T cell control of MCMV and tissue-localized immune suppression

翻译后摘要：巨细胞病毒（CMV）是在发达国家出生缺陷的主要传染性原因。通过 据估计，在美国，大约每100到150名儿童中就有1名出生时患有先天性 CMV和多达一半的这些儿童可能有长期的健康后果-包括听力损失，视力 残疾和精神残疾。传播给胎儿的最高风险发生在初次感染后 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 医学研究所的最高优先级。不幸的是，免疫系统在控制 CMV在上皮部位的进入和脱落，免疫系统是否可以调节是未知的 传播。因此，我们的长期目标是确定支持或限制病毒感染的组织定位途径。 传播和传播以及CMV特异性T细胞在这些部位的功能。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，其非常类似于人（H）CMV感染。两 巨细胞病毒和巨细胞病毒被认为是使用口鼻途径进入，我们发现， 在鼻粘膜中复制，鼻粘膜是感染的自然部位。我们假设组织定位机制 有助于这种持久性，并确定了在鼻粘膜中活跃的新途径， 唾液腺（脱落的主要部位）。具体地说，细胞外腺苷调节抗- 病毒T细胞和称为Resolvins的强效抗炎脂质，这些脂质在鼻腔中诱导， 粘膜MCMV感染，调制病毒滴度。然而，T细胞限制了鼻粘膜中的病毒滴度， 我们的数据表明它们也限制了造血细胞中的传播。因此， 这一建议是T细胞在其控制粘膜组织中病毒的能力方面受到至少2 组织定位的途径，但常驻记忆T细胞可能能够抑制CMV复制和限制 病毒从粘膜组织逃逸。具体目标1将检验消退素和细胞外 感染诱导的腺苷抑制组织局部免疫应答以支持长期MCMV 持久存在于鼻粘膜和唾液腺中。具体目标2将定义CD 4+使用的机制 T细胞控制鼻粘膜中的病毒复制，决定T细胞是否限制病毒传播到鼻粘膜。 感染的造血细胞，并测试驻留记忆T细胞是否可以限制MCMV的持久性， 在耐药和敏感品系小鼠中传播。我们的研究将提供第一个 描述了鼻腔感染后CMV、T细胞和组织环境之间的相互作用，并填补了 了解自然CMV感染和在粘膜组织中的持续性。

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.