The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies

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www.elsevierhealth.com/journals/jinf

REVIEW

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The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies J.W. Neal a,*, P. Gasque b a

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Infection and Immunity, Henry Wellcome Building, Cardiff University, Cardiff CF14 4XN, United Kingdom b Laboratoire d’Immunologie Clinique et Expe´rimentale de l’OI (LICE-OI), Centre recherche Immunoclinique des agents pathoge
nes de l’OI (CRIC-AP OI) Po^le Biologie Sante´, Ho^pital Fe´lix Guyon, CHU de la Re´union, Reunion Accepted 11 August 2016 Available online - - -

KEYWORDS Schwann cell; Peripheral neuropathy; Pathogens; Stem cell

Summary Numerous different pathogens are responsible for infective peripheral neuropathies and this is generally the result of the indirect effects of pathogen infection, namely anti pathogen antibodies cross reacting with epitopes on peripheral nerve, auto reactive T cells attacking myelin, circulating immune complexes and complement fixation. Primary infection of Schwann cells (SC) associated with peripheral nerve inflammation is rare requiring pathogens to cross the Blood Peripheral Nerve Barrier (BPNB) evade anti-pathogen innate immune pathways and invade the SC. Spirochetes Borrelia bourgdorferi and Trepomema pallidum are highly invasive, express surface lipo proteins, but despite this SC are rarely infected. However, Trypanosoma cruzi (Chaga’s disease) and Mycobacterium leprae. Leprosy are two important causes of peripheral nerve infection and both demonstrate primary infection of SC. This is due to two novel strategies; T. cruzi express a trans-silalidase that mimics host neurotrophic factors and infects SC via tyrosine kinase receptors. M. leprae demonstrates multi receptor SC tropism and subsequent infection promotes nuclear reprogramming and dedifferentiation of host SC into progenitor stem like cells (pSLC) that are vulnerable to M. leprae infection. These two novel pathogen evasion strategies, involving stem cells and receptor mimicry, provide potential therapeutic targets relevant to the prevention of peripheral nerve inflammation by inhibiting primary SC infection. ª 2016 Published by Elsevier Ltd on behalf of The British Infection Association.

* Corresponding author. E-mail addresses: [email protected] (J.W. Neal), [email protected], [email protected] (P. Gasque). http://dx.doi.org/10.1016/j.jinf.2016.08.006 0163-4453/ª 2016 Published by Elsevier Ltd on behalf of The British Infection Association. Please cite this article in press as: Neal JW, Gasque P, The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.08.006

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Introduction Peripheral inflammatory neuropathy due to virus, bacterial, protozoa, parasites and spirochete infections are one of the most important global cause of potentially treatable neurological illness and disability.1,2 The Schwann cell (SC) contributes an effective inflammatory anti pathogen response to combat infection by viruses and highly invasive spirochetes. By contrast, two obligate intracellular pathogens the protozoan Trypanosoma cruzi and Mycobacterium leprae are able to infect SC with persistent Peripheral nerve (PN) inflammation.123 The pathways SC against pathogens and the invasive pathways underlying the vulnerability of SC are reviewed and are potentially important therapeutic targets; the pathogens and clinical examples of PN inflammation discussed in this review are given in Table 1. The majority of systemic pathogens associated with peripheral nerve (PN) inflammation do not primarily infect SC or other cellular components of peripheral nerve. Therefore, PN inflammation due to systemic pathogens results from the indirect effects of pathogen infection on PN and include the formation of anti-pathogen antibodies forming immune complexes, these cross from the systemic circulation into the nerve resulting in demyelination and axonal injury.3,4 Molecular mimicry is a proposed mechanism that triggers peripheral nerve inflammation after systemic infection and vaccination with several pathogens (Campylobacter jejuni, Epstein Bar and Cytomegalo viruses).4e9 and relies upon the structural similarity between microbial antigens and host tissues. The T cells and complement fixing antibodies generated against the pathogen cross react with antigen located on the axon and SC producing macrophage and T cell infiltration into the nerve with an axonal motor and demyelinating neuropathy known as Guillian Barre syndrome (GBS).5e9 On this basis Peripheral nerve (PN) inflammation in the context of infection is generally considered to be the result of indirect (secondary) effects of the pathogen activating cellular constituents of PN (Schwann cells fibroblasts, macrophages).10 Pivotal to this response is the SC because it provides an important component of the adaptive and innate immune response directed against invading pathogens.10,11 Viral infection of SC has been described in vitro but clinical examples in non-immune suppressed cases are rare, this relates in part to the effective barrier between the SC and systemic circulation (the BNPB) and the range of PRR capable of detecting virus and initiating an effective anti virus response.11e13 Similarly, Trepomema pallidum (Syphilis) Borrelia burgdorferi (Lyme disease) are associated with peripheral neuropathies but the SC produces an effective anti spirochete response and this prevents intracellular infection.13e15 Despite an anti pathogen inflammatory response by SC T. cruzi (Chaga’s disease) is capable of invading the SC and stimulating chronic inflammation and injury to the Autonomic nervous system (ANS).16e18 The same is true for PN Leprosy M. leprae with extensive intracellular SC infection and chronic destructive inflammation, despite a significant innate and adaptive immune response.19e22 Schwann cells are especially vulnerable to M. leprae infection and this pathogen also disseminates throughout the PNS and other tissues.22 The conventional view that

J.W. Neal, P. Gasque SC has a limited response to pathogen attack and restricted to an inflammatory response has been revised in view of recent in vitro evidence demonstrating a novel interaction between M. leprae and SC based upon pathogen initiated nuclear reprogramming.23,24 This data has provided new insights into the contribution of the SC in the aetiology of peripheral nerve inflammation following infection and this takes into account the functional properties of SC especially the capacity for proliferation during PN repair following injury.25 Although the treatment of peripheral nerve inflammation due to pathogens relies upon antibiotics and anti inflammatory agents.26 The identification of a novel pathogeneSC interaction24 associated with peripheral nerve inflammation could provide new and important therapeutic targets.

