Viral Infection and Impairment of Immune Tolerance

描述（由申请人提供）：儿童早期呼吸道病毒（如呼吸道合胞病毒（RSV））的反复感染会增加以后患哮喘的风险。在成人中，呼吸道合胞病毒也是引起“流感样”疾病的重大健康风险。早期呼吸道合胞病毒感染造成哮喘风险的免疫学基础尚未得到充分调查。由于哮喘是一个重大的公共卫生问题，了解易患这种疾病的潜在因素是很重要的。我们之前对抑制过敏性气道疾病的免疫调节机制的研究表明，表达膜结合TGF-¿（mTGF-¿）的调节性T细胞（Tregs）在维持小鼠气道免疫耐受中的重要性。重要的是，人类母乳中的TGF-¿水平与婴儿喘息呈负相关。考虑到Tregs在抑制气道中不必要的过敏反应中的关键作用，我们研究了RSV感染是否会通过禁用Tregs来损害生命早期的免疫耐受。利用我们之前使用的气道耐受模型来证明mTGF-¿在气道耐受中的重要性，最近的研究表明，对抗原（Ag）卵清蛋白（OVA）耐受的母亲可以通过母乳将OVA和TGF-¿传递给新生儿，这与人类数据密切相关。该机制在新生小鼠中诱导免疫耐受，基于对新生小鼠活跃TGF-¿信号的依赖，诱导Tregs （iTregs）的作用被调用。如果新生儿感染RSV可以促进过敏性疾病，我们询问RSV是否会损害新生儿的Treg表型和功能，这在我们正在进行的实验中是显而易见的。由于RSV，特别是其糖蛋白G，与感染宿主的Th2反应有关，我们将研究其在RSV介导的Treg功能损伤中的作用。总的来说，我们有令人兴奋的数据表明，在RSV感染的肺部存在表达Foxp3和GATA-3的Tregs，这种表达由病毒诱导的th2型细胞因子促进，并被所有反式维甲酸（ATRA）减弱。体外和体内实验均表明，从感染小鼠的肺中分离出细胞后，Treg抑制功能严重受损。这些观察结果使我们提出了这一建议的主要假设，即RSV感染通过损害Treg功能来损害新生儿的母体获得性耐受机制。为了解决这个假设，我们将：目标1。探讨rsv诱导的Th2细胞因子在新生儿耐受性和Treg功能损伤中的作用。目标2。研究RSV G蛋白及其受体CX3CR1在RSV感染新生儿Treg功能损伤中的作用。目标3。检测雾化脂质体包封ATRA恢复rsv感染肺部Treg功能和气道耐受性的能力。

DESCRIPTION (provided by applicant): Recurrent infections in early childhood by respiratory viruses such as respiratory syncytial virus (RSV) increase the risk for developing asthma later in life. In adults too, RSV is a significant health risk inducing "flu-like" illnesses. The immunologi basis for why RSV infections in early life pose a risk for asthma has not been adequately investigated. Since asthma is a significant public health problem, it is important to understand the underlying factors that predispose to this disease. Our prior studies of immunoregulatory mechanisms that suppress allergic airways disease have shown the importance of regulatory T cells (Tregs) expressing membrane-bound TGF-¿ (mTGF-¿) in maintaining immune tolerance in the airways of mice. Importantly, the TGF-¿ level in the breast milk of humans has been inversely associated with wheezing in infants. Given the crucial role of Tregs in suppressing unwarranted allergic responses in the airways, we investigated whether RSV infection compromises immune tolerance in early life by disabling Tregs. Using the same model of airway tolerance previously used by us to demonstrate the importance of mTGF-¿ in airway tolerance, it was recently shown that mothers tolerized to the antigen (Ag) ovalbumin (OVA) can transfer OVA and TGF-¿ to their newborns via breast milk showing a close correspondence with human data. This mechanism was found to induce immune tolerance in the newborn mice and based on the dependence on active TGF-¿ signaling in the neonates, a role for induced Tregs (iTregs) was invoked. If RSV infection in newborns can promote allergic disease, we asked whether RSV compromises Treg phenotype and function in the newborns which is clearly evident in our ongoing experiments. Since RSV, in particular its glycoprotein G, has been associated with Th2 responses in infected hosts, we will study its role in the RSV-mediated impairment of Treg function. Collectively, we have exciting data that show the presence of Tregs expressing Foxp3 and GATA-3 in RSV infected lungs, which is promoted by Th2-type cytokines induced by the virus and attenuated by all trans retinoic acid (ATRA). Both in vitro and in vivo assays show severe impairment of Treg suppressive function when the cells are isolated from the lungs of infected mice. These observations lead us to formulate the major hypothesis of this proposal, which is that RSV infection impairs maternally-acquired tolerance mechanisms in newborns by compromising Treg function. To address this hypothesis we will: Aim 1. Investigate the role of RSV-induced Th2 cytokines in impairment of tolerance and Treg function in neonates. Aim 2. Study the contribution of the RSV G protein and its receptor CX3CR1 in impairment of Treg function in RSV-infected neonates. Aim 3. Examine the ability of aerosolized liposome-encapsulated ATRA to restore Treg function and airway tolerance in RSV-infected lungs.