Immune- and Nonimmune-Compartment-Specific Interferon Responses Are Critical Determinants of Herpes Simplex Virus-Induced Generalized Infections and Acute Liver Failure

Abstract

The interferon (IFN) response to viral pathogens is critical for host survival. In humans and mouse models, defects in IFN responses can result in lethal herpes simplex virus 1 (HSV-1) infections, usually from encephalitis. Although rare, HSV-1 can also cause fulminant hepatic failure, which is often fatal. Although herpes simplex encephalitis has been extensively studied, HSV-1 generalized infections and subsequent acute liver failure are less well understood. We previously demonstrated that IFN- IMPORTANCEHerpes simplex virus 1 (HSV-1) infection is an incurable viral infection with the most significant morbidity and mortality occurring in neonates and patients with compromised immune systems. Severe pathologies from HSV include the blindness-inducing herpetic stromal keratitis, highly debilitating and lethal herpes simplex encephalitis, and generalized infections that can lead to herpes simplex virus-induced acute liver failure. While immune compromise is a known factor, the precise mechanisms that lead to generalized HSV infections are unknown. In this study, we used and developed a mouse model system in combination with real-time bioluminescence imaging to demonstrate the relative importance of the immune and nonimmune compartments for containing viral spread and promoting host survival after corneal infection. Our results shed light on the pathogenesis of HSV infections that lead to generalized infection and acute liver failure. Herpes simplex virus 1 (HSV-1) is an enveloped DNA virus and a member of the Alphaherpesvirus subfamily with high seroprevalence in the human population (1). In most cases, HSV-1 causes relatively mild orolabial cold sores, but it can cause more serious localized diseases such herpes stromal keratitis, the leading cause of infectious blindness in the United States (2, 3). Serious sequelae for HSV-1 are more common in immunocompromised hosts and neonates, with uncontrolled viral replication leading to herpes simplex encephalitis (HSE) or, more rarely, HSV sepsis leading to acute liver failure (4, 5). HSV-induced acute liver failure (ALF) is an alarmingly deadly disease with a lethality rate approaching 75% (5). The importance of studying HSV-induced ALF is underscored by the immunocompromised populations it affects, mainly patients undergoing chemotherapy, bone marrow transplant recipients, HIV patients, and women in the third trimester of pregnancy (5, 6). HSV-1 infects via the mucosae of the mouth, eyes, or genitalia, where it undergoes lytic replication in the epithelium (7). During infection of these mucosae, the virus infects innervating sensory neurons, traveling in a retrograde direction in the facial neurons back to mostly sensory ganglia, wherein HSV-1 establishes latency (8). The ability of HSV to establish latency in neurons, a nondividing cell population, hinders the ability of the immune system to fully clear the virus and renders the virus refractory to cure with antiviral treatments (9). Immune dysregulation and other stimuli cause HSV-1 to erupt from latency,...

General Analysis of Resolution Enhancement on Time-Synchronized Sampling and its Multi-Resolution Solution in 20GSPS Acquisition System

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Multiplex qPCR facilitates identification of betaherpesviruses in patients with acute liver failure of unknown etiology

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Herpes Simplex Virus Evasion of Early Host Antiviral Responses

“…On the other hand, IFN-α βγ R −/− mice have been found to be highly susceptible to acute liver failure after HSV-1 corneal infection, with IFN-α βγ R expression in both, immune and non-immune cells playing relevant roles in the control of systemic HSV infection (Pasieka et al, 2011; Parker et al, 2016). Moreover, a key role for type-I IFN signaling has been identified in neurons, since immune cell and non-neuronal cell IFN responses do not protect from lethal corneal HSV infection when the these pathways are abrogated in neurons (Rosato and Leib, 2015).…”