title: Secreted herpes simplex virus-2 glycoprotein G modifies NGF-TrkA signaling to attract free nerve endings to the site of infection.
abstract: 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.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; Centro de Investigaciones Biologicas en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Jorge Rubén
authors.initials: JR
authors.lastname: Cabrera
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Abel
authors.initials: A
authors.lastname: Viejo-Borbolla
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Nadia
authors.initials: N
authors.lastname: Martinez-Martín
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Soledad
authors.initials: S
authors.lastname: Blanco
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; Centro de Investigaciones Biologicas en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Wandosell
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcamí
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D057809:HEK293 Cells; D006561:Herpes Simplex / Q000378:metabolism / Q000473:pathology*; D018258:Herpesvirus 2, Human / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D051379:Mice; D009411:Nerve Endings / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020932:Nerve Growth Factor / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014759:Viral Envelope Proteins / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D014759:Viral Envelope Proteins; C045464:glycoprotein G, herpes simplex virus type 2; D020932:Nerve Growth Factor; D020917:Receptor, trkA