Oral Immunobiology of MCMV-infected Mouse Salivary Glands

描述（由申请人提供）：正常的唾液腺功能对维持口腔健康和生理健康至关重要。唾液的功能是湿润口腔组织，作为语言的辅助工具，作为对味觉很重要的溶剂，以及作为咀嚼润湿剂/润滑剂，对吞咽食物很重要。唾液含有对口腔软组织和牙齿健康很重要的无机和有机成分。唾液腺功能障碍导致唾液分泌减少和/或唾液成分改变，导致主观感觉口干（口干症）。唾液在宿主防御中也起着重要作用，是上消化道先天宿主防御的主要贡献者。此外，唾液腺是口腔粘膜免疫系统的主要组成部分，对口腔和粘膜获得性病原体具有抗原特异性免疫。虽然人们早就知道唾液腺是口腔中重要的效应器官，但唾液腺是否能在免疫反应中作为诱导部位起作用的问题尚未得到解决。如果唾液腺是诱导部位而不是效应部位，那么对唾液腺的抗原刺激可能足以在远端粘膜部位诱导对病毒和其他病原体的免疫。了解唾液腺的免疫生物学也特别有趣，因为基因治疗和组织工程的进展很快，因为它与唾液腺有关。通过体内基因转移“重新设计”唾液腺的能力，从而原位恢复液体分泌，并利用唾液腺内分泌分泌途径进行全身基因治疗，这为更好地理解唾液腺免疫如何与转移基因的表达相互作用提供了额外的理由，特别是因为转移的基因经常使用重组病毒载体表达。小鼠巨细胞病毒（MCMV）感染已被用作研究唾液腺免疫的工具。此外，MCMV感染已经被用作人类巨细胞病毒感染的模型有一段时间了。人类巨细胞病毒感染是常见的，但不会导致免疫功能正常的健康成人显著疾病。然而，在免疫功能低下的患者（移植受者或艾滋病患者）中，巨细胞病毒感染成为一种严重的并发症和死亡来源。因此，了解对巨细胞病毒感染的免疫反应可以更好地了解人类巨细胞病毒感染的发病机制。此外，人类巨细胞病毒可通过口腔和呼吸道分泌物以及性传播传播。这使得研究粘膜对MCMV的反应，特别是与人类感染相关。在本研究中，我们利用MCMV建立了一种新的涎腺集中感染模型。目的1将探讨在共同粘膜免疫系统的背景下唾液腺可以作为诱导部位的假设。目的2将研究唾液腺在粘膜和全身部位对MCMV感染产生功能性保护性免疫的假设。

DESCRIPTION (provided by applicant): Proper salivary gland function is critical for the maintenance of oral health and physiological well-being. Saliva functions to moisten the oral tissues as an aid for speech, as a solvent important for taste, and as a masticatory wetting agent/lubricant important in swallowing food. Saliva contains inorganic and organic components important for the health of the oral soft tissues and the teeth. Salivary gland dysfunction resulting in diminished salivary output and/or altered salivary composition results in the subjective sensation of dry mouth (xerostomia). Saliva also plays an important role in host defense and is a major contributor of the innate host defense of the upper gastrointestinal tract. In addition, the salivary glands are a major component in the mucosal immune system of the oral cavity that confers antigen-specific immunity to oral and mucosally-acquired pathogens. Although it has long been known that the salivary gland is an important effector organ in the oral cavity, the issue of whether the salivary gland can function as an inductive site during an immune response has not been addressed. If the salivary gland is an inductive site in addition to an effector site, antigenic stimulation of the salivary gland may be sufficient to induce immunity to viruses and other pathogens even at distal mucosal sites. Understanding the immunobiology of the salivary glands is also of particular interest because of rapidly developing progress in gene therapy and tissue engineering as it relates to the salivary gland. The ability to "re-engineer" the salivary gland via gene transfer in vivo with the resultant in situ restoration of fluid secretion and to utilize salivary endocrine secretory pathways for systemic gene therapeutics provides additional reason for gaining a better understanding of how salivary gland immunity interacts with the expression of transferred gene(s), especially because the transferred gene(s) are frequently expressed utilizing recombinant viral vectors. Murine cytomegalovirus (MCMV) infections have served as a tool for investigating salivary gland immunity. In addition, MCMV infections have already been used for some time as models for human CMV infection. Human CMV infections are common but do not lead to significant disease in immunocompetent healthy adults. Nevertheless, in immunocompromised patients (transplant recipients or AIDS patients) CMV infection becomes a serious complication and source of mortality. Therefore, understanding the immune responses to MCMV infections can lead to a better understanding of the pathogenesis of CMV infections in humans. In addition, human CMV can be spread through oral and respiratory secretions and through sexual transmission. This makes investigating the mucosal responses to MCMV, in particular, relevant to infection in humans. In this application, we have developed a new model of focused salivary gland infection utilizing MCMV. Aim 1 will investigate the hypothesis that the salivary gland can function as an inductive site in the context of the common mucosal immune system. Aim 2 will investigate the hypothesis that the salivary gland generates functionally protective immunity to MCMV infection at both mucosal and systemic sites.