T cell control of MCMV and tissue-localized immune suppression

摘要：在发达国家，巨细胞病毒(CMV)是导致出生缺陷的主要感染原因。通过 据估计，美国大约每100到150名儿童中就有一名出生时患有先天性心脏病 巨细胞病毒和多达一半的儿童可能会有长期的健康后果-包括听力损失、视力下降 精神障碍和精神残疾。传播给胎儿的最高风险发生在初次感染之后。 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 被医学研究所列为最优先事项。不幸的是，免疫系统在控制方面做得很差。 CMV在上皮部位的进入和排出，目前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定位途径 CMV特异性T细胞在这些部位的传播和传播及其功能。为了解决这个问题，我们 使用了天然的小鼠病原体小鼠(M)CMV，它与人类(H)CMV感染非常相似。两者都有 HCMV和MCMV被认为是通过口鼻途径进入的，我们发现MCMV持续存在 在鼻黏膜中复制，这是一个自然的感染部位。我们假设组织局部化机制 有助于这种持久性，并已确定了活跃在鼻黏膜和 唾液腺(脱落的主要部位)。具体地说，胞外腺苷调节了抗肿瘤抗体的功能。 病毒T细胞和被称为Resolvins的有效抗炎脂，它们是在鼻腔诱导的 粘膜受MCMV感染，调节病毒滴度。然而，T细胞限制了鼻黏膜中的病毒滴度， 我们的数据表明，它们也限制了在造血细胞中的传播。因此，核心假设是 这一建议是，T细胞在控制粘膜组织中病毒的能力方面受到至少2%的限制 组织定位途径，但驻留记忆T细胞可能能够抑制CMV复制并限制 病毒从粘膜组织中逸出。特定目标1将检验解析素和细胞外 感染诱导的腺苷抑制组织局部免疫反应以支持长期MCMV 持续存在于鼻黏膜和唾液腺。具体目标2将定义CD4+使用的机制 控制鼻黏膜病毒复制的T细胞，确定T细胞是否将病毒传播限制在 感染造血细胞，并检测驻留记忆T细胞是否能限制MCMV的持续和 在耐药品系和敏感品系的小鼠中传播。共同努力，我们的研究将提供第一个 鼻腔感染后巨细胞病毒、T细胞与组织环境的相互作用及填补关键空白 了解巨细胞病毒在粘膜组织中的自然感染和持久性。

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.