Schwann cell structure and function; the blood peripheral nerve barrier (BPNB) endoneurium and immune privileged space The perineurium a connective tissue layer surrounds the compartment (endoneurium) containing the SC and axons and this presents a physical barrier to systemic pathogen invasion (see Fig. 1).19,27 It is composed of flat cells interconnected by tight junction complexes (TJ) containing the structural proteins claudins (1, 3, 3-3), occludins and Zo1.28e31 Capillaries penetrate the perineurium and are distributed in the endoneurium; they are composed of non-fenestrated sheets of endothelial cells with an occasional pericyte contributing to the BPNB.28 The individual endothelial cells are interconnected by tight junctions (TJ) to form a non-fenestrated and non-permeable barrier and this is analogous to the blood brain barrier (BBB) surrounding the CNS.12,28 The endoneurium contains SC, mast cells, macrophages and fibroblasts all capable of expressing a range of trophic factors32 important for axonal regeneration and SC plasticity/proliferation, together with several signalling pathways to support axonal repair and remyelination.33e35

Schwann cell inherent plasticity is essential for myelination and provides a vulnerable cell population for infection Schwann cells are derived from the embryonic neural crest day 19 in utero (Fig. 1). After birth the SC retain their inherent plasticity and differentiate into non-myelinating and myelinating populations controlled by signalling pathways between axon and SC.25,27 Schwann cell differentiation into mature myelinating cells is pivotal for remyelination and this is under the control of several transcription factors including Sox 10 (found in early development and glial cell development).25,33e35 Intra cellular SC pathogen infection will potentially disrupt these pathways preventing SC differentiating into cells capable of supporting re myelination and axon repair; this is an important factor in the relationship between SC and intracellular infection.

Please cite this article in press as: Neal JW, Gasque P, The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.08.006

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Table 1 Summary of the main clinical and neurological findings in the peripheral and autonomic systems as the result of infection due to the pathogens described in this review.1e9,14e17,19e23,129,138 Pathogen Bacteria Campylobacter jejuni

Mycobacterium tuberculosis Mycobacterium leprae

Spirochete Borrelia burgdorferi

Treponema pallidum

Virus Human immune deficiency virus (Retrovirus RNA)

Herpes simplex 1 and 2, (dsDNA) Herpes Zoster or VaricellaeZoster virus VZV (dsDNA)

Clinical presentation

Peripheral nervous system involvement

GI tract infection Associated with Guillian Barre Syndrome (GBS) triggered by anti-ganglioside antibodies. Upper respiratory tract infection; weight loss Painless skin patch with loss of sensation in tuberculoid but preservation in lepromatous leprosy, muscle wasting, skin ulceration. Later eye involvement. Wide tissue dissemination

Acute inflammatory demyelinating polyneuropathy

Mononeuritis Mononeuritis multiplex Distal symmetrical polyneuropathy Isolated cranial neuropathy Late onset neuropathy Autonomic neuropathy

Lyme disease infected bite from tic of Ioxdus genus Skin lesions flu-like illness joint pains late dissemination associated with PNS involvement Primary Syphilis, lesion painless chancre 3e6 weeks heals; secondary syphilis 3e8 weeks systemic involvement; tertiary syphilis neurological involvement.

Early cranial nerve radiculopathy Mono neuritis multiplex Late radicular pain with axonal neuropathy (Bannawarth) Cranial nerve involvement Cranial nerve involvement due to gumma

Flu-like symptoms, enlarged tender lymph nodes, maculopapular rash Occasional GBS

Acute inflammatory demyelinating polyneuropathy Mono neuritis Cranial nerve Sacral radiculitis, urinary retention

HSV 2 dormant in sacral root ganglia until reactivation. Child hood infection (Chicken pox) pneumonia with occasional GBS; adult infection (Shingles) due to reactivation in elderly and immune suppressed.

Cytomegalovirus (dsDNA) Human herpes virus -5

Glandular fever symptoms Can be associated with GBS Immuno suppressed individuals

Epstein Barr virus (dsDNA) Human herpes-4

Glandular fever symptoms Can be associated with GBS

Hepatitis C (RNA Flavivirus)

Liver involvement; Cryoglobulinaemia vasculitis One percent of infected cases have neuro invasive symptoms and of these three percent have acute flaccid paralysis of upper and lower limbs.

West Nile Fever (RNA Flavivirus)

Cranial nerve involvement

Acute inflammatory demyelinating polyneuropathy Cranial nerve neuropathy (Ramsay Hunt V III nerves) Postherpetic neuralgia in dermatomal distribution, shingles Acute inflammatory demyelinating polyneuropathy Distal peripheral neuropathy Mononeuritis Acute inflammatory demyelinating polyneuropathy Myeloradiculitis Axonal sensory neuropathy Motor nerve paralysis Demyelinating poly neuropathy

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Please cite this article in press as: Neal JW, Gasque P, The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.08.006

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J.W. Neal, P. Gasque Table 1 (continued ) Pathogen Protozoa Trypanosoma cruzi (parasitic euglenoid protozoan)

Clinical presentation

Peripheral nervous system involvement

Triatomine bugs (Triatoma infestans) bite skin, trypomastigote (blood stage) invades phagocytes at site of entry. Full life cycle with subsequent heart and GI tract involvement; cardiomyopathy, arrhythmias Chagas disease. Thromboembolism

Autonomic nervous system demyelination and inflammation in Myocardium and GI tract.

Schwann cells express an innate immune inflammatory response to pathogens Pathogen stimulated SC express an innate inflammatory response, composed of inflammatory cytokines IL-1b, IL1a, IL-6 and the anti-inflammatory cytokines TGFb and IL10, together with the classical complement pathway (CP) activation proteins C1q, opsonins C3 and iC3b, macrophage chemo attractants (C3a, C5a) and terminal pathway C5b-C9 generation.36e38 In vitro SC express functionally activate

Peripheral nerve (normal structure )

MHC class I and II molecules on exposure to IFN g and Il1Lb39,40 and a constituent of bacterial cell wall, Lipopolysaccharide (LPS), stimulates SC TNF a expression and contributes to PN injury.40 Similarly, pathogen stimulation of SC activated MHC expression and the presentation of antigens to infiltrating systemic T cells (CD8þ and CD4þ) providing a link between the innate and adaptive immune systems.39 Fig. 2 shows the typical histological changes accompanying peripheral nerve inflammation including widespread lymphocyte and HLA-DR immune positive staining cells with evidence of demyelination.

