9/26/2023 0 Comments Free nerve endings signalAmong them, neurotrophins are a family of secreted proteins that play relevant roles in neuronal survival, axonal growth and guidance in the PNS. Several axonal guidance cues and neurotrophic factors involved in neural targeting have been identified. Since herpesviruses are highly adapted pathogens that modify several aspects of both the immune and nervous systems, it is conceivable that they may modulate factors influencing neuronal functions to gain access to the nervous system. The mechanism(s) facilitating HSV neurotropism, which is crucial for latency and pathogenesis, are not well understood. Then, HSV reaches and infects free nerve endings (FNE) of sensory neurons and colonizes ganglia of the Peripheral Nervous System (PNS). Initial infection occurs in epithelial cells, generally within the skin and the mucosa of the oral tract and genitalia. Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2, respectively) are highly prevalent, neurotropic human pathogens. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. AVB and NMM were funded by JAE fellowships from Consejo Superior de Investigaciones Científicas. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedįunding: This work was funded by grants from the Spanish Ministry of Science and Innovation (SAF2009-07857, SAF2009-12249-C02-01), Instituto de Salud Carlos III (Red Española de Esclerosis Múltiple RD12/0032/0014 and CIBERNED), I+D-BIOMEDICINA-CAM 2010, and EU-FP7-2009-CT222887. Received: DecemAccepted: NovemPublished: January 22, 2015Ĭopyright: © 2015 Cabrera et al. Fremont, Washington University, UNITED STATES These results shed light on the modulation of neurotrophic factors by relevant human pathogens and on the mechanisms of colonization of the nervous system by HSV.Ĭitation: Cabrera JR, Viejo-Borbolla A, Martinez-Martín N, Blanco S, Wandosell F, Alcamí A (2015) Secreted Herpes Simplex Virus-2 Glycoprotein G Modifies NGF-TrkA Signaling to Attract Free Nerve Endings to the Site of Infection. Absence of a similar function for HSV-1 gG may indicate a preference for the infection of particular subsets of neurons by these viruses. These results were obtained in vitro, ex vivo and in the infected mouse, suggesting that this effect may permit a more efficient infection of NGF dependent free nerve endings by HSV-2. The enhancement in NGF activity results in an increase in axonal growth of neurons expressing the receptor for NGF. This constitutes the first description, to our knowledge, of a human pathogen with the ability to augment neurotrophic factor function. We show that HSV-2 glycoprotein G (SgG2) binds to and increases the function of nerve growth factor (NGF), a neurotrophin expressed in the skin and mucosa essential for axonal growth and neuronal survival. Understanding the mechanisms that allow these viruses to colonize the nervous system will permit devising antiviral strategies. Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2, respectively) establish latency in peripheral sensory ganglia, where they remain for the lifetime of the infected individual. 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. 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. 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. We could show, with microfluidic devices, that SgG2 reduced NGF-induced TrkA retrograde transport. SgG2 alters TrkA recruitment to lipid rafts and decreases TrkA internalization. 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. ![]() 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. Both viruses establish latency in peripheral neurons but the molecular mechanisms facilitating the infection of neurons are not fully understood. 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.
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