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Cell Biology of Intracellular Adaptation of in the Peripheral Nervous System

    Authors: Samuel Hess1, Anura Rambukkana2,3
    VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Medical Research Council (MRC) Centre for Regenerative Medicine; 2: Medical Research Council (MRC) Centre for Regenerative Medicine; 3: Centre for Edinburgh Infectious Diseases, University of Edinburgh, Edinburgh, United Kingdom; 4: Institut Pasteur, Paris, France; 5: Yale University School of Medicine, New Haven, Connecticut; 6: Institut Pasteur, Paris, France
    AUTHOR AND ARTICLE INFORMATION AUTHOR AND ARTICLE INFORMATION
    • Received 19 September 2018 Returned for Modification 29 May 2019 Published 19 July 2019
    • Anura Rambukkana, [email protected]
    • © 2019 American Society for Microbiology. All rights reserved.
  • Anura Rambukkana, [email protected]
  • Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.BAI-0020-2019
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  • Abstract:

    The mammalian nervous system is invaded by a number of intracellular bacterial pathogens which can establish and progress infection in susceptible individuals. Subsequent clinical manifestation is apparent with the impairment of the functional units of the nervous system, i.e., the neurons and the supporting glial cells that produce myelin sheaths around axons and provide trophic support to axons and neurons. Most of these neurotrophic bacteria display unique features, have coevolved with the functional sophistication of the nervous system cells, and have adapted remarkably to manipulate neural cell functions for their own advantage. Understanding how these bacterial pathogens establish intracellular adaptation by hijacking endogenous pathways in the nervous system, initiating myelin damage and axonal degeneration, and interfering with myelin maintenance provides new knowledge not only for developing strategies to combat neurodegenerative conditions induced by these pathogens but also for gaining novel insights into cellular and molecular pathways that regulate nervous system functions. Since the pathways hijacked by bacterial pathogens may also be associated with other neurodegenerative diseases, it is anticipated that detailing the mechanisms of bacterial manipulation of neural systems may shed light on common mechanisms, particularly of early disease events. This chapter details a classic example of neurodegeneration, that caused by , which primarily infects glial cells of the peripheral nervous system (Schwann cells), and how it targets and adapts intracellularly by reprogramming Schwann cells to stem cells/progenitor cells. We also discuss implications of this host cell reprogramming by leprosy bacilli as a model in a wider context.

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/content/journal/microbiolspec/10.1128/microbiolspec.BAI-0020-2019
2019-07-19
2019-08-20

Abstract:

The mammalian nervous system is invaded by a number of intracellular bacterial pathogens which can establish and progress infection in susceptible individuals. Subsequent clinical manifestation is apparent with the impairment of the functional units of the nervous system, i.e., the neurons and the supporting glial cells that produce myelin sheaths around axons and provide trophic support to axons and neurons. Most of these neurotrophic bacteria display unique features, have coevolved with the functional sophistication of the nervous system cells, and have adapted remarkably to manipulate neural cell functions for their own advantage. Understanding how these bacterial pathogens establish intracellular adaptation by hijacking endogenous pathways in the nervous system, initiating myelin damage and axonal degeneration, and interfering with myelin maintenance provides new knowledge not only for developing strategies to combat neurodegenerative conditions induced by these pathogens but also for gaining novel insights into cellular and molecular pathways that regulate nervous system functions. Since the pathways hijacked by bacterial pathogens may also be associated with other neurodegenerative diseases, it is anticipated that detailing the mechanisms of bacterial manipulation of neural systems may shed light on common mechanisms, particularly of early disease events. This chapter details a classic example of neurodegeneration, that caused by , which primarily infects glial cells of the peripheral nervous system (Schwann cells), and how it targets and adapts intracellularly by reprogramming Schwann cells to stem cells/progenitor cells. We also discuss implications of this host cell reprogramming by leprosy bacilli as a model in a wider context.

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Image of FIGURE 1
FIGURE 1

The adult nervous system comprises the PNS and CNS. The CNS is connected to the organs and limbs by the PNS, which also includes a sympathetic and parasympathetic nervous system. Infection of both the PNS and CNS by bacterial pathogens often leads to neurodegenerative diseases. Understanding how such bacterial pathogens target the nervous system and naturally cause disease not only provides insights into combating infectious neurodegenerative diseases but also sheds light on common themes of how neurodegenerative diseases are initiated. Some details of the adult PNS with innervation of skin and muscles are shown; these nerves are usually affected during PNS infections, leading to sensory loss and muscle atrophy, as in leprosy neuropathy.