Peripheral nerve with inflammaƟon and pathogen invasion

Epineurium surrounds fasicle

Blood vessel

Pathogens and macrophages cross the peripheral blood barrier BPNB into endoneurium Sc express inflammatory cytokines and chemoaƩractants. Macrophage crossing PNB to accesses endoneurium

Blood vessel

Capillary site of PNB Lymphocyte crossing PNB

Perineurium

Schwann cell

Endoneurium Unmyelinated axon Fibroblast

Neutrophil

Myelinated axon

Schwann cell express PRR and inflammatory cytokine expression

Pathogen Bacteria Virus Spirochete crossing PNB to accesses endoneurium

Figure 1 A schematic diagram showing the basic cellular components of the peripheral nerve in transverse section. The healthy immune privileged peripheral nerve is composed of individual fascicles surrounded by the epineurium. The perineurium surrounds the endoneurium this compartment contains Schwann cells surrounding myelinated axons occasional macrophages and fibroblasts; blood supply to the endoneurium is through capillaries and they contribute to the blood peripheral nerve barrier (BPNB) between the capillary wall and endoneurial space. Inflammation of a peripheral nerve due to pathogens (Bacteria, Viruses (DNA/RNA), protozoans) gaining access to the endoneurium. This is accompanied by B cells (BL) B lymphocytes, T lymphocytes and T regulatory cells Tregs with polymorphonuclear neutrophils PMN. All these cells enter the endoneurium through the BPNB and activate the SC with expression of inflammatory cytokines and complement activation. Please cite this article in press as: Neal JW, Gasque P, The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.08.006

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Primary infection of Schwann cells

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Figure 2 Histological appearance of an inflamed peripheral nerve. The individual was investigated for inflammatory peripheral nerve neuropathy with a possible underlying infective aetiology. In this case a pathogen was not identified despite extensive serum and tissue based investigations Peripheral nerve shows widespread lymphocyte infiltration mainly CD3 T cell and loss of myelin staining from individual axons. Peripheral nerve biopsy of sural nerve found histological evidence of inflammation (1) transverse section of peripheral nerve stained with Haematoxylin & Eosin showing infiltration of the perineurium and endoneurium with lymphocytes (2) shows a high power images with dense filtration of lymphocytes some in a perivascular distribution (3) transverse section showing widespread infiltration with immunohistochemical staining showing HLA-DRþ cells throughout the endoneurium (4) shows a longitudinal section of peripheral nerve stained with Kultschisky stain for myelin (black) arrow indicates absence of staining corresponding to loss of myelin from axons (5) shows the same nerve stained with Kultschisky in transverse section arrow shows loss of myelin staining (6) transverse section of peripheral nerve immunohistochemical staining shows widespread CD3 pan T cell marker throughout the endoneurium. Scale marker.

Schwann cell innate immune response during peripheral nerve injury; defence and repair in vivo The SC is pivotal to the early innate immune response to traumatic PN injury37 and these change are relevant to the early PN response to pathogen infection; whether or not the early event during PN injury are applicable to chronic inflammation due to pathogens remains to be determined. The first histological changes appear within 24e36 h of traumatic injury with SC proliferation axonal swelling and fragmentation, followed by myelin degradation and clearance by both SC and systemic macrophages peaking at day 7.19 This process is essential for axon repair and reduction in local inflammation and is regulated by SC expression of inflammatory cytokines and chemo attractants.37,38 Schwann cell in injured PN express inflammatory cytokines IL-1b, IL-1a and, TNFa and this stimulates fibroblasts to release IL-6 GMCSF and leukaemia inhibitory factor LIF very soon after injury.37 Following this the same inflammatory cytokines stimulate SC to express systemic macrophage chemo attractants, chemo attractant protein-1 (CCL2) and macrophages inflammatory protein 1a (MIP-a known as CCL3) to promote systemic macrophage infiltration across

endothelium (BPNB) into the endoneurim in addition to resident macrophage proliferation.41 Schwann cell also express inflammatory cytokines IL-1b, IL-1a and TNFa by signalling through TLR2 receptors activated by cell wall constituents of pathogens.13,42,43 Interestingly, the macrophage population is M2 phenotype (involved with repair) following sterile injury, but this was not found after LPS injection simulating pathogen invasion.44 Schwann cell, endothelial cells and fibroblasts express CP (membrane attack complex C5eC9) contributing to myelin and axon degeneration.45 degenerating myelin and pathogens are opsonised with iC3b and this facilitates phagocytosis by CR3þ macrophages.37 Furthermore, SC also expresses a wide range of IgG receptors (FcR) capable of phagocytosing opsonised pathogens.46 This is essential for the effective clearance of pathogens to prevent uncontrolled CP activation with bystander nerve injury and inhibition of axon repair.37,47,48 Schwann cell and fibroblasts stimulated by inflammatory cytokines also up regulate trophic molecule expression vital for remyelination and axon repair this includes Nerve growth factor, Brain derived neurotrophic factor, ciliary neurotrophic factor, fibroblast growth factor and leukaemia inhibitory factor (LIF).32,49

Please cite this article in press as: Neal JW, Gasque P, The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.08.006

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Schwann cell infection; clues from pathogens crossing the blood brain barrier (BBB) In vitro models using micro vascular and endothelial cells have proved important clues regarding the pathways involved in pathogen transport across the PNB.12 Relevant information concerning the structure of the BPNB can be extrapolated from different cell lines prepared from individual components of the BBB and infected with pathogens.50 In vitro infected with a range of RNA Flaviviruses demonstrate an increased lysosomal degradation of endothelial cell claudins disrupting the TJ and facilitating virus transport across the BBB.31,50e52 Virus entry into the host cell is a multi step process involving an interaction between claudin-1, -6, -9 and a family of adhesion molecules such as the tetraspanins (CD 63, CD81) all expressed by SC, epithelial cells, fibroblast and endothelial cells.50,52e54 The tetraspanins (CD63, CD81) are adhesion molecules are important for SC extension along axons although they are not vital for myelination; they facilitate SC interaction with the extracellular matrix.53 Putative factors facilitating virus attachment and subsequent entry into a wide range of cells include surface molecules such as glycoamino glycans, Heparan sulphate and heat shock proteins are expressed by a wide range of mammalian cell types.54e56 Despite the capacity in vitro for viruses to cross the BBB the incidence of CNS infection after systemic virus infection in vivo is low suggesting the BBB is an efficient anti virus barrier.50

Pathogens and inflammatory cells cross the endothelial layer within the BPNB Systemic pathogens gain accesses to the endoneurium as demonstrated for neutrophils infected by West Nile Fever virus (so called Trojan horse route) by stimulating SC and endothelial (MMP) production with disruption of the BBB.57,58 In vitro models of human bloodenerve barrier have been discussed at length elsewhere12 and they involve endothelial expression of adhesion molecules (integrins and ICAM), proinflammatory cytokines and T-helper and T-helper 17, all are capable of modulating leucocyte trafficking across the BPNB as for example in GBS.12 This process is increased by pathogen activation of SC with expression of TNFg and IFNa58 promoting CD8þ T cells, CD45þ lymphocytes and CD11þ cells trafficking across the endothelial barrier into the endoneurium.60

