{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:26:53Z","timestamp":1791498413933,"version":"4.3.4"},"reference-count":31,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T00:00:00Z","timestamp":1716940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research (CIHR), the Mpox Rapid Research Funding Initiative","doi-asserted-by":"publisher","award":["CIHR MZ1 187236"],"award-info":[{"award-number":["CIHR MZ1 187236"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research (CIHR), the Mpox Rapid Research Funding Initiative","doi-asserted-by":"publisher","award":["2023-2565"],"award-info":[{"award-number":["2023-2565"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research (CIHR), the Mpox Rapid Research Funding Initiative","doi-asserted-by":"publisher","award":["20\/COV\/0038"],"award-info":[{"award-number":["20\/COV\/0038"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020170","name":"Research Nova Scotia","doi-asserted-by":"publisher","award":["CIHR MZ1 187236"],"award-info":[{"award-number":["CIHR MZ1 187236"]}],"id":[{"id":"10.13039\/501100020170","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020170","name":"Research Nova Scotia","doi-asserted-by":"publisher","award":["2023-2565"],"award-info":[{"award-number":["2023-2565"]}],"id":[{"id":"10.13039\/501100020170","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020170","name":"Research Nova Scotia","doi-asserted-by":"publisher","award":["20\/COV\/0038"],"award-info":[{"award-number":["20\/COV\/0038"]}],"id":[{"id":"10.13039\/501100020170","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"Dalhousie Medical Research Foundation, the Li-Ka Shing Foundation, and Science Foundation Ireland (SFI)","doi-asserted-by":"publisher","award":["CIHR MZ1 187236"],"award-info":[{"award-number":["CIHR MZ1 187236"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"Dalhousie Medical Research Foundation, the Li-Ka Shing Foundation, and Science Foundation Ireland (SFI)","doi-asserted-by":"publisher","award":["2023-2565"],"award-info":[{"award-number":["2023-2565"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"Dalhousie Medical Research Foundation, the Li-Ka Shing Foundation, and Science Foundation Ireland (SFI)","doi-asserted-by":"publisher","award":["20\/COV\/0038"],"award-info":[{"award-number":["20\/COV\/0038"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Canada Research Chair in Translational Vaccinology and Inflammation","award":["CIHR MZ1 187236"],"award-info":[{"award-number":["CIHR MZ1 187236"]}]},{"name":"Canada Research Chair in Translational Vaccinology and Inflammation","award":["2023-2565"],"award-info":[{"award-number":["2023-2565"]}]},{"name":"Canada Research Chair in Translational Vaccinology and Inflammation","award":["20\/COV\/0038"],"award-info":[{"award-number":["20\/COV\/0038"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A common result of infection is an abnormal immune response, which may be detrimental to the host. To control the infection, the immune system might undergo regulation, therefore producing an excess of either pro-inflammatory or anti-inflammatory pathways that can lead to widespread inflammation, tissue damage, and organ failure. A dysregulated immune response can manifest as changes in differentiated immune cell populations and concentrations of circulating biomarkers. To propose an early diagnostic system that enables differentiation and identifies the severity of immune-dysregulated syndromes, we built an artificial intelligence tool that uses input data from single-cell RNA sequencing. In our results, single-cell transcriptomics successfully distinguished between mild and severe sepsis and COVID-19 infections. Moreover, by interpreting the decision patterns of our classification system, we identified that different immune cells upregulating or downregulating the expression of the genes CD3, CD14, CD16, FOSB, S100A12, and TCR\u0263\u03b4 can accurately differentiate between different degrees of infection. Our research has identified genes of significance that effectively distinguish between infections, offering promising prospects as diagnostic markers and providing potential targets for therapeutic intervention.<\/jats:p>","DOI":"10.3390\/ijms25115920","type":"journal-article","created":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T03:38:30Z","timestamp":1716953910000},"page":"5920","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Identification of Marker Genes in Infectious Diseases from ScRNA-seq Data Using Interpretable Machine Learning"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7656-0579","authenticated-orcid":false,"given":"Gustavo","family":"Sganzerla Martinez","sequence":"first","affiliation":[{"name":"Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4H7, Canada"},{"name":"Department of Pediatrics, Izaak Walton Killam (IWK) Health Center, Canadian Center for Vaccinology, Halifax, NS B3H 4H7, Canada"},{"name":"Department of Immunology, Shantou University Medical College, Shantou 512025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Garduno","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Trinity College Dublin, D08 NHY1 Dublin, Ireland"},{"name":"Department of Intensive Care Medicine, St. James\u2019s Hospital, D08 NHY1 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Toloue Ostadgavahi","sequence":"additional","affiliation":[{"name":"Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4H7, Canada"},{"name":"Department of Pediatrics, Izaak Walton Killam (IWK) Health Center, Canadian Center for Vaccinology, Halifax, NS B3H 4H7, Canada"},{"name":"Department of Immunology, Shantou University Medical College, Shantou 512025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0941-5720","authenticated-orcid":false,"given":"Benjamin","family":"Hewins","sequence":"additional","affiliation":[{"name":"Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4H7, Canada"},{"name":"Department of Pediatrics, Izaak Walton Killam (IWK) Health Center, Canadian Center for Vaccinology, Halifax, NS B3H 4H7, Canada"},{"name":"Department of Immunology, Shantou University Medical College, Shantou 512025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansi","family":"Dutt","sequence":"additional","affiliation":[{"name":"Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4H7, Canada"},{"name":"Department of Pediatrics, Izaak Walton Killam (IWK) Health Center, Canadian Center for Vaccinology, Halifax, NS B3H 4H7, Canada"},{"name":"Department of Immunology, Shantou University Medical College, Shantou 512025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5023-7618","authenticated-orcid":false,"given":"Anuj","family":"Kumar","sequence":"additional","affiliation":[{"name":"Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4H7, Canada"},{"name":"Department of Pediatrics, Izaak Walton Killam (IWK) Health Center, Canadian Center for Vaccinology, Halifax, NS B3H 4H7, Canada"},{"name":"Department of Immunology, Shantou University Medical College, Shantou 512025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5834-4063","authenticated-orcid":false,"given":"Ignacio","family":"Martin-Loeches","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Trinity College Dublin, D08 NHY1 Dublin, Ireland"},{"name":"Department of Intensive Care Medicine, St. James\u2019s Hospital, D08 NHY1 Dublin, Ireland"},{"name":"Multidisciplinary Intensive Care Research Organization (MICRO), St. James\u2019s Hospital, D08 NHY1 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Kelvin","sequence":"additional","affiliation":[{"name":"Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4H7, Canada"},{"name":"Department of Pediatrics, Izaak Walton Killam (IWK) Health Center, Canadian Center for Vaccinology, Halifax, NS B3H 4H7, Canada"},{"name":"Department of Immunology, Shantou University Medical College, Shantou 512025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16045","DOI":"10.1038\/nrdp.2016.45","article-title":"Sepsis and septic shock","volume":"2","author":"Hotchkiss","year":"2016","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock (sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1186\/s13054-020-02950-2","article-title":"Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019\u2014Results from a systematic review and meta-analysis","volume":"24","author":"Bauer","year":"2020","journal-title":"Crit. Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132017: Analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1186\/s13054-020-03398-0","article-title":"Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19","volume":"24","author":"Almansa","year":"2020","journal-title":"Crit. Care"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1137850","DOI":"10.3389\/fimmu.2023.1137850","article-title":"Model-interpreted outcomes of artificial neural networks classifying immune biomarkers associated with severe infections in ICU","volume":"14","author":"Martinez","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_7","unstructured":"Lundberg, S.M., and Lee, S.I. (2017, January 4\u20139). A unified approach to interpreting model predictions. Proceedings of the Advances in Neural Information Processing Systems, Long Beach, CA, USA."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.molimm.2018.09.020","article-title":"Using single cell analysis for translational studies in immune mediated diseases: Opportunities and challenges","volume":"103","author":"Sharma","year":"2018","journal-title":"Mol. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Erfanian, N., Heydari, A.A., Feriz, A.M., Ianez, P., Derakhshani, A., Ghasemigol, M., Farahpour, M., Razavi, S.M., Nasseri, S., and Safarpour, H. (2023). Deep learning applications in single-cell genomics and transcriptomics data analysis. Biomed. Pharmacother., 165.","DOI":"10.1016\/j.biopha.2023.115077"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1111\/nph.18053","article-title":"Identification of new marker genes from plant single-cell RNA-seq data using interpretable machine learning methods","volume":"234","author":"Yan","year":"2022","journal-title":"New Phytol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2221428","DOI":"10.1080\/19490976.2023.2221428","article-title":"Microbial genes outperform species and SNVs as diagnostic markers for Crohn\u2019s disease on multicohort fecal metagenomes empowered by artificial intelligence","volume":"15","author":"Gao","year":"2023","journal-title":"Gut Microbes"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e14487","DOI":"10.7717\/peerj.14487","article-title":"An artificial neural network classification method employing longitudinally monitored immune biomarkers to predict the clinical outcome of critically ill COVID-19 patients","volume":"10","author":"Martinez","year":"2022","journal-title":"PeerJ"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.hfc.2021.11.004","article-title":"Using Artificial Intelligence to Better Predict and Develop Biomarkers","volume":"18","author":"Michelhaugh","year":"2022","journal-title":"Heart Fail. Clin."