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      A zebrafish model for ocular tuberculosis

      research-article
      Author(s): 1 , 1 , 2 , *
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      Publication date (Electronic):
      Journal: PLoS ONE
      Publisher: Public Library of Science

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          Abstract

          Ocular tuberculosis (TB) commonly causes severe inflammation and vision loss in TB-endemic countries. The mechanism by which tuberculous infection becomes established in the eye is poorly understood. We have developed the zebrafish larva infected with Mycobacterium marinum as a model to study the early pathogenesis of ocular TB. We find that hematogenous bacterial seeding of the eye occurs despite a functional blood retinal barrier. Prototypical early granulomas form in response to bacteria in the eye. These granulomas involve the retinal vasculature and retinal pigment epithelium-choroid complex which are characteristic locations for human ocular TB. We find that peripheral blood monocytes are recruited to the nascent ocular granuloma further suggesting that the immune privileged nature of the eye is breached by this inflammatory focus.

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          The role of the granuloma in expansion and dissemination of early tuberculous infection.

          J. Muse Davis, Lalita Ramakrishnan (2009)
          Granulomas, organized aggregates of immune cells, form in response to persistent stimuli and are hallmarks of tuberculosis. Tuberculous granulomas have long been considered host-protective structures formed to contain infection. However, work in zebrafish infected with Mycobacterium marinum suggests that granulomas contribute to early bacterial growth. Here we use quantitative intravital microscopy to reveal distinct steps of granuloma formation and assess their consequence for infection. Intracellular mycobacteria use the ESX-1/RD1 virulence locus to induce recruitment of new macrophages to, and their rapid movement within, nascent granulomas. This motility enables multiple arriving macrophages to efficiently find and phagocytose infected macrophages undergoing apoptosis, leading to rapid, iterative expansion of infected macrophages and thereby bacterial numbers. The primary granuloma then seeds secondary granulomas via egress of infected macrophages. Our direct observations provide insight into how pathogenic mycobacteria exploit the granuloma during the innate immune phase for local expansion and systemic dissemination.
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            Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism.

            Kristin N. Adams, Kevin Takaki, Lynn E. Connolly … (2011)
            Treatment of tuberculosis, a complex granulomatous disease, requires long-term multidrug therapy to overcome tolerance, an epigenetic drug resistance that is widely attributed to nonreplicating bacterial subpopulations. Here, we deploy Mycobacterium marinum-infected zebrafish larvae for in vivo characterization of antitubercular drug activity and tolerance. We describe the existence of multidrug-tolerant organisms that arise within days of infection, are enriched in the replicating intracellular population, and are amplified and disseminated by the tuberculous granuloma. Bacterial efflux pumps that are required for intracellular growth mediate this macrophage-induced tolerance. This tolerant population also develops when Mycobacterium tuberculosis infects cultured macrophages, suggesting that it contributes to the burden of drug tolerance in human tuberculosis. Efflux pump inhibitors like verapamil reduce this tolerance. Thus, the addition of this currently approved drug or more specific efflux pump inhibitors to standard antitubercular therapy should shorten the duration of curative treatment. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Zebrafish early macrophages colonize cephalic mesenchyme and developing brain, retina, and epidermis through a M-CSF receptor-dependent invasive process.

              P Herbomel, B Thisse, C Thisse (2001)
              The origin of resident (noninflammatory) macrophages in vertebrate tissues is still poorly understood. In the zebrafish embryo, we recently described a specific lineage of early macrophages that differentiate in the yolk sac before the onset of blood circulation. We now show that these early macrophages spread in the whole cephalic mesenchyme, and from there invade epithelial tissues: epidermis, retina, and brain--especially the optic tectum. In the panther mutant, which lacks a functional fms (M-CSF receptor) gene, early macrophages differentiate and behave apparently normally in the yolk sac, but then fail to invade embryonic tissues. Our video recordings then document for the first time the behavior of macrophages in the invaded tissues, revealing the striking propensity of early macrophages in epidermis and brain to wander restlessly among epithelial cells. This unexpected behavior suggests that tissue macrophages may be constantly "patrolling" for immune and possibly also developmental and trophic surveillance. At 60 h post-fertilization, all macrophages in the brain and retina undergo a specific phenotypic transformation, into "early (amoeboid) microglia": they become more highly endocytic, they down-regulate the L-plastin gene, and abruptly start expressing high levels of apolipoprotein E, a well-known neurotrophic lipid carrier. Copyright 2001 Academic Press.
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                Author and article information

                Contributors
                Kevin Takaki: Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing – review & editing
                Lalita Ramakrishnan: Role: ConceptualizationRole: Funding acquisitionRole: SupervisionRole: Writing – review & editing
                Soumyava Basu:
                ORCID: http://orcid.org/0000-0002-6513-8786
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Olivier Neyrolles: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 27 March 2018
                Publication date Collection: 2018
                Volume: 13
                Issue: 3
                Electronic Location Identifier: e0194982
                Affiliations
                [1 ] Molecular Immunity Unit, Department of Medicine, MRC Laboratory of Molecular Biology, University of Cambridge, Cambridge, United Kingdom
                [2 ] Brien Holden Eye Research Centre, L V Prasad Eye Institute, MTC Campus, Bhubaneswar, India
                Institut de Pharmacologie et de Biologie Structurale, FRANCE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-6513-8786
                Article
                Publisher ID: PONE-D-18-01282
                DOI: 10.1371/journal.pone.0194982
                PMC ID: 5871003
                PubMed ID: 29584775
                SO-VID: e7d5865e-8a8b-4d9e-a355-812813522918
                Copyright © © 2018 Takaki et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 13 January 2018
                Date accepted : 14 March 2018
                Page count
                Figures: 4, Tables: 0, Pages: 8
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001411, Indian Council of Medical Research;
                Award Recipient :
                ORCID: http://orcid.org/0000-0002-6513-8786
                The work was partially funded by Short-term fellowship to Soumyava Basu by Department of Health Research, Indian Council of Medical Research (Reference number: DHR/HRD/Short Term Foreign/ Type-II/1/2015).
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Ophthalmology
                Subject: Eye Diseases
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Eyes
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Eyes
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Eyes
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Eyes
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Immune Cells
                Subject: Granulomas
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: Granulomas
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: Granulomas
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Bacteria
                Subject: Actinobacteria
                Subject: Mycobacterium Tuberculosis
                Subject: Medicine and Health Sciences
                Subject: Infectious Diseases
                Subject: Bacterial Diseases
                Subject: Tuberculosis
                Subject: Medicine and Health Sciences
                Subject: Tropical Diseases
                Subject: Tuberculosis
                Subject: Research and Analysis Methods
                Subject: Experimental Organism Systems
                Subject: Model Organisms
                Subject: Zebrafish
                Subject: Research and Analysis Methods
                Subject: Model Organisms
                Subject: Zebrafish
                Subject: Research and Analysis Methods
                Subject: Experimental Organism Systems
                Subject: Animal Models
                Subject: Zebrafish
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Eukaryota
                Subject: Animals
                Subject: Vertebrates
                Subject: Fish
                Subject: Osteichthyes
                Subject: Zebrafish
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Life Cycles
                Subject: Larvae
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Blood
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Body Fluids
                Subject: Blood
                Custom metadata
                Data Availability All relevant data are within the paper.

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