Multistage pathogenesis and disease associations of Mycobacterium avium subsp. paratuberculosis

Mycobacterium avium subsp. paratuberculosis (MAP) is the primary causative agent of Johne's disease (JD) in ruminants and bears potential public-health implications. Cumulative epidemiological and molecular evidence implies MAP may contribute to Crohn's 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-lysosome 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-particularly the inability of polymerase chain reaction (PCR) to distinguish viable from non-viable organisms-and highlight 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.