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.
Highlights
Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2, respectively) are highly prevalent, neurotropic human pathogens [1]
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
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
Summary
Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2, respectively) are highly prevalent, neurotropic human pathogens [1]. Neurotrophins are a family of secreted proteins that play relevant roles in neuronal survival, axonal growth and guidance in the PNS. Members of this family include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and NT4/5 [3]. NT3 can bind TrkA and TrkB, with lower affinity [3] Both mature neurotrophins and immature precursors (proneurotrophins) bind p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor (TNF) receptor superfamily. We hypothesized that HSV could modify nerve ending navigational cues during the early steps of PNS colonization
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