Schwann cells express a range of pattern recognition receptors an effective system to detect infiltrating pathogens Unique pathogen associated molecular patterns (PAMPS) are detected by highly conserved pattern recognition receptors (PRR) located on SC plasma membrane and endoplasmic reticulum13,61 such as the Toll like receptors (TLR 2, 4, 6, 7) and the C lectins, DC-SIGN and MMR distributed on cell surface.61 An additional group of pathogen receptors include structural proteins (laminin and dystroglycan) and trophic molecule receptors (Tyrosine receptor kinase TRkc) localized on host cells (SC, endothelial

J.W. Neal, P. Gasque cells, fibroblasts and myoblasts) (see Table 1).61e85 Once internalized “non self” pathogen nucleic acids and other PAMPs (in the case of M. leprae Phenolic glycolipid-162 activate PRR linked intracellular signalling and transcription pathways with the expression of anti-pathogen inflammatory cytokines and anti-virus proteins.13,61 (see Table 2). Bacterial infection of SC is well described for example mannose receptor (MMR) related internalization of Streptococcus pneumonia.64 However M. leprae demonstrates tropism for SC and this contributes to the high intracellular pathogen load contributing to nerve inflammation. The basis for M. leprae tropism is multi-step process with M. leprae binding to different structural proteins within the basal laminae of the SC each functioning as M. leprae entry receptors.63,84

Virus infection of host cells results in expression of host inflammatory cytokines anti virus response and anti-virus proteins The consequences of virus infection of host cells are well described.86 Briefly, the host cell such as SC detects viral PAMPS (surface proteins and viral nucleic acids) through PRR. For example, Toll Like Receptors (TLR) are located within endosomes and they detect virus nucleic acid and this initiates several intracellular signalling pathways with activation of transcription factors NF-kB and MyD 88 regulating synthesis of IFNg, IFNa/b, interleukins and TNF a.61 An anti-virus protective response by the host (type 1IFN) involves IFNa/b binding to IFN surface receptors on adjacent cells with activation of Janus kinases and phosphorylation of transcription factors STAT1 and STAT2. These two factors drive host genes expressing interferon stimulated genes and the synthesis of anti-virus proteins, 2e5 oligoadenylate synthetase (OAS), dsRNA dependent kinase (PKR) RNA deaminases ADAR1 to block virus related transcription and virus replication.85 Virus replication is blocked by initiation of host cell apoptosis, following inflammatory cytokine (TNF family) stimulation of the extrinsic pathway.86

Primary infection of Schwann cells by viruses is responsible for a limited range of infective peripheral inflammatory neuropathies Table 3 presents the findings of an extensive literature search for examples of primary intracellular SC infection with viruses commonly associated with PN inflammation. A common cause of distal peripheral neuropathy is the Human immunodeficiency virus (HIV)1e3 it is not clear if this represents either intracellular infection or activation of SC with expression of inflammatory cytokines.87,88 Primary infection of SC by HIV is not regarded as essential for PN inflammation because HIV gp120 protein binds to a chemokine receptor, CXCR4, expressed by SC, and this releases inflammatory cytokines RANTES and TNFa, both stimulate axons and neurons to release TNFR-1 with subsequent axon and myelin injury.88 Conversely, SC adjacent to the axon have a protective role because they release erythropoietin providing neuro protection to counter the effect of inflammatory cytokines.88

Please cite this article in press as: Neal JW, Gasque P, The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.08.006

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Primary infection of Schwann cells 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

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Table 2 The table shows the potential pathogen entry receptors related to Schwann cell and peripheral nerve (PNS) involved with neuroinfection. The PNS contains Schwann cells (SC) together with fibroblasts, perivascular and endothelial cells, these also express receptors. The blood peripheral nerve barrier (BPNB) components include endothelial and perivascular cells also express FcR receptors. The function of the potential virus entry receptors is given together with the putative ligand associated with the individual pathogens. Potential pathogen entry receptor on SC

PNS cell expressing entry receptors

Pathogen receptor function

Pathogens detected

Mannose Membrane Receptor (CD206) C-Type lectin64e66

Perivascular macrophages Schwann cell64 Endothelial cell65

DV E protein66 Influenza virus68

DC-SIGN (CD209) Dendritic cells specific intercellular-3 grabbing non integrin. C-Type lectin67,69

Schwann cell67 Perivascular macrophages69 Endothelial cells70

Toll like receptors (TLR) TRL-1/2 heterodimer55 TLR-255 TRL-3 TLR-4 TRL-7

Schwann cell58 Schwann cell

Mannose carbohydrates (PAMPs) on viruses endocytosed and processed for antigen presentation67 Mannose complex internal branched glycoproteins on virus endocytosed for antigen processing Mycobacterium Leprae mannose capped lipoarabinomannan67 Bacterial and Spirochete lipoprotein in conjunction with CD1474,79 Detects dsRNA76 Detect ssRNA to initiate anti virus response and inflammatory cytokines77 Detects pathogens opsonised with IgG, IgM38,76

FcR76,80

Dystroglycan63

Neurotrophin receptor TrkC

43

Schwann cell Schwann cell TLRs also present on peripheral nerve macrophages13 Schwann cell38

Surface of Schwann cell-axon Schwann cell basal lamina Schwann cells , neurons epithelial cells (17 )

Laminin-a2 e M. leprae complex binds to a, b62 Dystroglycan (PGL-1)63 Binds to parasite derived neurtrophic factor a trans sialidase (PDNF)

Herpes Simplex virus (HSV) and Herpes Zoster Virus/ Varicella Zoster Virus (HSV/VZV) experimentally have been shown to infect SC in vitro, but again the clinical importance of this for primary SC infection is not clear.89e91 Experimental studies with intra peritoneal and intranasal injection of HSV into mice found the virus had infected Schwann cells, but not involved the adjacent axons.89e94 whereas in vitro infection of rat dorsal ganglion and SC cells also found HSV particles within SC.92 More recently using in situ hybridization and transcription analysis of dorsal root ganglia neurons and SC are infected and express Class I MHC following subcutaneous inoculation of mice with HSV. Injection of HSV into whisker region of mice resulted in perineural nerve cell uptake of the virus using TLR.94 Whereas HSV has a direct route into the CNS after injection into the cornea.95,96 For VZV an occasional in vitro report, together with of

