{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:02:57Z","timestamp":1789448577524,"version":"build-2803163510"},"reference-count":123,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005356","name":"Zhejiang Shuren University","doi-asserted-by":"publisher","award":["202501001, 2023R049"],"award-info":[{"award-number":["202501001, 2023R049"]}],"id":[{"id":"10.13039\/501100005356","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    <jats:italic>Mycobacterium avium<\/jats:italic>\n                    subsp.\n                    <jats:italic>paratuberculosis<\/jats:italic>\n                    (MAP) is the primary causative agent of Johne\u2019s disease (JD) in ruminants and bears potential public-health implications. Cumulative epidemiological and molecular evidence implies MAP may contribute to Crohn\u2019s disease (CD), whereas its links to multiple sclerosis (MS), type 1 diabetes mellitus (T1DM), and amyotrophic lateral sclerosis (ALS) remain associative without proven causality. This narrative review synthesizes MAP environmental distribution, strain genotyping, transmission routes, and multistage pathogenic mechanisms. MAP breaches the intestinal barrier via fibronectin attachment protein (FAP)-mediated invasion of microfold cells and establishes intracellular persistence within macrophages. It deploys virulence factors including protein kinase G (PknG) to inhibit phagosome\u2013lysosome fusion, the stringent response regulator RelA for metabolic reprogramming, and the ESX-3 secretion system for iron acquisition, while subverting host immunity through M2 macrophage polarization and interleukin-10 (IL-10)\/interleukin-6 (IL-6)-mediated anti-inflammatory responses, ultimately driving chronic granulomatous inflammation and tissue injury. We also critically assess diagnostic limitations\u2014particularly the inability of polymerase chain reaction (PCR) to distinguish viable from non-viable organisms\u2014and\u00a0highlight major research challenges, including extrapolation of virulence mechanisms from other mycobacterial species. This work provides a theoretical framework for prevention, diagnosis, and targeted intervention of MAP-associated disorders.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1948490","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:26:57Z","timestamp":1789446417000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multistage pathogenesis and disease associations of Mycobacterium avium subsp. paratuberculosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Ruoxi","family":"Tao","sequence":"first","affiliation":[{"name":"Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanying","family":"Zheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Peng","sequence":"additional","affiliation":[{"name":"Hangzhou Cining Hospital","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuojie","family":"Lv","sequence":"additional","affiliation":[{"name":"Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingjing","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1186\/s12864-023-09752-0","article-title":"The pan-genome of Mycobacterium avium subsp. paratuberculosis (Map) confirms ancestral lineage and reveals gene rearrangements within Map type S","volume":"24","author":"Hodgeman","year":"2023","journal-title":"BMC Genomics"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.01691-07","article-title":"Mycobacterium avium subsp. paratuberculosis and M. avium subsp. avium are independently evolved pathogenic clones of a much broader group of M. avium organisms","volume":"190","author":"Turenne","year":"2008","journal-title":"J Bacteriol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.28.7.1591-1596.1990","article-title":"Identification of two groups of Mycobacterium paratuberculosis strains by restriction endonuclease analysis and DNA hybridization","volume":"28","author":"Collins","year":"1990","journal-title":"J Clin Microbiol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.660002","article-title":"Whole-genome analysis of Mycobacterium avium subsp. paratuberculosis IS900 insertions reveals strain type-specific modalities","volume":"12","author":"Conde","year":"2021","journal-title":"Front Microbiol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1186\/s13567-015-0203-2","article-title":"Genetic diversity of Mycobacterium avium subspecies paratuberculosis and the influence of strain type on infection and pathogenesis: A review","volume":"46","author":"Stevenson","year":"2015","journal-title":"Vet Res"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2022.109416","article-title":"Evidence for local and international spread of Mycobacterium avium subspecies paratuberculosis through whole genome sequencing of isolates from the Island of Ireland","volume":"268","author":"Perets","year":"2022","journal-title":"Vet Microbiol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fvets.2021.718987","article-title":"Johne's disease in dairy cattle: An immunogenetic perspective","volume":"8","author":"Mallikarjunappa","year":"2021","journal-title":"Front Vet Sci"},{"key":"B8","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1186\/s12917-019-1943-4","article-title":"Control of paratuberculosis: Who, why and how. 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