Immunomodulatory effects of cytomegalovirus-induced salivary soluble form of NHC class I

项目总结/摘要 人类巨细胞病毒（CMV）是一种β-疱疹病毒，感染了超过一半的美国人口。虽然 这种持续性/潜伏性感染在健康个体中是无症状的，CMV在健康个体中引起多器官疾病。 免疫受损群体（例如，艾滋病患者与实体器官/造血干细胞移植 收件人）。CMV不仅引起口腔病变（口腔溃疡、牙周病、涎腺炎、唾液腺 肿瘤），以及严重的全身性疾病（肺炎、脑炎、肝炎、结肠炎、胃炎）。CMV包涵体 在CMV感染过程中，常见于婴儿和成人的唾液腺， 脱落现在是人传人的一个公认来源。我们假设 CMV感染的唾液腺对宿主产生免疫影响。在以前的报告中，人类自然 表达活化CD 94/NKG 2C受体（CD 94和NKG 2C的异源二聚体）的杀伤（NK）细胞是 在CMV血清阳性成人中表达频率更高，并且在CMV病毒血症期间优先应答。 已知CD 94/NKG 2C识别不变的人白细胞抗原（HLA）-E糖蛋白，其是免疫球蛋白。 人主要组织相容性复合体（MHC）I类分子家族。此外，HLA-E是丰富的 在唾液腺中表达，并且可溶形式的HLA配体可以以金属蛋白酶依赖性的方式释放。 时尚.根据这些事实，我们假设CMV感染改变了HLA-E配体上的肽库， 唾液腺，产生活化CD 94/NKG 2C受体（或抑制CD 94/NKG 2C受体）的高亲和力配体。 CD 94/NKG 2A受体），将可溶形式的HLA-E配体脱落到唾液中，导致NK细胞活化（或 抑制）通过口咽腔中的粘膜免疫系统（例如，扁桃体和Peyer's patch）。 为了验证这一假设，我们提出了两个具体目标。目的1将确定结合的肽的性质 HLA-E在CMV感染与未感染的唾液腺细胞中的表达。目标2将 鉴定CMV诱导的HLA-E/肽复合物，其优先结合活化CD 94/NKG 2C， 抑制性CD 94/NKG 2A受体。在未来的研究计划中，我们将评估候选肽的能力， 结合并激活原代人口腔NK细胞。 我们的研究旨在确定唾液中可溶形式的MHC I类分子在它们出现时的作用。 在CMV感染的情况下唾液中。此外，从临床角度来看，我们建议的研究是 旨在确定HLA-E/肽复合物是否值得作为一种潜在的新的研究， 口腔CMV感染的治疗策略。

Project Summary/Abstract Human Cytomegalovirus (CMV) is a beta-herpesvirus that infects more than half of the US population. Although this persistent/latent infection is asymptomatic in healthy individuals, CMV causes multi-organ diseases in the immune-compromised population (e.g., AIDS patients and solid organ/hematopoietic stem cell transplant recipients). CMV causes not only oral lesions (oral ulceration, periodontal disease, sialadenitis, salivary gland tumor) but also severe systemic diseases (pneumonia, encephalitis, hepatitis, colitis, gastritis). CMV inclusions are frequent in the salivary glands of infants and adults during the course of CMV infection, and oropharyngeal shedding is now a well-established source of human-to-human transmission. We hypothesize that saliva from CMV-infected salivary gland provides immunological impact on the host. In previous reports, human natural killer (NK) cells expressing the activating CD94/NKG2C receptor (heterodimer of CD94 and NKG2C) are expressed in higher frequency in CMV-seropositive adults and preferentially respond during CMV viremia. CD94/NKG2C is known to recognize the invariant human leukocyte antigen (HLA)–E glycoprotein, which is the family of human major histocompatibility complex (MHC) class I molecules. Moreover, HLA-E is abundantly expressed in salivary gland, and soluble form of HLA ligand can be released in a metalloproteinase-dependent fashion. By these facts, we hypothesize that CMV infection alters the peptide repertoire on HLA-E ligand in salivary gland, generating high affinity ligands for the activating CD94/NKG2C receptor (or for the inhibitory CD94/NKG2A receptor), shedding soluble form of HLA-E ligands into saliva, resulting in NK cell activation (or inhibition) through mucosal immune system in oral-pharyngeal cavity (e.g., tonsil and Peyer's patch). To test this hypothesis we propose the two specific aims. Aim 1 will determine the nature of the peptides bound to HLA-E in CMV-infected versus uninfected salivary gland cells by mass spectrometric analysis. Aim 2 will identify CMV-induced HLA-E/peptide complexes that preferentially bind to the activating CD94/NKG2C versus inhibitory CD94/NKG2A receptors. In future research plan, we will assess the ability of candidate peptides to bind and activate primary human oral NK cells. Our studies are intended to determine the role of salivary soluble form of MHC class I molecule as they appear in saliva in the context of CMV infection. Further, from a clinical perspective, the studies we propose are designed to determine whether the HLA-E/peptide complexes deserve investigation as a potential new therapeutic strategy for oral CMV infection.