Complex carbohydrates on WNF, HIV, JEV, Ebola virus70e73 Mycobacterium Leprae67

Mycobacterium Leprae lipoproteins42,43 Borrelia burgdorferi TrP in vitro74,75,78,79 WNF entry across BBB77 TLR2 lipoproteins from ML43 WNF77

Borrelia burgdorferi in vitro81,82 Possible T. Pallidum in vitro76,80 Mycobacteria Leprae83 Mycobacterium Leprae63 Lassa fever virus85

Trypanosoma cruzi (17 )

autopsy cases have identified VZV within SC,98,99 but it was not clear if peripheral nerve inflammation was associated with this virus.96e100 As outlined in Table 3 both DNA and RNA viruses are responsible for SC intracellular infection but not associated consistently with PN inflammation.101e113 An exception is the apparent tropism for SC by the RNA virus Lassa Fever/ LCH, this is based upon this virus binding to SC surface molecule dystroglycan,85 the same receptor that binds to M. leprae facilitating its entry into SC.63 However, unlike M. leprae, sensory neural deafness, but not peripheral inflammatory neuropathy, has been reported with Lassa fever virus infection. This is an interesting exception, because although the same entry receptor, dystroglycan is responsible for Lasa/LCH entry,63,85 unlike M. leprae, the Lasa/ LCH virus is associated with intracellular infection nor peripheral nerve inflammation.85

Please cite this article in press as: Neal JW, Gasque P, The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.08.006

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Virus

Host

Schwann cell infection in vitro

Schwann cell infection human and non human in vivo

Virus receptors

Human Immunodeficiency Virus Retrovirus RNA Herpes simplex HSV I and HSV2 dsDNA

Human

Not found

Not primary infected but express CXCR4 a receptor for HIV gp12087,88

CXCR87,88 DC-SIGN63,64

Human

DRG cellsþ for HSV in neuritis model89e92

Heparan sulphates on surface proteoglycans, a member of the TNF family and Ig immunoglobulins95

Herpes Zoster ds DNA

Human

Fetal SC culture infected with VZV94

Cytomegalovirus DNA Human polyomavirus (JC) DNA Flavivirus ssRNA WNF JEV RNA Canine distemper Paramyxovirus ssRNA Influenza A ssRNA Nipah virus Paramyxovirus ssRNA Theiler’s Picornavirus ssRNA Borna RNA Bornaviridae Lassa fever/ Lymphocytic choriomeningitis Arenaviridae ssRNA

Human

Not described

SC after whisker region HSV injection n rodents93 Axonal transport from cornea into Trigeminal ganglia with SC94 VZV Cowdry A inclusions in SC endothelial cells from AIDS98 cases VZV encephalitis SC were positive99 V nerve nuclei HZV97 CMV inclusions in Schwann cells101

Human

Human fetal brain JCV T antigen only in Schwann cells102 WNF infects Sc MHC II in vitro103

Not described

Not described in Schwann cells

WNF infects SC104 birds

TLRs, DC-SIGN

Dogs

Present in Olfactory ensheathing cells in vitro105

No evidence for SC infection in canine CNS

Nectin 4 on neurons and epithelial cells106

Humans

No evidence for SC infection

TLR3,7,9

Bat

Present in SC cultured with Influenza A107 Not described

Present in Pig Schwann cells and systemic organs108

Ephrin receptors

Mouse

Replication in SC in vitro109,110

Not described

P0 myelin glycoprotein111

Sheep, Horses, Cattle, Humans

SC in vitro112

Astrocytes and Schwann cells112,113

Not described

Humans, Rodents

SC infection due to a dystroglycan on surface; disrupts dystroglycan laminin-2 interaction preventing myelination85

Not described

a dystroglycan on SC85

Mosquito

Insulin degrading receptor100

DC SIGN

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J.W. Neal, P. Gasque

Please cite this article in press as: Neal JW, Gasque P, The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.08.006

Table 3 Table shows data from a search of the literature regarding DNA and RNA viruses and their association with primary Schwann cell infection. Evidence for in vivo and in vitro studies involving Schwann cells are given together with the putative host entry receptor for the same virus.

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Primary infection of Schwann cells 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

Primary infection of Schwann cells by spirochetes a limited contribution to Peripheral inflammatory neuropathy Spirochete infection of PN is rarely described, although both syphilis T. pallidum and Borrelia burgdorferi (Lyme disease) are both associated with PN inflammation and occasionally neuropathy.1e3 Both spirochetes share the capacity to infiltrate connective tissues and cross endothelial cell barriers, from the systemic circulation into peri vascular space and endoneurium using a flagellum.13,14,80,115,116 Although inflammation of PN is rare, cranial nerve inflammation has been recorded in early primary syphilitic infection of which 25e60% have accompanying CNS invasion.13,80 Similarly in Lyme disease (Borrelia burgdorferi)transmitted by the tick (genus Ixodes). 40% of cases have a painful radiculopathy, cranial nerve involvement and chronic poly axonopathy, accompanied by dorsal root ganglia and leptomeningeal inflammation.2,15,114 Primary syphilis with subsequent systemic spread (secondary syphilis) emphasizing the invasive properties of T. pallidum by a flagella capable of migrating through endothelial tight junctions with evidence of transcytosis117,118; T. pallidum express surface lipoproteins adhering to host epithelial cells and extracellular proteins,117,118 this is associated with the up regulation of MMP and collaginase with endothelial disruption and collagen degradation.119 Borrelia are invasive due to surface lipo proteins that adhere to integrins and extracellular glycoaminoglycosans, especially decorin a constituent of connective tissue covering the PN.119e121 Schwann cell infection has not been reported despite the invasive properties of these two spirochetes.116,122 Neither T. pallidum nor Borrelia burgdorferi express toxins, LPS or glycolipids14,15; tissue inflammation is the result of the activation of host inflammatory response through PRR such as TLR2 and CD1474,124e126 rather than intra cellular invasion. Contact between Borrelia burgdorferi and SC in vitro stimulated expression of CCL2, IL-6 and IL-8, all inflammatory cytokines and essential for an anti pathogen response.126,127 In vitro live Borrelia burgdorferi and T. pallidum are opsonised with IgG are avidly phagocytosed by macrophages expressing FcR,81,82,78,79,128 and express an innate immune response including cytokine initiated NO production126,127; in vivo BR have been demonstrated in PN macrophages.114 Despite the marked anti pathogen response and opsonisation82,128 both Syphilis and Lyme disease can become chronic infections despite the absence of evidence for persistent in vitro infection.13,114

Peripheral nerve neuropathies with definite evidence for SC infection The SC contributes an effective anti-inflammatory, anti pathogen response to combat infection by viruses and highly invasive spirochetes. By contrast T. cruzi and the Mycobacterium are able to infect SC and sustain persistent PN inflammation. The entry pathways underlying and invasive strategies adopted by these two pathogens are described.

