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

基本信息

批准号：
10348755
负责人：
Christopher M Snyder
金额：
$ 53.02万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10348755
关键词：
ADORA2A gene 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 Epithelial 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 Murid herpesvirus 1 Mus Myeloid Cells Nasal cavity Nasopharynx Newborn Infant Nose Occupations Outcome Pathway interactions Persons Pharyngeal structure 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 memory cell T-Lymphocyte Testing Time Tissues United States Vaccines Viral Virus Virus Replication Visual impairment base congenital cytomegalovirus disability experimental study extracellular fluorophore hearing impairment high risk immunological intervention immunoregulation motor deficit mucosal site novel pathogen prevent transmission process viral transmission

项目摘要

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）是发达国家出生缺陷的主要原因。经过据估计，在美国，大约每 100 名儿童中就有 1 人到 150 名儿童中就有 1 人出生时患有先天性 CMV 和其中多达一半的儿童可能会产生长期健康后果 - 包括听力丧失、视力丧失损伤和精神障碍。原发感染后传播给胎儿的风险最高或母亲在怀孕期间再次感染。因此，预防 CMV 传播的疫苗被认为是一种有效的疫苗。医学研究所的最高优先级。不幸的是，免疫系统在控制方面做得很差。 CMV 位于上皮细胞的进入和脱落部位，尚不清楚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局部途径这些位点的传播和传播以及 CMV 特异性 T 细胞的功能。为了解决这个问题，我们使用天然小鼠病原体鼠（M）CMV，它非常模仿人类（H）CMV感染。两个都 HCMV 和 MCMV 被认为使用口鼻途径进入，我们发现 MCMV 持续存在在自然感染部位鼻粘膜中复制。我们假设组织局部机制有助于这种持久性，并已经确定了在鼻粘膜和中活跃的新途径唾液腺（脱落的主要部位）。具体来说，细胞外腺苷调节抗- 病毒 T 细胞和被称为 Resolvins 的强效抗炎脂质，它们是在鼻腔中诱导的粘膜受MCMV感染，调节病毒滴度。然而，T 细胞限制了鼻粘膜中的病毒滴度，并且我们的数据表明它们还限制了造血细胞中的传播。因此，中心假设该提议认为，T 细胞控制粘膜组织中病毒的能力至少受到 2 倍的限制。组织局部途径，但常驻记忆 T 细胞可能能够抑制 CMV 复制并限制病毒从粘膜组织逃逸。具体目标 1 将检验 Resolvins 和细胞外蛋白的假设感染诱导的腺苷抑制组织局部免疫反应以支持长期 MCMV 持久存在于鼻粘膜和唾液腺中。具体目标 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 细胞是否限制病毒传播感染的造血细胞，并测试常驻记忆 T 细胞是否可以限制 MCMV 持久性和在耐药和敏感品系小鼠中传播。我们的研究将共同提供第一个鼻腔感染后 CMV、T 细胞和组织环境之间相互作用的图片，填补了关键空白有关自然巨细胞病毒感染及其在粘膜组织中持续存在的知识。