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3238","DOI":"10.1038\/s41598-021-81749-9","article-title":"An in silico deep learning approach to multi-epitope vaccine design: A SARS-CoV-2 case study","volume":"11","author":"Yang","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Martinez, G.S., Dutt, M., Kelvin, D.J., and Kumar, A. (2024). PoxiPred: An Artificial-Intelligence-Based Method for the Prediction of Potential Antigens and Epitopes to Accelerate Vaccine Development Efforts against Poxviruses. Biology, 13.","DOI":"10.3390\/biology13020125"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2930","DOI":"10.1093\/bioinformatics\/btab191","article-title":"Drug repurposing against breast cancer by integrating drug-exposure expression profiles and drug-drug links based on graph neural network","volume":"37","author":"Cui","year":"2021","journal-title":"Bioinformatics"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Dohmen, J., Baranovskii, A., Ronen, J., Uyar, B., Franke, V., and Akalin, A. (2022). Identifying tumor cells at the single-cell level using machine learning. Genome Biol., 23.","DOI":"10.1186\/s13059-022-02683-1"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Cui, H., Wang, C., Maan, H., Pang, K., Luo, F., Duan, N., and Wang, B. (2024). scGPT: Toward building a foundation model for single-cell multi-omics using generative AI. Nat. Methods, 1\u201311.","DOI":"10.1038\/s41592-024-02201-0"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e2220272120","DOI":"10.1073\/pnas.2220272120","article-title":"Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19","volume":"120","author":"Moreira","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Jimenez-Duran, G., Luque-Martin, R., Patel, M., Koppe, E., Bernard, S., Sharp, C., Buchan, N., Rea, C., de Winther, M.P., and Turan, N. (2020). Pharmacological validation of targets regulating CD14 during macrophage differentiation. EBioMedicine, 61.","DOI":"10.1016\/j.ebiom.2020.103039"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e431","DOI":"10.1016\/S2666-5247(23)00041-1","article-title":"Effect of viral storm in patients admitted to intensive care units with severe COVID-19 in Spain: A multicentre, prospective, cohort study","volume":"4","author":"Motos","year":"2023","journal-title":"Lancet Microbe"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Martin, T.R., Wurfel, M.M., Zanoni, I., and Ulevitch, R. (2020). Targeting innate immunity by blocking CD14: Novel approach to control inflammation and organ dysfunction in COVID-19 illness. EBioMedicine, 57.","DOI":"10.1016\/j.ebiom.2020.102836"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"665773","DOI":"10.3389\/fimmu.2021.665773","article-title":"Transcriptional Changes in CD16+ Monocytes May Contribute to the Pathogenesis of COVID-19","volume":"12","author":"Chilunda","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"103215","DOI":"10.1016\/j.isci.2021.103215","article-title":"The immune landscape of SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Children (MIS-C) from acute disease to recovery","volume":"24","author":"Syrimi","year":"2021","journal-title":"iScience"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"35950","DOI":"10.1074\/jbc.M306220200","article-title":"Structure\/function analysis of the murine cd95l promoter reveals the identification of a novel transcriptional repressor and functional CD28 response element","volume":"278","author":"Crist","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_26","first-page":"907078","article-title":"The role of S100A12 as a systemic marker of inflammation","volume":"2012","author":"Meijer","year":"2012","journal-title":"Int. J. Inflamm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.4049\/jimmunol.1600599","article-title":"The Essential Role of Neutrophils during Infection with the Intracellular Bacterial Pathogen Listeria monocytogenes","volume":"197","author":"Witter","year":"2016","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1128\/CVI.00752-12","article-title":"Association of \u03b3\u03b4 T cells with disease severity and mortality in septic patients","volume":"20","author":"Ballester","year":"2013","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/s41423-020-0473-0","article-title":"More Bricks in the Wall Against SARS-CoV-2 Infection: Involvement of g9d2 T Cells","volume":"17","author":"Rijkers","year":"2020","journal-title":"Cell. Mol. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1111\/imcb.12623","article-title":"Circulating effector \u03b3\u03b4 T cell populations are associated with acute coronavirus disease 19 in unvaccinated individuals","volume":"101","author":"Nguyen","year":"2023","journal-title":"Immunol. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Martinez, G.S., P\u00e9rez-Rueda, E., Sarkar, S., Kumar, A., and Silva, S.d.e. (2022). Machine learning and statistics shape a novel path in archaeal promoter annotation. BMC Bioinform., 23.","DOI":"10.1186\/s12859-022-04714-x"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/5920\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:49:56Z","timestamp":1760107796000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/5920"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,29]]},"references-count":31,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["ijms25115920"],"URL":"https:\/\/doi.org\/10.3390\/ijms25115920","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,29]]}}}