Sprouting of Nervous Fibers and Upregulation of C‐X‐C Chemokine Receptor Type 4 Expression in Hippocampal Formation of Rats with Enhanced Spatial Learning and Memory

Bao-gui, SU; Pan, Sanqiang; He, Xin; Li, Peng; Liang, Yubin

doi:10.1002/ar.21518

Cited by 8 publications

(3 citation statements)

References 19 publications

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“…SgG2 seems to bind both chemokines and NGF simultaneously and this property could play a relevant role during in vivo infection due to the contribution of chemokines and neurotrophins in the crosstalk between the immune and nervous system. Chemokines are essential in the antiviral response but they can also modulate the responsiveness of axons to guidance cues, acting as antagonists of axonal repulsion and inducing axonal sprouting [ 56 – 58 ]. Neurotrophic factors are essential elements of the nervous system and also play relevant roles in inflammation and pain modulation [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Secreted Herpes Simplex Virus-2 Glycoprotein G Modifies NGF-TrkA Signaling to Attract Free Nerve Endings to the Site of Infection

et al. 2015

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Herpes simplex virus type 1 (HSV-1) and HSV-2 are highly prevalent viruses that cause a variety of diseases, from cold sores to encephalitis. Both viruses establish latency in peripheral neurons but the molecular mechanisms facilitating the infection of neurons are not fully understood. Using surface plasmon resonance and crosslinking assays, we show that glycoprotein G (gG) from HSV-2, known to modulate immune mediators (chemokines), also interacts with neurotrophic factors, with high affinity. In our experimental model, HSV-2 secreted gG (SgG2) increases nerve growth factor (NGF)-dependent axonal growth of sympathetic neurons ex vivo, and modifies tropomyosin related kinase (Trk)A-mediated signaling. SgG2 alters TrkA recruitment to lipid rafts and decreases TrkA internalization. We could show, with microfluidic devices, that SgG2 reduced NGF-induced TrkA retrograde transport. In vivo, both HSV-2 infection and SgG2 expression in mouse hindpaw epidermis enhance axonal growth modifying the termination zone of the NGF-dependent peptidergic free nerve endings. This constitutes, to our knowledge, the discovery of the first viral protein that modulates neurotrophins, an activity that may facilitate HSV-2 infection of neurons. This dual function of the chemokine-binding protein SgG2 uncovers a novel strategy developed by HSV-2 to modulate factors from both the immune and nervous systems.

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Section: Discussionmentioning

confidence: 99%

Secreted Herpes Simplex Virus-2 Glycoprotein G Modifies NGF-TrkA Signaling to Attract Free Nerve Endings to the Site of Infection

et al. 2015

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“…Axonal sprouting was observed in the rat hippocampus in a spatial learning paradigm, and in the visual cortex during recovery from retinal lesions 91,92 (see Chapter 16). Maladaptive axonal sprouting is also seen in neuronal network remodeling in many epilepsy models 93 (see Chapter 27).…”

Section: Axonal Sproutingmentioning

confidence: 97%

Network Control Mechanisms

Faingold

2014

Neuronal Networks in Brain Function, CNS Disorders, and Therapeutics

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“…Moreover, rSgG1 and rSgG2 bind chemokines and enhance their potency, increasing leukocyte migration ( 16 ). Chemokines and neurotrophic factors are involved in the interplay between the immune and nervous systems, with chemokines antagonizing axonal repulsion and with IL-17c, NGF, and others regulating the innate immune response and inducing inflammation ( 17 – 20 ). gG is the most divergent glycoprotein between HSV-1 and HSV-2.…”

Section: Introductionmentioning

confidence: 99%

Herpes Simplex Virus 2 Counteracts Neurite Outgrowth Repulsion during Infection in a Nerve Growth Factor-Dependent Manner

Kropp

López-Muñoz

Ritter

et al. 2020

J Virol

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During primary infection, herpes simplex virus type 2 (HSV-2) replicates in epithelial cells and enters neurites to infect neurons of the peripheral nervous system. Growth factors, attractive and repulsive directional cues influence neurite outgrowth and neuronal survival. We hypothesised that HSV-2 modulates the activity of such cues to increase neurite outgrowth. To test this hypothesis we exposed sensory neurons to nerve growth factor (NGF) and mock or HSV-2-infected HEK-293T cells, since they express repellents of neurite outgrowth. We show that HEK-293T cells secreted factors that inhibit neurite outgrowth, while infection with HSV-2 strains MS and 333 reduced this repelling phenotype, increasing neurite numbers. The HSV-2 mediated restoration of neurite outgrowth required the activity of NGF. In the absence of infection, however, NGF did not overcome the repulsion mediated by HEK-293T cells. We previously showed that recombinant, soluble glycoprotein G of HSV-2 (rSgG2) binds and enhances NGF activity, increasing neurite outgrowth. However, the effect of gG2 during infection had not been investigated. Therefore, we addressed whether gG2 contributed to overcoming neurite outgrowth repulsion. To do so, we generated viruses lacking gG2 expression and complemented them by exogenous expression of gG2. Overall, our results suggest that HSV-2 infection of non-neuronal cells reduced their repelling effect on neurite outgrowth in an NGF-dependent manner. gG2 contributed to this phenotype but it was not the only factor. The enhanced neurite outgrowth may facilitate HSV-2 spread from epithelial cells into neurons expressing NGF receptors and increase HSV-2 mediated pathogenesis. Importance: Herpes simplex virus type 2 (HSV-2) is a prevalent human pathogen that establishes life-long latency in neurons of the peripheral nervous system. Colonization of neurons is required for HSV-2 persistence and pathogenesis. The viral and cellular factors required for efficient infection of neurons are not fully understood. We show here that non-neuronal cells repel neurite outgrowth of sensory neurons, while HSV-2 infection overcomes this inhibition, and rather stimulates neurite outgrowth. HSV-2 glycoprotein G and nerve growth factor contribute to this phenotype, which may attract neurites to sites of infection and facilitate virus spread to neurons. Understanding the mechanisms that modulate neurite outgrowth and facilitate HSV-2 infection of neurons might foster the development of therapeutics to reduce HSV-2 colonization of the nervous system and provide insights on neurite outgrowth and regeneration.

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Sprouting of Nervous Fibers and Upregulation of C‐X‐C Chemokine Receptor Type 4 Expression in Hippocampal Formation of Rats with Enhanced Spatial Learning and Memory

Cited by 8 publications

References 19 publications

Secreted Herpes Simplex Virus-2 Glycoprotein G Modifies NGF-TrkA Signaling to Attract Free Nerve Endings to the Site of Infection

Secreted Herpes Simplex Virus-2 Glycoprotein G Modifies NGF-TrkA Signaling to Attract Free Nerve Endings to the Site of Infection

Network Control Mechanisms

Herpes Simplex Virus 2 Counteracts Neurite Outgrowth Repulsion during Infection in a Nerve Growth Factor-Dependent Manner

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