Adherence of Mycobacterium leprae to Schwann cells in vitro

ABSTRACT The ability of microbial pathogens to target specific cell types is a key aspect of the pathogenesis of infectious disease. Mycobacterium leprae, by infecting Schwann cells, contributes to nerve injury in patients with leprosy. Here, we investigated mechanisms of host-pathogen interaction in the peripheral nerve lesions of leprosy. We found that the expression of the C-type lectin, CD209, known to be expressed on tissue macrophages and to mediate the uptake of M. leprae, was present on Schwann cells, colocalizing with the Schwann cell marker, CNPase (2′,3′-cyclic nucleotide 3′-phosphodiesterase), along with the M. leprae antigen PGL-1 in the peripheral nerve biopsy specimens. In vitro, human CD209-positive Schwann cells, both from primary cultures and a long-term line, have a higher binding of M. leprae compared to CD209-negative Schwann cells. Interleukin-4, known to be expressed in skin lesions from multibacillary patients, increased CD209 expression on human Schwann cells and subsequent Schwann cell binding to M. leprae, whereas Th1 cytokines did not induce CD209 expression on these cells. Therefore, the regulated expression of CD209 represents a common mechanism by which Schwann cells and macrophages bind and take up M. leprae, contributing to the pathogenesis of leprosy.

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Structure-Guided Computational Approaches to Unravel Druggable Proteomic Landscape of Mycobacterium leprae

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.663301 ◽

2021 ◽

Vol 8 ◽

Author(s):

Sundeep Chaitanya Vedithi ◽

Sony Malhotra ◽

Marta Acebrón-García-de-Eulate ◽

Modestas Matusevicius ◽

Pedro Henrique Monteiro Torres ◽

...

Keyword(s):

Drug Discovery ◽

Schwann Cells ◽

Protein Structures ◽

Mycobacterium Leprae ◽

Data Bank ◽

Nerve Damage ◽

Structural Proteomics ◽

Bacterial Survival ◽

Functional Sites

Leprosy, caused by Mycobacterium leprae (M. leprae), is treated with a multidrug regimen comprising Dapsone, Rifampicin, and Clofazimine. These drugs exhibit bacteriostatic, bactericidal and anti-inflammatory properties, respectively, and control the dissemination of infection in the host. However, the current treatment is not cost-effective, does not favor patient compliance due to its long duration (12 months) and does not protect against the incumbent nerve damage, which is a severe leprosy complication. The chronic infectious peripheral neuropathy associated with the disease is primarily due to the bacterial components infiltrating the Schwann cells that protect neuronal axons, thereby inducing a demyelinating phenotype. There is a need to discover novel/repurposed drugs that can act as short duration and effective alternatives to the existing treatment regimens, preventing nerve damage and consequent disability associated with the disease. Mycobacterium leprae is an obligate pathogen resulting in experimental intractability to cultivate the bacillus in vitro and limiting drug discovery efforts to repositioning screens in mouse footpad models. The dearth of knowledge related to structural proteomics of M. leprae, coupled with emerging antimicrobial resistance to all the three drugs in the multidrug therapy, poses a need for concerted novel drug discovery efforts. A comprehensive understanding of the proteomic landscape of M. leprae is indispensable to unravel druggable targets that are essential for bacterial survival and predilection of human neuronal Schwann cells. Of the 1,614 protein-coding genes in the genome of M. leprae, only 17 protein structures are available in the Protein Data Bank. In this review, we discussed efforts made to model the proteome of M. leprae using a suite of software for protein modeling that has been developed in the Blundell laboratory. Precise template selection by employing sequence-structure homology recognition software, multi-template modeling of the monomeric models and accurate quality assessment are the hallmarks of the modeling process. Tools that map interfaces and enable building of homo-oligomers are discussed in the context of interface stability. Other software is described to determine the druggable proteome by using information related to the chokepoint analysis of the metabolic pathways, gene essentiality, homology to human proteins, functional sites, druggable pockets and fragment hotspot maps.

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Effects of a derivative of serotonin (deoxyfructoserotonin) and other antileprosy drugs on attachment and uptake of Mycobacterium leprae by Schwann cells in vitro.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.33.6.866 ◽

1989 ◽

Vol 33 (6) ◽

pp. 866-870 ◽

Cited By ~ 1

Author(s):

A Choudhury ◽

N F Mistry ◽

N H Antia

Keyword(s):

Schwann Cells ◽

Mycobacterium Leprae

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Expression of cytotactin in the normal and regenerating neuromuscular system.

