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This study introduces ImmuDef, a novel algorithm for precisely and quantitatively assessing anti\u2010infection immune defense function based on RNA\u2010seq data. ImmuDef selects immune signatures through comparisons of acquired immunodeficiency syndrome (AIDS) or severe sepsis vs. healthy controls (HC) and reduces dimension to construct a latent space via a variational autoencoder (VAE) model (QImmuDef\u2010VAE), a representation deep learning model. Based on this model, a defense immune score (DImmuScore) was calculated by measuring the distance between a patient and HC within latent space. We validated ImmuDef on 3202 samples across four immune states: immunodeficiency, immunocompromised, immunocompetent, and immunoactive. As a result, DImmuScore achieves high classification accuracy (mean accuracy: 71.75%\u201376.25%) among samples with various immune states and infections. Furthermore, DImmuScore can serve as a metric for infectious disease severity, where its gradient directly quantifies disease severity. As an application, DImmuScore can be a strong prognostic indicator, effectively stratifying mortality\/survival in both sepsis and COVID\u201019 patients with no symptomatic difference. This framework was validated across five infectious diseases, establishing the first quantitative standard for cross\u2010disease immune defense assessment.<\/jats:p>","DOI":"10.1002\/advs.202515929","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T08:47:16Z","timestamp":1768466836000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Deep Representation Learning Method for Quantitative Immune Defense Function Evaluation and Its Clinical Applications"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3406-9003","authenticated-orcid":false,"given":"Zhen\u2010Lin","family":"Tan","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory of Bioinformatics and Molecular\u2010imaging College of Life Science and Technology Huazhong University of Science and Technology  Wuhan Hubei China"},{"name":"Department of Laboratory Medicine West China 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