9

Trypanosomes express surface molecules that mimic host trophic factors resulting in Schwann cell invasion and intracellular parasite survival T. cruzi is an obligate, intra cellular, protozoan parasite prevalent in South America and Australia, The amastigate stage is capable of invading a wide range of cells types including monocytes, SC and glia cells but not neurons.1,2,17,18 Chronic infection (Chaga’s disease) is associated with persistent intracellular infection degeneration of parasympathetic ganglia with functional loss of autonomic nervous system (ANS) innervation to heart and gastro Intestinal tracts resulting in cardiac myopathy with arrhythmias and dys mobility of the large intestine.129,131 Real time imaging microscopy show Trypanosoma gambiense (African Sleeping Sickness) is capable of traversing the BBB soon after systemic infection, with up regulation of endothelial adhesion factors and disruption of the BBB.131 It is possible the same process is responsible for T. cruzi gaining access to BPNB and infecting SC, but the details regarding transport of T. cruzi across the BBB are not yet understood preventing any extrapolation to explain how T. cruzi crosses the BPNB.18,131

Trypanosomes infect SC by exploiting molecular mimicry Host response to infection involves TLR 2 and TLR 9 detecting GPI proteins and parasite DNA respectively, together with MHC associated peptides from trans-sialidase surface proteins on the Trypanosome activating CD8þ lymphocytes; this initiates an inflammatory response accompanied by host cell injury.17,18,83,130,132 To counter the anti pathogen response, T. cruzi is able to invade a wide variety of cells types17,18 including SC expressing the tyrosine kinase receptors (Trk) A, B and C; these are trans membrane glycoprotein receptors for several mammalian neurotrophic factors (NF).83 The cell surface of T. cruzi contains a trans-silalidase or Parasite derived neurotrophic factor (PDNF) and this functions as a mimic for mammalian NF and binds with TrkC to invade host cells including SC (through TrkB and C) promoting parasite survival and replication.83,134 Once inside the SC, parasite survival is dependent upon TrkC phosphorylation and the Erk1/2 and Akt phosphorylation pathways; this is essential for T. cruzi to replicate conferring an intracellular growth advantage on this parasite.83 Furthermore, PNDF is also an immune suppressor reducing Tcell CD8þ activation and inhibiting apoptosis of infected host cells promoting the survival of T. cruzi.83,130,132 Animal experiments administrating PDNF resulted in an increase MCP-1 and fractalkine both chemo attractants at site of myocardial inflammation and tissue repair. The same effect could be equally effective at the autonomic nervous system. This effect was the result of PDNF interacting with TrkC and this was not dependent TLR-My D88 pathways and provides a new potential target to inhibit inflammation.132 The T. cruzi e Trkc interaction facilitates intra cellular survival resulting in chronic inflammation; the inhibition of this pathway provides a potential therapeutic target.83,131

Please cite this article in press as: Neal JW, Gasque P, The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.08.006

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Leprosy a chronic peripheral nerve inflammation with M. leprae infection of Schwann cells M. leprae is an obligate intra cellular pathogen dependent upon host cell for its survival.133 M. leprae is responsible for Leprosy, a chronic multi tissue infection; the most important consequence of leprosy is neurological disability resulting from PN involvement owing to destructive inflammation and chronic M. leprae infection.20,22,134 One of the most consistent histological features of peripheral PN inflammation is the intracellular location of M. leprae within SC and macrophages, implying intracellular distribution are an important factor contributing to the pathological events resulting in nerve injury.136,137 Inoculation of M. leprae in several animal models has found M. leprae has a widespread intracellular distribution SC, muscle, adrenal gland and endothelium within the BPNB where it well placed to infect the SC and macrophages.22,138 Ultra structural studies have identified electron dense material, interpreted as M. leprae, inside both SC and endothelial cells from nerve biopsies from infected animals patients with leprosy.135e137 Neither the identity surface entry receptors nor the molecular basis to explain how M. leprae crosses the PNB are known; this information would help identify a potential therapeutic target preventing the early stages of M. leprae infection. Although the early steps in SC infection in M. leprae are less well described,138 the presence of intracellular M. leprae has raised the possibility that this bacterium maintains SC infection through novel strategies exploiting the inherent regenerative properties of adult SC.139e141 The Schwann cell provides M. leprae with host factors critical to support its obligate intracellular survival and for this reason the interaction between M. leprae and SC would be expected contribute to long term pathogen survival.140 Clearly, understanding the interaction between M. leprae and SC is important for designing therapeutic agents to prevent pathogen entry into PN and inhibit the subsequent pathogen expansion.

M. leprae entry infects peripheral nerve macrophages and SC using multiple receptor pathways Table 1 shows the range of individual receptors C type lectins (DC SIGN, MMR) Toll like receptors expressed by both SC58 as well as macrophages.54 C receptors (CR) detect M. leprae cell wall constituents including lipoarabinomannan (Man-LAM) results in formation of the opsonin C3; FcR and macrophage complement receptors CR1, CR3 and CR4 detect myelin opsonised with C proteins (C3, C3b)with subsequent internalization. Phenolic glycolipid (PGL-1) a glyconjugate specific to M. leprae142 binds to C3 in serum and facilitates phagocytosis of M. leprae by monocytes82 these are not destroyed but persist within SC.135e137

J.W. Neal, P. Gasque

M. leprae tropism for Schwann cells is the result of multiple receptors M. leprae demonstrates tropism for the SC and is an early vital step contributing to the vulnerability of SC to pathogen infection. However, this is not only example of intracellular infection of SC by bacteria, as demonstrated by the internalization of S. pneumonia using the PRR Mannose membrane receptor.64 The basis for M. leprae tropism is a multi-step process invading the basal lamina of the axon surrounding the SC.62 In the first step M. leprae binds to the G domain of the a2 chain in laminin 2 on the SC basal lamina84 for the second step the M. leprae e laminin G combination binds to a- and b-dsytroglycan a laminin receptor and part of the dystrophin dystroglycan complex on the surface of the SC.56,63 In addition to host receptors, the M. leprae surface wall contains phenoglycolipid (PGL-I) this glycolipid also binds to laminin-2 located in SC basal lamina and in combination with LBP21 (an M. leprae surface antigen) gains access to the SC.62 A further important surface protein on M. leprae cell wall is a 21 kda histone e like protein, LBP21, coded by the ML1683 gene and functions as an adhesion molecule for SC to facilitate M. leprae invasion of peripheral nerve.142

