Abstract
Tuberculous meningitis (TBM) is one of the most severe extrapulmonary manifestations of tuberculosis, with a high morbidity and mortality. Characteristic pathological features of TBM are Rich foci, i.e. brain- and spinal-cord-specific granulomas formed after hematogenous spread of pulmonary tuberculosis. Little is known about the early pathogenesis of TBM and the role of Rich foci. We have adapted the zebrafish model of Mycobacterium marinum infection (zebrafish–M. marinum model) to study TBM. First, we analyzed whether TBM occurs in adult zebrafish and showed that intraperitoneal infection resulted in granuloma formation in the meninges in 20% of the cases, with occasional brain parenchyma involvement. In zebrafish embryos, bacterial infiltration and clustering of infected phagocytes was observed after infection at three different inoculation sites: parenchyma, hindbrain ventricle and caudal vein. Infection via the bloodstream resulted in the formation of early granulomas in brain tissue in 70% of the cases. In these zebrafish embryos, infiltrates were located in the proximity of blood vessels. Interestingly, no differences were observed when embryos were infected before or after early formation of the blood-brain barrier (BBB), indicating that bacteria are able to cross this barrier with relatively high efficiency. In agreement with this observation, infected zebrafish larvae also showed infiltration of the brain tissue. Upon infection of embryos with an M. marinum ESX-1 mutant, only small clusters and scattered isolated phagocytes with high bacterial loads were present in the brain tissue. In conclusion, our adapted zebrafish–M. marinum infection model for studying granuloma formation in the brain will allow for the detailed analysis of both bacterial and host factors involved in TBM. It will help solve longstanding questions on the role of Rich foci and potentially contribute to the development of better diagnostic tools and therapeutics.
Highlights
They characterized the initial phases of zebrafish infection by using different routes of bacteria inoculation at early developmental stages; in most of the zebrafish embryos both local and systemic injections caused abundant brain infection, with formation of bacterial clusters that were identified as early granulomas
Implications and future directions This study shows that the zebrafish–M. marinum model is suitable for characterization of the early steps in the formation of brain granulomas, their immunological composition and the effect of bacterial virulence factors in the context of Tuberculous meningitis (TBM)
We show that the zebrafish model of M. marinum infection is an accessible and reproducible model to analyze the pathogenesis of early Central nervous system (CNS) granuloma formation and the factors involved in this process
Summary
Central nervous system (CNS) involvement, most commonly leading to tuberculous meningitis (TBM), is the most severe extra-pulmonary complication of TB and accounts for ~1% of all TB cases (Wolzak et al, 2012). Tuberculous meningitis (TBM), involving the central nervous system (CNS), represents the most severe extra-pulmonary complication of tuberculosis (TB). It is caused by infection with Mycobacterium tuberculosis and affects, in particular, children below the age of 5 years. A clear neuropathological feature of TBM is the formation of granulomas (i.e. collections of immune cells) in the brain tissue or meninges These pathological structures are the so-called Rich foci, which form after the spread of pulmonary TB via the bloodstream. It is necessary to improve knowledge of the initial stages of meningitis development, which might contribute to the design of early stage diagnostic tools as well as of novel therapeutic approaches and vaccines
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