Viral Infection and Impairment of Immune Tolerance

病毒感染和免疫耐受受损

• 批准号: 8513588
• 负责人: Prabir Ray
• 金额: $ 37.44万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2013-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513588
• 关键词: Address; Adult; Affect; Allergic Disease; Antibodies; Antigens; Asthma; Attenuated; Binding; Biological Assay; Birth; CD4 Positive T Lymphocytes; CX3CL1 gene; Cell physiology; Cells; Characteristics; Data; Dendritic Cells; Dependence; Development; Disease; Effector Cell; Encapsulated; Flu virus; GTP-Binding Proteins; Goals; Harvest; Health; Human; Human Milk; Hyperplasia; Immune Tolerance; Immune system; Impairment; In Vitro; Infant; Infection; Inflammation; Influenza; Interleukin-13; Interleukin-4; Irrigation; Knock-out; Lead; Life; Liposomes; Liquid substance; Literature; Lung; Lung diseases; Mediating; Membrane; Modeling; Monoclonal Antibodies; Mothers; Mucous body substance; Mus; Neonatal; Newborn Infant; Ovalbumin; Phenotype; Play; Predisposing Factor; Production; Public Health; Pulmonary Pathology; Recurrence; Regulatory T-Lymphocyte; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Respiratory syncytial virus RSV G glycoprotein; Risk; Role; Signal Transduction; Sorting - Cell Movement; Stress; Study models; Testing; Tretinoin; Virus; Virus Diseases; Wheezing; aerosolized; allergic airway disease; allergic response; attenuation; base; cytokine; early childhood; fetal; flu; glycoprotein G; human CX3CR1 protein; human data; in vivo; mouse model; neonate; novel; receptor; research study; respiratory; respiratory infection virus; respiratory virus; response; transcription factor

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.

描述（由申请方提供）：儿童早期呼吸道病毒（如呼吸道合胞病毒（RSV））的复发性感染会增加日后发生哮喘的风险。在成人中，RSV也是一种引起“流感样”疾病的重大健康风险。为什么RSV感染在生命早期会造成哮喘风险的免疫学基础尚未得到充分研究。由于哮喘是一个重要的公共卫生问题，因此了解易患这种疾病的潜在因素非常重要。我们先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-β（mTGF-β）的调节性T细胞（Tcells）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-β水平与婴儿喘息呈负相关。考虑到THBE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感染是否通过使THBE失能而损害早期生命中的免疫耐受。使用我们以前使用的相同的气道耐受模型来证明mTGF-β在气道耐受中的重要性，最近显示对抗原（Ag）卵清蛋白（OVA）耐受的母亲可以通过母乳将OVA和TGF-β转移给新生儿，这与人类数据密切相关。发现这种机制在新生小鼠中诱导免疫耐受，并且基于对新生小鼠中活性TGF-β信号传导的依赖性，引发了诱导TcB（iTcB）的作用。如果新生儿中的RSV感染可以促进过敏性疾病，我们询问RSV是否损害新生儿中的Treg表型和功能，这在我们正在进行的实验中是明显的。由于RSV，特别是其糖蛋白G，已与感染宿主的Th 2应答相关，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，显示在RSV感染的肺中存在表达Foxp 3和加塔-3的T细胞，其由病毒诱导的Th 2型细胞因子促进并由全反式视黄酸（ATRA）减弱。体外和体内试验均显示，当从感染小鼠的肺部分离细胞时，Treg抑制功能会严重受损。这些观察结果使我们形成了该提议的主要假设，即RSV感染通过损害Treg功能而损害新生儿中的母体获得性耐受机制。为了解决这个假设，我们将：目标1。研究RSV诱导的Th 2细胞因子在新生儿耐受和Treg功能受损中的作用。目标二。研究RSV G蛋白及其受体CX 3CR 1在RSV感染新生儿Treg功能受损中的作用。目标3。检查雾化脂质体包封的ATRA恢复RSV感染肺中Treg功能和气道耐受性的能力。