Integrating fish models in tuberculosis vaccine development

Abstract

Tuberculosis is a chronic infection by Mycobacterium tuberculosis that results in over 1.5 million deaths worldwide each year. Currently, there is only one vaccine against tuberculosis, the Bacillus Calmette–Guérin (BCG) vaccine. Despite widespread vaccination programmes, over 10 million new M. tuberculosis infections are diagnosed yearly, with almost half a million cases caused by antibiotic-resistant strains. Novel vaccination strategies concentrate mainly on replacing BCG or boosting its efficacy and depend on animal models that accurately recapitulate the human disease. However, efforts to produce new vaccines against an M. tuberculosis infection have encountered several challenges, including the complexity of M. tuberculosis pathogenesis and limited knowledge of the protective immune responses. The preclinical evaluation of novel tuberculosis vaccine candidates is also hampered by the lack of an appropriate animal model that could accurately predict the protective effect of vaccines in humans. Here, we review the role of zebrafish (Danio rerio) and other fish models in the development of novel vaccines against tuberculosis and discuss how these models complement the more traditional mammalian models of tuberculosis.

Adult zebrafish as advanced models of human disease

“…One bacterial infection that has been extensively studied in zebrafish, including adults, is Mycobacterium marinum, a close genetic relative of the human pathogen Mycobacterium tuberculosis. Using adult zebrafish in infection studies has helped build our understanding of the role of adaptive immune responses to mycobacterial infection (Swaim et al, 2006) and could lead to the development of improved vaccines for tuberculosis (Saralahti et al, 2020). Furthermore, introducing mutations or knockout of key immune signalling molecules to adult zebrafish has dissected the complexity of immune responses to M. marinum infection (Brewer et al, 2022), including more-unique features, such as granuloma formation (Cronan et al, 2021), that are conserved in tuberculosis in humans (Ramakrishnan, 2023).…”

Comparative pathology of experimental pulmonary tuberculosis in animal models

“…In adult zebrafish, initial TB-like granulomas characterised by cellular and bacterial aggregation have been reported at 2 wpc using both high and low infection doses. In advanced stages of the disease (16-20 wpc), mature granulomas are observed, featuring a caseous necrotic core surrounded by infected macrophages, epithelioid cells, neutrophils, infiltrating T and B lymphocytes, and a fibrous capsule (124,129,(132)(133)(134)(135). However, unlike mammalian tuberculous granulomas, zebrafish lesions contain fewer lymphocytes, and the presence of mineralisation has not been reported (124,129,131).…”

Editorial: The Function of Phagocytes in Non-Mammals

“…For example, extracellular chromatin from phagocytes participates in host defenses found in both invertebrates and vertebrates (5). Indeed, the use of zebrafish models has advanced our understanding of phagocyte functions, in human tuberculosis, for example (6). The composition of phagocytes in non-mammals is more diverse.…”