Genetic Analysis of Interactions Between Oral Innate Immunity and a Herpesvirus

描述（由申请人提供）：口腔是与外界接触的独特身体部位，因此不断遇到各种各样的微生物。疱疹病毒是人类重要的口腔常驻病原体。然而，关于宿主在口腔初次感染、潜伏和再激活过程中如何感知和响应疱疹病毒，特别是关于先天免疫系统，我们知之甚少。病毒与其具有免疫能力的宿主共存需要病毒复制和宿主清除之间的微妙平衡。阐明先天免疫系统和疱疹病毒之间的相互作用将有助于了解这种平衡是如何完成和调节的。小鼠γ疱疹病毒-68 （MHV-68）感染的小鼠模型为探索口腔中病毒-宿主相互作用提供了一个很好的系统，原因如下。首先，口服给药后，MHV-68在口鼻腔和唾液腺中复制。其次，一种可适应的遗传系统可用于诱变MHV-68病毒基因组。第三，MHV-68感染多种实验室小鼠品系，这使得在体内研究细胞基因在病毒感染过程中的作用成为可能。

DESCRIPTION (provided by applicant): The oral cavity represents a unique body part that is in contact with the external world and therefore constantly encounters a vast diverse of microbes. Herpesviruses are significant resident oral pathogens in humans. However, little is known about how the host senses and responds to herpesviruses during primary infection, latency and reactivation in the oral cavity, especially in regards to the innate immune system. Coexistence of a virus and its immunocompetent host entails a delicate balance between viral replication and host clearance. Elucidating the interactions between the innate immune system and herpesviruses will provide insights to how the balance is accomplished and regulated. A mouse model of murine gammaherpesvirus-68 (MHV-68) infection provides an excellent system to explore virus-host interactions in the oral cavity for several reasons. First, following oral administration, MHV-68 replicates in the oronasal cavity and the salivary gland. Second, an amenable genetic system is available to mutagenize the MHV-68 viral genome. Third, MHV-68 infects a variety of laboratory strains of mice, which allows the role of cellular genes during viral infection to be studied in vivo. The long-term goal of our discovery driven approach is to determine the role of viral and cellular proteins in virus-associated pathogenesis by employing knock-out mice and a collection of MHV-68 mutant viruses. The MHV-68 genome is randomly disrupted by an insertion of a transponson. There are 32 viral ORFs that are not required for replication in fibroblast cells and potentially involved in modulating virus-host interactions. The object of this exploratory R21 application is to define the in vivo sensing and defending role of TLR and its signaling pathway using a mouse model of oral MHV-68 infection. Furthermore, we will systematically screen viral genes that are capable of inhibiting the activation of anti-viral responses in cells, an essential step for understanding virus-host interactions.