The Journal of Cell Biology ◽

10.1083/jcb.108.2.625 ◽

1989 ◽

Vol 108 (2) ◽

pp. 625-635 ◽

Cited By ~ 69

Author(s):

J K Daniloff ◽

K L Crossin ◽

M Pinçon-Raymond ◽

M Murawsky ◽

F Rieger ◽

...

Keyword(s):

Cell Adhesion ◽

Neuromuscular Junction ◽

Schwann Cells ◽

Node Of Ranvier ◽

Myotendinous Junction ◽

Neuromuscular System ◽

Peripheral Nerve Damage ◽

Neural Cell Adhesion ◽

Developing Cerebellum

Cytotactin is an extracellular glycoprotein found in a highly specialized distribution during embryonic development. In the brain, it is synthesized by glia, not neurons. It is involved in neuron-glia adhesion in vitro and affects neuronal migration in the developing cerebellum. In an attempt to extend these observations to the peripheral nervous system, we have examined the distribution and localization of cytotactin in different parts of the normal and regenerating neuromuscular system. In the normal neuromuscular system, cytotactin accumulated at critical sites of cell-cell interactions, specifically at the neuromuscular junction and the myotendinous junction, as well at the node of Ranvier (Rieger, F., J. K. Daniloff, M. Pinçon-Raymond, K. L. Crossin, M. Grumet, and G. M. Edelman. 1986. J. Cell Biol. 103:379-391). At the neuromuscular junction, cytotactin was located in terminal nonmyelinating Schwann cells. Cytotactin was also detected near the insertion points of the muscle fibers to tendinous structures in both the proximal and distal endomysial regions of the myotendinous junctions. This was in striking contrast to staining for the neural cell adhesion molecule, N-CAM, which was accumulated near the extreme ends of the muscle fiber. Peripheral nerve damage resulted in modulation of expression of cytotactin in both nerve and muscle, particularly among the interacting tissues during regeneration and reinnervation. In denervated muscle, cytotactin accumulated in interstitial spaces and near the previous synaptic sites. Cytotactin levels were elevated and remained high along the endoneurial tubes and in the perineurium as long as muscle remained denervated. Reinnervation led to a return to normal levels of cytotactin both in inner surfaces of the nerve fascicles and in the perineurium. In dorsal root ganglia, the processes surrounding ganglionic neurons became intensely stained by anticytotactin antibodies after the nerve was cut, and returned to normal by 30 d after injury. These data suggest that local signals between neurons, glia, and supporting cells may regulate cytotactin expression in the neuromuscular system in a fashion coordinate with other cell adhesion molecules. Moreover, innervation may regulate the relative amount and distribution of cytotactin both in muscle and in Schwann cells.

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Remyelination of Demyelinated CNS Axons by Transplanted Human Schwann Cells: The Deleterious Effect of Contaminating Fibroblasts

Cell Transplantation ◽

10.3727/000000001783986774 ◽

2001 ◽

Vol 10 (3) ◽

pp. 305-315 ◽

Cited By ~ 27

Author(s):

C. M. H. Brierley ◽

A. J. Crang ◽

Y. Iwashita ◽

J. M. Gilson ◽

N. J. Scolding ◽

...

Keyword(s):

Multiple Sclerosis ◽

Schwann Cell ◽

Schwann Cells ◽

Axonal Degeneration ◽

Autologous Transplantation ◽

Growth Factor Receptor ◽

Adult Rats ◽

Demyelinating Lesions ◽

Cell Implantation

Areas of demyelination can be remyelinated by transplanting myelin-forming cells. Schwann cells are the naturally remyelinating cells of the peripheral nervous system and have a number of features that may make them attractive for cell implantation therapies in multiple sclerosis, in which spontaneous but limited Schwann cell remyelination has been well documented. Schwann cells can be expanded in vitro, potentially affording the opportunity of autologous transplantation; and they might also be spared the demyelinating process in multiple sclerosis. Although rat, cat, and monkey Schwann cells have been transplanted into rodent demyelinating lesions, the behavior of transplanted human Schwann cells has not been evaluated. In this study we examined the consequences of injecting human Schwann cells into areas of acute demyelination in the spinal cords of adult rats. We found that transplants containing significant fibroblast contamination resulted in deposition of large amounts of collagen and extensive axonal degeneration. However, Schwann cell preparations that had been purified by positive immunoselection using antibodies to human low-affinity nerve growth factor receptor containing less than 10% fibroblasts were associated with remyelination. This result indicates that fibroblast contamination of human Schwann cells represents a greater problem than would have been appreciated from previous studies.