Leprosy peripheral neuropathy The functional consequences of leprosy peripheral neuropathy, i.e. sensory and motor impairment, are the result of demyelination and axonal injury.20e22 The traditional role of SC in M. leprae PN inflammation is the expression of an innate immune inflammatory response resulting in PN inflammation.19,20,139 The histological features are classified as either tuberculoid or lepromatous histological phenotypes and are present during the late stages of M. leprae infection. Typically in both histological types macrophages and infiltrating T cells are frequent. However, in lepromatous leprosy clusters of unmyelinated SC are preferentially infected with M. leprae there are also nerves with evidence of regeneration and excessive perineurial fibrosis.135 Tuberculoid leprosy nerve biopsies, contain scarce intra cellular bacilli whereas giant cells and granuloma formation are both common, providing an explanation for nerve injury in the absence of obvious bacilli. In addition to PN infection M. leprae spreads to other tissue types.19e21 The traditional view that M. leprae activates SC to produces an innate immune inflammatory response is unable to explain all the findings in M. leprae peripheral nerve inflammation. For example, long duration of incubation,21 chronic inflammation with M. leprae infection requires continual intracellular survival, despite the loss of SC due to inflammation and the failure of host to eliminate M. leprae.68,69 Furthermore, infection of SC by M. leprae does not explain the subsequent spread of M. leprae to other tissues (muscle, smooth muscle connective tissues)22 or generation of PN fibrosis.19e21,138

Please cite this article in press as: Neal JW, Gasque P, The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.08.006

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Primary infection of Schwann cells 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

Schwann cells express an inflammatory response an important factor contributing to nerve injury in leprosy Schwann cell in PN respond to intracellular infection with M. leprae through expression of several inflammatory and anti inflammatory cytokines.29e31 Schwann cells uptake of M. leprae by DC SIGN (CD 209) is influenced by local inflammation because this is regulated by inflammatory cytokine IL-4.143 Together with MHC II proteins providing an opportunity to present M. leprae antigens to T cells (especially CD8þ T cells) resulting in SC lysis144. Activated T cells also express inflammatory cytokines and this is potentially responsible for SC and bystander PN injury as found in tuberculoid leprosy. M. leprae cell wall components are detected by SC in vitro data demonstrates activation of SC TLR 2 receptors’ by exposure to M. leprae lipoproteins with SC apoptosis and expression on leucocytes68,69 and SC increased the detection of PAMPS such as lipoarabinomannan a Mycobacterium cell wall component with expression of SC inflammatory cytokine TNFa; this regarded a major cause for tissue injury in tuberculoid leprosy.136,138 The same PAMP, Man-LAM, activate the SC with CP with formation of the opsonin C3 and cytolytic MAC; macrophage complement receptors CR1, CR3 and CR4 detect myelin opsonised with C proteins (C3, C3b).145

Pathogen directed nuclear reprogramming of host cells by pathogens; a strategy for pathogen survival in peripheral nerve infection The introduction of retroviral vectors in vitro containing RNA as found in many RNA viruses into host cells can result in nuclear reprogramming initiating host cell dedifferentiation with the generation of stem cells.23,24 The location of SC within an immune privileged space and its inherent plasticity exemplified by proliferation in response to injury22,27 and infection137,138 makes SC a vulnerable target for pathogen directed nuclear reprogramming.23,24 Schwann cell also expresses a wide range of PRR and their activation is capable of sustaining an inflammatory innate immune response. The former is required for the initial phase of the nuclear reprogramming response13,24; an up regulation of innate immune genes is related to the detection of intracellular pathogen viral nucleic acid or PAMPS by TRL-1/TLR-2,68,69 this actives the intracellular signalling pathways stimulating proinflammatory cytokine expression.23,24 Subsequent up regulation of embryonic transcription factors and down regulation of factors associated with the mature SC phenotype results in dedifferentiation and Progenitor, stem like cell formation.24,140,141 (see Fig. 3 summarizes the putative pathways associated with M. leprae infection of SC and generation of pSLC and granuloma formation) Despite these findings the details of the signalling pathways involved with bacteria related re programming of host cell, in this case the SC, remain to be determined.

11

Intracellular infection with M. leprae promotes nuclear reprogramming in Schwann cells; the importance of stem cells for M. leprae survival and pathogen dissemination The histological appearances in nerve biopsies of SC containing intracellular bacilli provides clues as to the strategy adopted by M. leprae to infection.21,22 As an obligate intracellular pathogen M. leprae expansion is dependent upon maintaining a population of host cells capable of supporting bacterial growth.133 An important clue to explain these findings was provided by the interaction between M. leprae and myelinated SC in vivo and in vitro.84,139,141 This resulted in demyelination with generation of a population of dedifferentiated SC; these phenotypic changes were due to M. leprae activating the Erk1/2MAPK signalling pathway.141 The dedifferentiated SC were especially vulnerable to M. leprae infection as found in M. leprae nerve biopsies134 and provide a renewable population of host cells available for pathogen infection.140 To further understand this interaction between M. leprae and SC dedifferentiated SC from adult mouse nerve were infected with M. leprae in vitro.24 The interaction between M. leprae and SC exploited the inherent plasticity of SC and promoted nuclear reprogramming of adult SC cells to form pSCL (progenitor/stem-like cells).24 In summary, in vitro nuclear re programming of SC by M. leprae was initiated by an innate immune inflammatory response against the pathogen followed by an increased expression of embryonic transcription factors including the down regulation of myelin/SC linage genes (SOX10) and up regulation of genes associated with mesodermal differentiation (Skeletal and smooth muscle) and transforms infected mature SC into pSCL with a connective tissue phenotype and reduced capacity to contribute to remyelination and axon repair.15,141 Reprogramming of SC into pSLC with mesenchymal features will also provide an explanation for the spread of M. leprae to skeletal muscle and the increased amounts of fibrous connective tissue as found in PN biopsies.21,22,134 pSLC in vivo infected with M. leprae have the potential to migrate and differentiate into mature skeletal muscle and fibrous tissues containing the pathogen a typical feature of leprosy.20,21 Furthermore the generation of pSLC provides a population especially vulnerable to M. leprae infection and creates a bacterial niche (inside the immune privileged endoneurium) capable of supporting persistent infection by M. leprae as seen in lepromatous neuropathy.135,136,140 Furthermore, pSLC infected macrophages express trophic factors and chemo attractants promoting macrophage recruitment forming granuloma-like structures containing M. leprae infected macrophages.24 Traditionally granuloma is considered to prevent pathogen dissemination, but studies in Zebra fish have shown early granulomas can increase pathogen dissemination.146 In addition, systemic Msc with immuno regulatory properties have been identified in granulomas from Mycobacterium tuberculosis infected lung,147,148 and it is possible this finding applies to

