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Understanding the immune response to Mpox infection is essential for improving disease management and guiding vaccine development. In this study, we used several machine learning algorithms to analyze time series gene expression data from macaques infected with Mpox, aiming to uncover key immune-related genes involved in different stages of infection. The dataset covered early infection, late infection, and rechallenge phases. We applied nine feature ranking methods to analyze the feature importance, obtaining nine feature lists. Then, the incremental feature selection method was applied to each list to extract key genes and build efficient prediction models and classification rules for each list. This procedure employed twelve classification algorithms and the Synthetic Minority Oversampling Technique. Key genes\u2014such as CD19, MS4A1, and TLR10\u2014were repeatedly identified from multiple feature lists, and are known to play vital roles in B-cell activation, antibody production, and innate immunity. Furthermore, we identified several novel key genes (HS3ST1, SPAG16, and MTARC2) that have not been reported previously. These findings offer valuable insights into the host immune response and highlight potential molecular targets for monitoring and intervention in Mpox infections.<\/jats:p>","DOI":"10.3390\/life15071039","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T06:18:36Z","timestamp":1751264316000},"page":"1039","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Unveiling Immune Response Mechanisms in Mpox Infection Through Machine Learning Analysis of Time Series Gene Expression Data"],"prefix":"10.3390","volume":"15","author":[{"given":"Qinglan","family":"Ma","sequence":"first","affiliation":[{"name":"School of Life Sciences, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianchao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3068-1583","authenticated-orcid":false,"given":"Lei","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Information Engineering, Shanghai Maritime University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyan","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Guangdong AIB Polytechnic College, Guangzhou 510507, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusheng","family":"Bao","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Guo","sequence":"additional","affiliation":[{"name":"Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1975-9693","authenticated-orcid":false,"given":"Tao","family":"Huang","sequence":"additional","affiliation":[{"name":"Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China"},{"name":"Department of Artificial Intelligence and Digital Health, CAS Engineering Laboratory for Nutrition, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5664-7979","authenticated-orcid":false,"given":"Yu-Dong","family":"Cai","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,30]]},"reference":[{"key":"ref_1","first-page":"181","article-title":"Mpox global health emergency: Insights into the virus, immune responses, and advancements in vaccines part i: Insights into the virus and immune responses","volume":"42","author":"Prompetchara","year":"2024","journal-title":"Asian Pac. 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