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Dendritic epidermal gamma/delta T cells (DETC) activated in vivo proliferate in vitro in response to Mycobacterium leprae antigens

International Journal of Dermatology ◽

10.1046/j.1365-4362.2000.00966.x ◽

2000 ◽

Vol 39 (8) ◽

pp. 603-608 ◽

Cited By ~ 5

Author(s):

Marek J. Kaminski ◽

Tomasz F. Mroczkowski ◽

Wojciech A Krotoski

Keyword(s):

T Cells ◽

Mycobacterium Leprae ◽

Gamma Delta T Cells ◽

Gamma Delta

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The neural crest population responding to endothelin-3 in vitro includes multipotent cells

Journal of Cell Science ◽

10.1242/jcs.110.14.1673 ◽

1997 ◽

Vol 110 (14) ◽

pp. 1673-1682 ◽

Cited By ~ 1

Author(s):

J.G. Stone ◽

L.I. Spirling ◽

M.K. Richardson

Keyword(s):

Neural Crest ◽

Schwann Cells ◽

Cell Types ◽

Developmental Potential ◽

Colony Assay ◽

Cellular Targets ◽

Multipotent Cells ◽

Endothelin 3

The peptide endothelin 3 (EDN3) is essential for normal neural crest development in vivo, and is a potent mitogen for quail truncal crest cells in vitro. It is not known which subpopulations of crest cells are targets for this response, although it has been suggested that EDN3 is selective for melanoblasts. In the absence of cell markers for different precursor types in the quail crest, we have characterised EDN3-responsive cell types using in vitro colony assay and clonal analysis. Colonies were analysed for the presence of Schwann cells, melanocytes, adrenergic cells or sensory-like cells. We provide for the first time a description of the temporal pattern of lineage segregation in neural crest cultures. In the absence of exogenous EDN3, crest cells proliferate and then differentiate. Colony assay indicates that in these differentiated cultures few undifferentiated precursors remain and there is a low replating efficiency. By contrast, in the presence of 100 ng/ml EDN3 differentiation is inhibited and most of the cells maintain the ability to give rise to mixed colonies and clones containing neural crest derivatives. A high replating efficiency is maintained. In secondary culture there was a progressive decline in the number of cell types per colony in control medium. This loss of developmental potential was not seen when exogenous EDN3 was present. Cell type analysis suggests two novel cellular targets for EDN3 under these conditions. Contrary to expectations, one is a multipotent precursor whose descendants include melanocytes, adrenergic cells and sensory-like cells; the other can give rise to melanocytes and Schwann cells. Our data do not support previous claims that the action of EDN3 in neural crest culture is selective for cells in the melanocyte lineage.

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In Vitro Evaluation of the Growth and Migration of Schwann Cells on Electrospun Silk Fibroin Nanofibers

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.175-176.220 ◽

2011 ◽

Vol 175-176 ◽

pp. 220-223 ◽

Cited By ~ 2

Author(s):

Ai Jun Hu ◽

Bao Qi Zuo ◽

Feng Zhang ◽

Qing Lan ◽

Huan Xiang Zhang

Keyword(s):

Tissue Engineering ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Schwann Cells ◽

Silk Fibroin ◽

Nerve Tissue ◽

Nerve Tissue Engineering ◽

And Migration ◽

Silk Fibroin Nanofibers

Schwann cells (SCs) are primary structural and functional cells in peripheral nervous system and play a crucial role in peripheral nerve regeneration. Current challenge in peripheral nerve tissue engineering is to produce an implantable scaffold capable of bridging long nerve gaps and assist Scs in directing the growth of regenerating axons in nerve injury recovery. Electrospun silk fibroin nanofibers, fabricated for the cell culture in vitro, can provide such experiment support. Silk fibroin scaffolds (SFS) were fabricated with formic acid (FA), and the average fiber diameter was 305 ± 24 nm. The data from microscopic, immunohistochemical and scanning electron micrograph confirmed that the scaffold was beneficial to the adherence, proliferation and migration of SCs without exerting any significant cytotoxic effects on their phenotype. Thus, providing an experimental foundation accelerated the formation of bands of Bünger to enhance nerve regeneration. 305 nm SFS could be a candidate material for nerve tissue engineering.

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