Herpes Simplex Virus and Interferon Signaling Induce Novel Autophagic Clusters in Sensory Neurons

Abstract

IMPORTANCEHerpes simplex virus type 1 (HSV-1) is a ubiquitous virus and a significant cause of morbidity and some mortality. It is the causative agent of benign cold sores, but it can also cause blindness and life-threatening encephalitis. The success of HSV-1 is largely due to its ability to establish lifelong latent infections in neurons and to occasionally reactivate. The exact mechanisms by which neurons defend against virus infection is poorly understood, but such defense is at least partially mediated by autophagy, an intracellular pathway by which pathogens and other unwanted cargoes are degraded. The study demonstrates and investigates a new autophagic structure that appears to be specific to the interaction between neurotropic herpesviruses and murine primary sensory neurons. This work may therefore have important implications for our understanding of latency and reactivation. Herpes simplex virus 1 (HSV-1) is a highly prevalent human pathogen that establishes lifelong infection in the neurons of sensory and autonomic ganglia (1, 2). Initial infection and lytic replication at mucosal sites are followed by infection of innervating axonal termini of sensory neurons. Virions then travel in a retrograde direction to the soma, where they may replicate or immediately establish latency, depending partly on the infected neuronal subtype (3). Virions resulting from periodic reactivation events travel in an anterograde direction along the axon, allowing reinfection of the oral epithelium, thereby facilitating viral shedding and host-to-host transmission (2).Innate immune responses are critical in controlling virulence of HSV-1 and many other viruses through a variety of antiviral pathways (4-12), and viruses have coevolved to counter these host responses (13)(14)(15)(16)(17)(18)(19)(20). Cells detect the presence of incoming virus through pattern recognition receptors (21, 22) that, in turn, lead to the activation of pivotal transcription factors such as IRF (5, 23) and NF-B (24). These factors subsequently induce the production of type I interferon (IFN), which drives IFN-stimulated gene (ISG) expression (25) through a JAK-STAT-dependent pathway (26,27). This further stimulates production of type I IFN and ISGs to establish an antiviral state that consists of transcriptional and translational arrest, cytokine production, and apoptosis (28,29).Defects in innate immunity are often associated with increased susceptibility to HSV infection in both mice and humans, with frequent neurological sequelae (8,12,(30)(31)(32). That said, the IFNdriven responses of neurons themselves are muted and atypical (12,33). Nondestructive clearance is especially critical for postmitotic adult neurons, a population of irreplaceable cells that is essential for both the success and survival of the host. Indeed, there is mounting evidence that neurons depend on autophagy rather than inflammatory or cell-destructive responses for the control of intracellular pathogens (34-37). Autophagy is a highly conserved response to starvation, during...

Isolation, Purification, and Culture of Primary Murine Sensory Neurons

“…For the study of HSV-neuron interactions, there has been significant recent focus on the sensory trigeminal ganglion or TG [3–6]. To achieve this, the TG must be dissected, enzymatically digested to liberate the neurons, and the neurons isolated by gradient separation.…”

Rapid Etiologic Diagnosis of Herpes Virus Infections in Children

“…Furthermore, human herpes viruses have a tendency to be latent and may be reactivated under some conditions such as weakened immunity. The reactivation of latent infections may lead to serious consequences such as postherpetic neuralgia, encephalitis, and EBV associated tumors (4)(5)(6). Moreover, many children in the world are infected with herpes viruses (5,7,8).…”

Epigenetic Treatment of Persistent Viral Infections

“…Vitamin A elicits a broad array of immune responses through its metabolite, retinoic acid [Hall et al, ; Miller et al, ; Goswami and Kaplan, ], and retinol and/or retinoic acid have been shown to increase the expression of RIG‐I, and to inhibit murine norovirus replication using both in vitro and in vivo models [Lee and Ko, ]. The eye and, more precisely, the retina and optic nerve, are considered to be an extension of brain tissue [Vladan and Panfoli, ; More et al, ], and it is well‐established that HSV1 infection (the causative agent of benign cold sores) can cause blindness (HSV keratitis) and life‐threatening encephalitis [Ruderfer and Krilov, ; Katzenell and Leib, ]. Ocular viral infections are a growing problem in clinical therapy [Song et al, ].…”