Abstract
Molecular underpinning of mycobacteria-induced CNS-pathology is not well understood. In the present study, zebrafish were infected with Mycobacterium fortuitum and the prognosis of CNS-pathogenesis studied. We observed M. fortuitum triggers extensive brain-pathology. Evans blue extravasation demonstrated compromised blood-brain barrier (BBB) integrity. Further, decreased expression in tight-junction (TJ) and adherens junction complex (AJC) genes were noted in infected brain. Wnt-signaling has emerged as a major player in host-mycobacterial immunity but its involvement/role in brain-infection is not well studied. Sustained expression of wnt2, wnt3a, fzd5, lrp5/6 and β-catenin, with concordant decline in degradation complex components axin, gsk3β and β-catenin regulator capn2a were observed. The surge in ifng1 and tnfa expression preceding il10 and il4 suggested cytokine-interplay critical in M. fortuitum-induced brain-pathology. Therefore, we suggest adult zebrafish as a viable model for studying CNS-pathology and using the same, conclude that M. fortuitum infection is associated with repressed TJ-AJC gene expression and compromised BBB permeability. Our results implicate Wnt/β-catenin pathway in M. fortuitum-induced CNS-pathology wherein Th1-type signals facilitate bacterial clearance and Th2-type signals prevent the disease sequel.
Keywords:
CNS-pathology; Cytokines; Mycobacterium fortuitum; Wnt-signaling; Zebrafish.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adherens Junctions / genetics
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Animals
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Axin Protein / metabolism
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Blood-Brain Barrier / metabolism
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Blood-Brain Barrier / microbiology*
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Brain / microbiology
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Brain / pathology*
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Calpain / metabolism
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Cytokines / metabolism*
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Fish Diseases / immunology*
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Fish Diseases / microbiology
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Glycogen Synthase Kinase 3 beta / metabolism
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Interferon-gamma / immunology
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Interleukin-10 / immunology
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Interleukin-4 / immunology
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Low Density Lipoprotein Receptor-Related Protein-5 / metabolism
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Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
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Mycobacterium Infections, Nontuberculous / pathology
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Mycobacterium Infections, Nontuberculous / veterinary
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Mycobacterium fortuitum / immunology*
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Mycobacterium fortuitum / pathogenicity
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Receptors, Cell Surface / metabolism
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Th1 Cells / immunology
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Th2 Cells / immunology
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Tight Junctions / genetics
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Tumor Necrosis Factor-alpha / immunology
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Wnt Proteins / metabolism
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Wnt Signaling Pathway / immunology*
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Wnt3A Protein / metabolism
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Zebrafish / immunology*
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Zebrafish / microbiology
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Zebrafish Proteins / metabolism
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beta Catenin / metabolism
Substances
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Axin Protein
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Cytokines
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Low Density Lipoprotein Receptor-Related Protein-5
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Low Density Lipoprotein Receptor-Related Protein-6
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Receptors, Cell Surface
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Tumor Necrosis Factor-alpha
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Wnt Proteins
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Wnt3A Protein
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Wnt3a protein, zebrafish
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Zebrafish Proteins
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axin2 protein, zebrafish
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beta Catenin
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ctnnb1 protein, zebrafish
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fzd5 protein, zebrafish
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wnt2ba protein, zebrafish
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Interleukin-10
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Interleukin-4
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Interferon-gamma
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Glycogen Synthase Kinase 3 beta
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Calpain