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

巨细胞病毒诱导的 NHC I 类唾液可溶形式的免疫调节作用

基本信息

批准号：
10534609
负责人：
Taichiro Nonaka
金额：
$ 0.75万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-03 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10534609
关键词：
Immunomodulatory effects cytomegalovirus induced salivary

项目摘要

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.

项目摘要/摘要人类巨细胞病毒(CMV)是一种贝塔疱疹病毒，感染了超过一半的美国人口。虽然这种持续/潜伏的感染在健康人中是无症状的，CMV会在健康的人中引起多器官疾病免疫受损人群(例如，艾滋病患者和实体器官/造血干细胞移植收件人)。巨细胞病毒不仅会引起口腔病变(口腔溃疡、牙周病、涎腺炎、唾液腺但也有严重的全身疾病(肺炎、脑炎、肝炎、结肠炎、胃炎)。CMV包裹体在CMV感染过程中，婴儿和成人的唾液腺和口咽部常见脱落现在是人与人之间传播的一个公认的来源。我们假设唾液来自感染CMV的唾液腺对宿主产生免疫影响。在以前的报告中，人类的自然表达CD94/NKG2C受体(CD94和NKG2C的异源二聚体)的NK细胞在CMV血清阳性的成人中表达频率较高，在CMV病毒血症时优先反应。已知CD94/NKG2C识别不变的人类白细胞抗原(HLA)-E糖蛋白，它是人类主要组织相容性复合体(MHC)I类分子家族。此外，人类白细胞抗原-E基因丰富在唾液腺中表达，并可在唾液腺中以可溶性形式释放出一种金属蛋白酶依赖的配体时尚。根据这些事实，我们假设巨细胞病毒感染改变了人类白细胞抗原-E配体上的多肽库。唾液腺，产生高亲和力配体激活CD94/NKG2C受体(或抑制CD94/NKG2C受体 CD94/NKG2a受体)，将可溶性形式的HLA-E配体释放到唾液中，导致NK细胞激活(或抑制)通过口腔-咽腔粘膜免疫系统(如扁桃体和Peyer‘s斑块)。为了检验这一假设，我们提出了两个具体目标。目标1将确定结合的多肽的性质用质谱仪分析巨细胞病毒感染与未感染唾液腺细胞对人类白细胞抗原-E的影响。目标2将鉴定CMV诱导的人类白细胞抗原-E/多肽复合体优先与活化的CD94/NKG2C结合抑制CD94/NKG2A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类口腔NK细胞。我们的研究旨在确定唾液可溶形式的MHC I类分子在它们出现时的作用在巨细胞病毒感染的背景下唾液中。此外，从临床角度来看，我们建议的研究包括旨在确定人类白细胞抗原-E/多肽复合体是否值得作为一种潜在的新的口腔巨细胞病毒感染的治疗策略。