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...

Modern human activity fueled by economic development is profoundly altering our relationship with microorganisms. This altered interaction with microbes is believed to be the major driving force behind the increased rate of emerging infectious diseases from animals. The spate of recent infectious disease outbreaks, including Ebola virus disease and Middle East respiratory syndrome, emphasize the need for development of new innovative tools to manage these emerging diseases. Disseminating vaccines are one such novel approach to potentially interrupt animal to human (zoonotic) transmission of these pathogens.

Ebolaviruses pose significant public health problems due to their high lethality, unpredictable emergence, and localization to the poorest areas of the world. In addition to implementation of standard public health control procedures, a number of experimental human vaccines are being explored as a further means for outbreak control. Recombinant cytomegalovirus (CMV)-based vectors are a novel vaccine platform that have been shown to induce substantial levels of durable, but primarily T-cell-biased responses against the encoded heterologous target antigen. Herein, we demonstrate the ability of rhesus CMV (RhCMV) expressing Ebola virus (EBOV) glycoprotein (GP) to provide protective immunity to rhesus macaques against lethal EBOV challenge. Surprisingly, vaccination was associated with high levels of GP-specific antibodies, but with no detectable GP-directed cellular immunity.

Interferon regulatory factors IRF-3 and IRF-7 are central to the establishment of the innate antiviral response. This study examines HSV-1 pathogenesis in IRF-3−/−, IRF-7−/− and double-deleted IRF3/7−/− (DKO) mice. Bioluminescence imaging of infection revealed that DKO mice developed visceral infection following corneal inoculation, along with increased viral burdens in all tissues relative to single knockout mice. While all DKO mice synchronously reached endpoint criteria 5 days post infection, the IRF-7−/− mice survived longer, indicating that although IRF-7 is dominant, IRF-3 also plays a role in controlling disease. Higher levels of systemic proinflammatory cytokines were found in IRF7−/− and DKO mice relative to wild-type and IRF-3−/− mice, and IL-6 and G-CSF, indicative of sepsis, were increased in the DKO mice relative to wild-type or single-knockout mice. In addition to controlling viral replication, IRF-3 and −7 therefore play coordinating roles in modulation of inflammation during HSV infection.

The European Medicines Agency provides Scientific Advice to medicines developers and patient input has been an integral part of this process for many years. As end users of medicines, patients bring their perspectives to many different processes along EMA's regulatory pathway, complementing the scientific expertise. While the value of including patients has been well-demonstrated over the years, requests for evidence of their impact continue. Using Scientific Advice as a case study, data was collected over a four-year period to assess the number of patients involved, where they contributed, as well as the impact and added value of their input. In this paper, we show that patients' contributions have a tangible impact on the recommendations provided to developers and in over half of the cases, this led to further discussion on relevant patient perspectives. These data provide quantitative evidence of the value of patient input in medicines development and supports EMA's continued inclusion of their voice throughout the medicine's lifecycle.