]},"article-number":"1281111"}}