T cell control of MCMV and tissue-localized immune suppression

T 细胞对 MCMV 的控制和组织局部免疫抑制

• 批准号: 10579272
• 负责人: Christopher M Snyder
• 金额: $ 56.35万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-11 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579272
• 关键词: ADORA2A gene; Acceleration; Address; Adenosine; Adult; Anti-Inflammatory Agents; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Child; Cognitive; Congenital Abnormality; Cytomegalovirus; Cytomegalovirus Infections; Data; Distant; Environment; Enzyme-Linked Immunosorbent Assay; Epithelium; Fetus; Goals; Health; Hematopoietic; Histologic; Human; Immune; Immune Targeting; Immune response; Immune system; Immunosuppression; Infection; Institute of Medicine (U.S.); Knockout Mice; Knowledge; Lipids; Mass Spectrum Analysis; Morbidity - disease rate; Mothers; Mouse Strains; Mucous Membrane; Mus; Myeloid Cells; Nasal cavity; Nasopharynx; Newborn Infant; Nose; Occupations; Outcome; Pathway interactions; Persons; Pharyngeal structure; Predisposition; Pregnancy; Primary Infection; Production; Psyche structure; Public Health; Purinergic P1 Receptors; Regulatory Pathway; Resistance; Role; Route; Salivary Glands; Series; Signal Transduction; Site; Stream; Structure of mucous membrane of nose; T-Lymphocyte; Testing; Time; Tissues; United States; Vaccines; Viral; Virus; Virus Replication; Visual impairment; congenital cytomegalovirus; disability; experimental study; extracellular; fluorophore; hearing impairment; high risk; immunological intervention; immunoregulation; motor deficit; mucosal site; novel; pathogen; prevent; tissue resident memory T cell; transmission process; viral transmission

Abstract: Cytomegalovirus (CMV) is the leading infectious cause of birth defects in the developed world. By some estimates, approximately 1 in 100 to 1 in 150 children in the United States will be born with congenital CMV and up to half of these children may have long-term health consequences - including hearing loss, vision impairment and mental disabilities. The highest risk for transmission to the fetus occurs after primary infection or reinfection of the mother during pregnancy. Thus, a vaccine to prevent CMV transmission is considered a highest priority by the Institute of Medicine. Unfortunately, the immune system does a poor job at controlling CMV in epithelial sites of entry and shedding and it is unknown whether the immune system can regulate dissemination. Thus, our long-term goal is to define tissue-localized pathways that support or limit viral dissemination and transmission and the function of CMV-specific T cells in these sites. To address this, we have used the natural mouse pathogen murine (M)CMV, which closely mimics human (H)CMV infection. Both HCMV and MCMV are thought to use an oronasal route of entry and we found that MCMV persistently replicates in the nasal mucosa, a natural site of infection. We hypothesize that tissue-localized mechanisms contribute to this persistence and have identified novel pathways that are active in the nasal mucosa and salivary gland (the major site of shedding). Specifically, extracellular adenosine modulated the function of anti- viral T cells and the potent anti-inflammatory lipids known as Resolvins, which were induced in the nasal mucosa by MCMV infection, modulated viral titers. However, T cells limited viral titers in the nasal mucosa and our data suggest that they also restricted dissemination in hematopoietic cells. Thus, the central hypothesis of this proposal is that T cells are limited in their ability to control of the virus in mucosal tissues by at least 2 tissue-localized pathways, but that resident memory T cells may be able to inhibit CMV replication and limit viral escape from the mucosal tissue. Specific Aim 1 will test the hypothesis that Resolvins and extracellular adenosine induced by infection suppress tissue-localized immune responses to support long-term MCMV persistence in the nasal mucosa and salivary gland. Specific Aim 2 will define the mechanisms used by CD4+ T cells to control viral replication in the nasal mucosa, determine whether T cells confine viral dissemination to infected hematopoietic cells, and test whether resident memory T cells can restrict MCMV persistence and dissemination in both resistant and susceptible strains of mice. Together, our studies will provide the first picture of the interplay between CMV, T cells and tissue environment after nasal infection and fill key gaps in knowledge about natural CMV infection and persistence in mucosal tissues.

摘要：巨细胞病毒（CMV）是发达国家先天缺陷的主要传染病。经过 一些估计，在美国，大约有150名儿童中的100至1中大约有先天性 CMV和最多一半的孩子可能会带来长期的健康后果 - 包括听力损失，远见 障碍和精神残疾。原发性感染后发生的最高风险向胎儿传播 或在怀孕期间重新感染母亲。因此，预防CMV传输的疫苗被认为是 医学研究所的最高优先事项。不幸的是，免疫系统在控制方面做得很差 进入和脱落的上皮部位的CMV，未知免疫系统是否可以调节 传播。因此，我们的长期目标是定义支持或限制病毒的组织关闭途径 这些位点中CMV特异性T细胞的传播和传播以及CMV特异性T细胞的功能。为了解决这个问题，我们 已经使用了天然小鼠病原体鼠（M）CMV，它们紧密模仿了人（H）CMV感染。两个都 HCMV和MCMV被认为使用Ororanasal进入途径，我们发现MCMV持续 在自然感染部位鼻粘膜中复制。我们假设该组织定位的机制 有助于这种持久性，并确定了在鼻粘膜和 唾液腺（脱落的主要位置）。具体而言，细胞外腺苷调节了抗 - 病毒T细胞和有效的抗炎脂质称为Resolvins，在鼻腔中诱导 MCMV感染的粘膜，调节病毒滴度。然而，T细胞限制了鼻粘膜中的病毒滴度和 我们的数据表明，它们还限制了造血细胞中的传播。因此，中心假设 该建议是，T细胞在控制粘膜组织中控制病毒的能力中至少受到至少2个 组织关闭的途径，但是驻留的记忆T细胞可能能够抑制CMV复制并限制 病毒从粘膜组织逃脱。特定的目标1将检验分解和细胞外的假设 感染诱导的腺苷抑制组织 - 定位的免疫反应以支持长期MCMV 鼻粘膜和唾液腺的持久性。特定目标2将定义CD4+使用的机制 T细胞控制鼻粘膜中的病毒复制，确定T细胞是否将病毒传播局限于 感染造血细胞，并测试居民记忆T细胞是否可以限制MCMV持久性和 小鼠的抗性和易感性菌株的传播。一起，我们的研究将提供第一个 鼻感染后CMV，T细胞和组织环境之间相互作用的图片，并填补关键空白 关于粘膜组织中天然CMV感染和持久性的知识。