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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）是发达国家导致出生缺陷的主要传染病。通过