Herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2) are amongst the most common human infectious viral pathogens capable of causing serious clinical diseases at every stage of life, from fatal disseminated disease in newborns to cold sores genital ulcerations and blinding eye disease. Primary mucocutaneous infection with HSV-1 & HSV-2 is followed by a lifelong viral latency in the sensory ganglia. In the majority of cases, herpes infections are clinically asymptomatic. However, in symptomatic individuals, the latent HSV can spontaneously and frequently reactivate, reinfecting the muco-cutaneous surfaces and causing painful recurrent diseases. The innate and adaptive mucosal immunities to herpes infections and disease remain to be fully characterized. The understanding of innate and adaptive immune mechanisms operating at muco-cutaneous surfaces is fundamental to the design of next-generation herpes vaccines. In this paper, the phenotypic and functional properties of innate and adaptive mucosal immune cells, their role in antiherpes immunity, and immunopathology are reviewed. The progress and limitations in developing a safe and efficient mucosal herpes vaccine are discussed. 1. Introduction Herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2) are among the most common human infectious viral pathogens [1–3]. So many people have HSV-1 and/or HSV-2 but do not know that they have it [4, 5]. These two viruses can cause lifelong diseases with clinical manifestations including cold sores, genital ulcerations, corneal blindness, and encephalitis [6–8]. In cases of vertical transmission to the newborn, HSV-1 and HSV-2 can cause fatal neonatal encephalitis [9–11]. In the past two decades, there have been increasing reports of a worldwide pandemic of herpes infections despite the widespread use of antiviral drug therapies (reviewed in [12]). At the site of primary infection, HSV undergoes a productive replication within the epithelial cells lining the mucosa. Thereafter, the virus enters nearby sensory neurons, and the viral genome is transported to the neuronal nuclei in the sensory ganglia (trigeminal (TG) or dorsal root (DRG)) that innervate the infected site. During the first week after infection, HSV replication takes place in ganglionic sensory neurons, but within a few days no virus can be detected. While epithelial cells are destroyed during lytic HSV replication, most neuronal cells appear largely intact and serve as a reservoir for the latent virus. During reactivation, the virus travels from the TG and DRG back to the site of primary infection
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