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.BAI-0020-2019
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Image of FIGURE 2
FIGURE 2

() Functional units of the adult human peripheral nerves, i.e., myelinated and nonmyelinated Schwann cell–axon units, depicting the distinct basal lamina that surrounds each Schwann cell–axon unit . Red arrows indicate the basal lamina (BL) completely surrounding both myelinated (top inset) and nonmyelinated (bottom inset) Schwann cell–axon units. The Schwann cell membrane (M) is shown by black arrows. SC, Schwann cells; Ax, axons; MS, myelin sheath. () Sites of bacterial pathogens’ targets and entry into epithelia and peripheral nerves. Pathogenic bacteria enter epithelia at the apical side of the cells which anchor the basal lamina, whereas neurotrophic bacterial pathogens (e.g., ) must cross the basal lamina barrier, and thus attach to the basal lamina matrix proteins deposited around Schwann cell–axon units. The micrograph (adapted from reference 70 ) shows myelinated Schwann cell–axon units with the basal lamina (BL), Schwann cell membrane (SCM), and the axons ensheathed by the myelin sheath (MS).

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.BAI-0020-2019
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FIGURE 3

Molecular basis of neural tropism of . Interaction of -specific PGL-1 on the bacterial cell wall with the tissue-specific α2LG domain on the basal lamina. () PGL-1 binding to the recombinant G modules of the α2LG domain. OD, optical density. () Subunits of the laminin-2 isoform comprising α, β, and γ chains with the cell-binding α2G domain and its modules α2LG1 to α2LG5. () Composition of PGL-1. () Crystal structure of PGL-1-binding α2LG5 and α2LG4-5 modules of the α2LG domain. () PGL-1 binding (green) to the native α2LG domain (red) on the basal lamina surrounding a myelinated Schwann cell–axon unit (outer surface of nerve fiber is labeled in red to demarcate the α2G domain) colocalized with PGL-1 (green) when cultures were incubated with a PGL-1 suspension.

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.BAI-0020-2019
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FIGURE 4

Schwann cell receptors α/β-dystroglycan and receptor tyrosine kinase ErbB2 serve as receptors for on the Schwann cell membrane (SCM) in an α2LG domain-dependent and -independent manner. () Basal lamina (BL) and cell membrane of myelinated Schwann cells . Their molecular assembly is shown in the schematic (). () infection in an Schwann cell–neuron coculture system, where (blue) associates with α2LG in the basal lamina (red) and ErbB2 on the Schwann cell membrane (green). () Schematic showing the molecular basis of interaction with α2LG, α/β-dystroglycan, and ErbB2 of Schwann cell–axon units in the peripheral nerves and potential activation of kinase domain of ErbB2, which initiate signaling cascades like phosphorylation of the Erk1/2 mitogen-activated protein kinase pathway.

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.BAI-0020-2019
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FIGURE 5

induction of demyelination by direct injection into sciatic nerves of adult Rag-1 knockout mice, suggesting that early demyelination can be caused by the activation of signaling pathways in the absence of immune responses. () Schematic showing the activation of Erk1/2 MAPK signaling pathways by extracellular (a) and intracellular (b) via two different pathways and their role in proliferation and demyelination. binds to the ErbB2 receptor to induce Schwann cell demyelination and proliferation. (a) The binding of (ML) to ErbB2 on the surface of myelinated Schwann cells triggers demyelination through the Ras-Raf-MEK-ERK pathway. ErbB2 inhibitors such as herceptin, PKI166, and U0126 block activation of this pathway in response to . (b) Intracellular induces proliferation of nonmyelinated Schwann cells through a different route to ERK that involves PKCε and Lck and that is independent of signaling through the Ras-Raf-MEK pathway. ( and ) Direct injection of into sciatic nerves of Rag knockout mice induces demyelination (), in contrast to injection of phosphate-buffered saline alone, which shows almost intact myelinated Schwann cell–axon units ().

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.BAI-0020-2019
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FIGURE 6

Proposed model of how adult Schwann cell reprogramming to stem cell-like cells by intracellular promotes dissemination of infection. () Infected Schwann cells in the adult peripheral nerves undergo a reprogramming process whereby Schwann cell differentiation and myelination program-associated genes are turned off and embryonic genes of mesenchymal and neural crest development are turned on. The resulting pSLC acquire migratory properties and immunomodulatory characteristics and thus release immune factors, chemokines, cytokines, and growth and remodeling factors, which not only increase the permeability of the BNB but also recruit macrophages. () Acquired migratory properties promote -laden pSLC to exit by breaching the BNB and disseminate to other preferred tissue niches, such as smooth muscles and skeletal muscles, where they are exposed to respective tissue microenvironments and undergo direct differentiation and thus transfer bacteria passively to these tissues. () By recruiting macrophages, pSLC can transfer and form typical granuloma-like structures, which then release bacterium-laden macrophages, a mechanism by which reprogrammed cells may channel bacterial dissemination via systemic routes. DAPI, 4′,6-diamidino-2-phenylindole; GFP, green fluorescent protein-tagged pSLC; AF, acid-fast labeling of .

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.BAI-0020-2019
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