Resistance to HSV-1 infection in the epithelium resides with the novel innate sensor, IFI-16

STING is a protein in the cytosolic DNA and cyclic dinucleotide sensor pathway that is critical for the initiation of innate responses to infection by various pathogens. Consistent with this, herpes simplex virus 1 (HSV-1) causes invariable and rapid lethality in STING-deficient (STING ؊/؊ ) mice following intravenous (i.v.) infection. In this study, using real-time bioluminescence imaging and virological assays, as expected, we demonstrated that STING ؊/؊ mice support greater replication and spread in ocular tissues and the nervous system. In contrast, they did not succumb to challenge via the corneal route even with high titers of a virus that was routinely lethal to STING ؊/؊ mice by the i.v. route. Corneally infected STING ؊/؊ mice also showed increased periocular disease and increased corneal and trigeminal ganglia titers, although there was no difference in brain titers. They also showed elevated expression of tumor necrosis factor alpha (TNF-␣) and CXCL9 relative to control mice but surprisingly modest changes in type I interferon expression. Finally, we also showed that HSV strains lacking the ability to counter autophagy and the PKR-driven antiviral state had near-wild-type virulence following intracerebral infection of STING ؊/؊ mice. Together, these data show that while STING is an important component of host resistance to HSV in the cornea, its previously shown immutable role in mediating host survival by the i.v. route was not recapitulated following a mucosal infection route. Furthermore, our data are consistent with the idea that HSV counters STING-mediated induction of the antiviral state and autophagy response, both of which are critical factors for survival following direct infection of the nervous system. Herpes simplex virus 1 (HSV-1) is a member of the Alphaherpesvirus subfamily with high seroprevalence in the human population (1). Infection at mucosal surfaces such as the mouth, eyes, and genitalia leads initially to lytic replication in mucosal epithelial cells, followed by infection of the innervating sensory neurons. HSV-1 then travels in a retrograde direction to the neuronal cell body, where it establishes latency. It is this ability to establish latency that renders HSV-1 refractory to clearance by the immune system, allowing persistence for the lifetime of the host. During periods of reactivation from latency, HSV-1 can travel in the anterograde direction to mucosal tissues, causing diseases ranging in severity from the common cold sore to herpetic stromal keratitis (HSK), the most common cause of infectious blindness in the developed world (2). HSV-1 can also gain entry into the central nervous system (CNS) to cause herpes simplex encephalitis (HSE) (3). HSE is a leading cause of viral encephalitis, further underscoring the significant morbidity and mortality associated with HSV-1.In order to effectively respond to infection, host cells have evolved a broad spectrum of sensors of evolutionarily conserved pathogen-associated molecular patterns (PAMPS) (for reviews, see refer...

Section: Discussionsupporting

confidence: 75%

supporting

confidence: 59%

Role of the DNA Sensor STING in Protection from Lethal Infection following Corneal and Intracerebral Challenge with Herpes Simplex Virus 1

Parker

Murphy

Leib

2015

“…Innate immune responses are critical in controlling virulence of HSV-1 and many other viruses through a variety of antiviral pathways (4)(5)(6)(7)(8)(9)(10)(11)(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).…”

mentioning

confidence: 99%

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

Katzenell

Leib

2016

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...

“…The endosomal TLR3 and TLR7, as well as the cytoplasmic RIG-I (RNA helicase retinoic acid-inducible gene I), sense single-or double-stranded RNAs. The endosomal TLR9 and a number of cytosolic molecules, such as DAI (DNAdependent activator of interferon-regulatory factor), IFI16 (gamma interferon-inducible protein 16), and AIM2 (absent in melanoma 2), etc., sense double-stranded DNA (2,3).…”

mentioning

confidence: 99%

Type I Interferon and NF-κB Activation Elicited by Herpes Simplex Virus gH/gL via αvβ3 Integrin in Epithelial and Neuronal Cell Lines

Gianni

Leoni

Campadelli-Fiume

2013

␣v␤3 integrin represents a novel sensing system which detects herpes simplex virus (HSV) and bacterial constituents. In cooperation with Toll-like receptor 2 (TLR2), it elicits an innate response that leads to activation of type I interferon (IFN), NF-B, and a specific set of cytokines. We report that this defensive branch is functional in cells which represent experimental models of epithelial, including keratinocytic, and neuronal cells. These are the major targets of HSV in vivo. HSV entered the three cell lines via distinct routes. Hence, the defensive response was independent of the route of virus entry. Soluble gH/gL sufficed to elicit type I IFN and NF-B activation and represents the viral pathogen-associated molecular pattern (PAMP) of this defense system. P attern recognition receptors (PRRs) are responsible for sensing pathogens and for initiating signaling cascades which culminate in the innate response, whose hallmarks are the production of interferons (IFNs) and proinflammatory cytokines and the activation of the transcription factor NF-B (1). Based on the nature of the pathogen-associated molecular pattern (PAMP) and the properties of the respective PRR, the innate response to herpesviruses can be divided into three main branches (for an indepth review, see reference 2). Thus, the Toll-like receptors (TLRs) localized at the plasma membranes, e.g., TLR2, recognize proteic or lipidic PAMPs. The endosomal TLR3 and TLR7, as well as the cytoplasmic RIG-I (RNA helicase retinoic acid-inducible gene I), sense single-or double-stranded RNAs. The endosomal TLR9 and a number of cytosolic molecules, such as DAI (DNAdependent activator of interferon-regulatory factor), IFI16 (gamma interferon-inducible protein 16), and AIM2 (absent in melanoma 2), etc., sense double-stranded DNA (2, 3).Until recently, the prevalent paradigm has been that the IFN production occurs in response to activation of the cytosolic sensors, whereas the TLRs located at the plasma membrane elicit a predominantly inflammatory response (4-6). In particular, until recently, TLR2 was known to sense bacteria and was thought not to be involved in recognition of viruses. When a role for TLR2 against herpes simplex virus (HSV) and other herpesviruses was documented, TLR2 was found to be polarized toward an inflammatory response (7,8). Kurt-Jones and coworkers (9) found that encephalitis caused by HSV was less severe in mice lacking TLR2, thus providing evidence for a role of TLR2 in the response to HSV and highlighting an inflammatory effect (10). In contrast with this view, Barbalat et al. (11) demonstrated that TLR2 was capable of inducing a type I IFN in response to viral ligands in inflammatory monocytes; the PAMPs remained elusive. Key to understanding the significance of the multiple, apparently redundant, innate defense branches against herpesviruses is the fact that they have been often demonstrated in highly specific cell types. For example, the TLR9 response was observed in plasmacytoid cells, the TLR9 and TLR2 responses were observed i...