Please cite this article in press as: Neal JW, Gasque P, The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.08.006

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J.W. Neal, P. Gasque

M. leprae related PN inflammation. These phenotypic changes in vitro resemble the pathological findings in tuberculoid peripheral neuropathy (granuloma and infected macrophages).21,22 Whether or not nuclear reprogramming is applicable to other intracellular SC pathogens, for example. T. cruzi, associated chronic inflammation remains to be determined (Fig. 3).

Clinical relevance of pathogen infection of SC for treatment of peripheral infective neuropathies Several reviews have discussed the therapeutic options for treating the consequences of peripheral neuropathies, these include administration of reagents based upon factors expressed by SC for example, neurotrophins (NGF) and

eyrthropoetin are neuro protective, whereas progesterone (myelin formation) and ascorbic acid (SC differentiation) promote nerve repair; the majority have not been shown to enhance clinical recovery.26 On this basis, rather than treatment aimed at stimulating repair a better understanding of the early events leading to SC infection with pathogens including M. leprae and T. cruzi are warranted. This approach will require development of appropriate animal models to investigate the interaction between pathogen and entry receptors located on the BPNB and host cell surface.12,138 In vitro, infection of SC with M. leprae found demeylination was the result of M. leprae binding to the SC Erb2 pathway, humanized anti-Erb2 antibodies (Herceptin) prevented M. leprae interacting with this pathway, whereas, a small peptide Pki-166 inhibited the Erb1-Erb2 kinase and reduced M. leprae related demyelination in vitro and in vivo.141,148

Pathogens ini ate reprogramming of host cells to produce stem cells and innate immune inflamma on Bacteria Virus Spirochetes Peripheral nerve blood barrier

V V

Endoneurium Immuno privledge Protected niche

TLR3 Pathogen infecƟon of Schwann cell Reprogramming produces pluripoten al stem cell pSLC

V

Viral ds RNA

TLR 2 TLR 4

V

SC

pSLC migrate and differen ate

Reprogramming ini ates TLR inflammatory cytokines and chemotac c factors for macrophages

Macrophages pSLC pSLC

Infected pSLC differen ate into Muscle and fibrous ssue with increased pathogen increase

Granuloma like structure

Infected Macrophages disseminate and provide a secondary niche for bacterial expansion

Figure 3 Systemic pathogens noticeably M. leprae infects SC with dedifferentiation and enhanced dissemination in peripheral nerve, muscle and connective tissue. Mycobacterium, spirochetes, parasites, viruses penetrate the PNB are detected PRR on Schwann cell (SC) and initiate an anti pathogen response. These PRR are expressed as part of an upregulation of host cell innate immune inflammatory response (TLR3, TLR2, TLR4) following Schwann cell infection with subsequent anti virus cytokine formation and chemoattractants for macrophages; Intracellular Mycobacterium (M. leprae) infection of SC produces nuclear reprogramming with subsequent formation of mesenchymal progenitor like stem cells pSLC. Intracellular mycobacteria reprogramme the infected host SC by initiating an innate immune response and subsequently increasing embryonic transcription factors and down regulation of SOX 10 genes promoting production of pluripotential stem cells pSLC. The pSLC have immunoregulatory and migratory features increasing pathogen survival and dissemination. Granuloma like structures are formed by pSLC and macrophages reacting to chemo attractants expressed by stem cells. Subsequent shedding of infected macrophages from the granuloma increases dissemination throughout the systemic tissues including peripheral nerve. Dedifferentiated stem cells infected by a pathogen differentiate into in skeletal muscle and fibrous tissue infiltrate into host tissues increasing distribution of pathogen beyond the peripheral nerve. Please cite this article in press as: Neal JW, Gasque P, The role of primary infection of Schwann cells in the aetiology of infective inflammatory neuropathies, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.08.006

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Primary infection of Schwann cells 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

A recent study using Mycobacterium tuberculosis found the protein Mce3e inhibits Erb signalling pathway preventing host innate immune response and this increased the survival of intracellular pathogen.149 Similarly experimental infection with T. cruzi found PDNF/trans-sialidase interacted with host Trkc to facilitate intracellular pathogen survival inflammatory cell infiltration and fibrosis (chronic inflammation)132; this pathway provides an obvious target for developing appropriate therapeutic agents to block parasite entry and reduce associate inflammation.83,132,150 The PDNF e TrKc has been exploited by identification of a small synthetic peptide Y21 composed of 21 amino acids from within the PDF sequence. In vitro Y21 inhibits PDF binding to Trkc reducing trypanosome entry but its clinical application remains untested.150

Conclusion Peripheral neuropathy due to pathogens is an important global cause of clinical disability. Virus and spirochetes gain accesses to the endoneurium provoke an effective anti pathogen response from macrophages and SC with subsequent nerve inflammation. On this basis primary infection of SC is rare, except for two pathogens M. leprae and T. cruzi, both employ novel strategies to produce SC infection and peripheral nerve inflammation. T. cruzi expresses PNDF a “molecular mimic” and ligand for host NF receptor Trkc facilitating SC infection, whereas, M. leprae demonstrates tropism for SC by a multi-receptor process and a novel pathogen host interaction resulting in the generation of SC/pSLC stem cells. This pSLC population provides a constant source of cells vulnerable to M. leprae infection and pathway for pathogen dissemination.147 A similar interaction between T. cruzi and SC could provide a vulnerable population of stem cells and a source for persistent infection and inflammation. Further studies are required to establish if therapeutic inhibition of these two novel pathogen pathways are applicable to treating chronic infection due to pathogens with involvement of tissues outside the peripheral nervous system.

Uncited reference Q14

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