Mycobacterium marinum Immune Evasion in Zebrafish

Abstract

Fish mycobacteriosis, a chronic progressive disease caused by nontuberculous mycobacteria (NTM), affects marine, brackish, and freshwater fish. Mycobacterium marinum (M. marinum), the most important of the NTM, infects fresh and marine water fish causing necrotizing granulomas and associated morbidity and mortality. M. marinum causes disease in zebrafish in a dose-dependent fashion. The M. marinum-induced disease in the zebrafish is associated with the development of necrotizing granulomas with abundant bacteria in the necrotic areas. Acute infection with high infectious doses of M. marinum infection in zebrafish was characterized by uncontrolled replication of the pathogen and death of all fish within 16 days, while chronic infections were marked by the formation of granulomas in different organs and longer survival in the range of 4-8 weeks. This review therefore synthesizes recent advances in our understanding of M. marinum's infection of zebrafish, molecular pathogenesis, virulence mechanisms, and immune evasion strategies in zebrafish, while also highlighting the host immune effector responses and the virulence mechanisms of M. marinum.

Keywords: Mycobacterium marinum; adaptive immune system; granuloma; immune evasion; innate immune system; macrophages; mycobacteriosis; nontuberculous mycobacteria; zebrafish.

Figure 1

Schematic overview of the host–pathogen interface during M. marinum infection in zebrafish. The infection process begins with bacterial entry through various routes, followed by macrophage uptake, mycobacterial dissemination, and subsequent immune evasion mechanisms leading to different outcomes based on the immune status of the zebrafish. ESAT-1 activation and ESAT-6 secretion are important virulence mechanisms that allow M. marinum to escape the potentially growth-inhibitory environment of the subcellular phagosome of the zebrafish macrophage. ESX-1, EsxA, secreted by the ESAT-6 secretion system 1; ESAT-6, early secreted antigenic target 6 kDa. Created in BioRender 201. Kumar, P. (https://BioRender.com/r35ntbc accessed on 21 August 2025).

Figure 2

Key virulence factors of M. marinum and their roles in pathogenesis. M. marinum can evade immune action due to a variety of gene products, which can influence the outcome of infection in zebrafish. The above key virulence factors are listed with their associated roles in pathogenesis and modulation of the zebrafish immune system: ESX-1, EsxA, secreted by the ESAT-6 secretion system 1: EsxA, 6 kDa early secretory antigenic target, known as ESAT-6; CFP-10, 10 kDa culture filtrate protein; PDIMs, Phthiocerol dimycocerosates; Erp, exported repetitive protein; WhiB4, an oxygen-sensing transcriptional regulator in M. marinum; TLR2, Toll-like receptor 2; and CCR2, C-C chemokine receptor type 2. Created in BioRender. Kumar, P. (https://BioRender.com/p3wgb8v accessed on 21 August 2025).