Clinical immune response to rhinovirus challenge in human asthmatics

人类哮喘患者对鼻病毒攻击的临床免疫反应

• 批准号: 9075457
• 负责人: LARRY C BORISH
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-18 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9075457
• 关键词: Address; Adenoidal structure; Allergic; Antiviral Agents; Apoptotic; Asthma; Automobile Driving; Biology; Biopsy; CCL11 gene; CCL24 gene; CCL26 gene; CXCL1 gene; CXCL10 gene; Caspase-1; Cell Death; Cells; Cessation of life; Child; Clinical; Defect; Development; Epigenetic Process; Epithelial; Epithelial Cells; Etiology; Evolution; Gene Expression Profile; Health; Human; Human Volunteers; Immune; Immune response; Immune system; Immunity; Immunology; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response; Interferon-alpha; Interferons; Interleukin-15; Interleukin-18; Measures; Mediator of activation protein; Modification; Molecular; Monitor; Morbidity - disease rate; Nasal Epithelium; Nature; Necrosis; Nose; Pathology; Pathway interactions; Pattern; Predisposition; Process; RANTES; Research Personnel; Rhinovirus; Role; Severities; TLR3 gene; TLR7 gene; TSLP gene; Testing; Time; Universities; Viral; Viral Load result; Virginia; Virus Diseases; Vision; adaptive immunity; adverse outcome; allergic airway disease; asthmatic; asthmatic airway; base; clinical investigation; cytokine; design; eosinophil; expectation; in vivo; prevent; programs; response; viperin; virology; young adult

DESCRIPTION (provided by applicant): Most asthma exacerbations in children and young adults result from rhinovirus (RV) infections. As the most important cause of asthma-related morbidity it is essential that clinical investigations be performed in humans to define the underlying mechanisms. We hypothesize that the immune responses generated in the nose of asthmatics underlie subsequent systemic modulation of the immune system, and that - in susceptible individuals (those with pre-existing asthma) - this modified nasal milieu is responsible for the asthma exacerbation. Specifically, we propose that this modification produces a distinct pattern of immune responsiveness to RV in the upper airway of asthmatics, which triggers the development of a Th2 cytokine "signature" state that drives the adverse outcome of RV infection in the lower airway of asthmatics. In addition, we propose that the intensity of this Th2-inducing nasal airway milieu is further exaggerated in these allergic asthmatics, by a concomitant defect in the development and expression of effective anti-RV immune responses, leading to greater susceptibility to RV. Determining the etiology of rhinovirus-induced asthma exacerbations will identify specific targets to prevent and treat these episodes. Specific Aim 1 will address the hypothesis that epigenetic changes develop in nasal epithelial cells (EC) during the evolution of allergic airway disease as a result of which nasal EC are programmed to produce cytokines central to orchestrating an allergic inflammatory immune response. We will primarily determine whether nasal epithelium from allergic asthmatics, when infected with RV, is programmed to secrete cytokines that promote a Th2 cytokine "signature" (IL-25, IL- 33, and TSLP). Specific Aim 2 will interrogate the complementary hypothesis that increased susceptibility to RV and extent of nasal infections in asthmatics amplifies the consequences of this Th2-inducing bias. Specifically we propose that over time nasal epithelium in asthmatics is epigenetically re-programmed, resulting in the greater susceptibility of EC to RV infection. Initially we will analyze nasal EC ex vivo to test the hypothesis that EC from asthmatics will be more susceptible to RV infection as manifested by a greater magnitude of RV replication, a more rapid tempo of infection and overall greater death of RV-infected cells. We will then corroborate this in vitro analysis with in vivo studies by infecting asthmatics and controls with RV, monitoring viral load over time as a measure of the pace of infection. Most importantly, we will perform nasal biopsies at the peak of infection to determine the extent of viral infection and whether this represents cytopathic (necrotic) or apoptotic cell death. And, finally, Specific Aim 3 will address the molecular and cellular basis for the defect in anti-viral immunity in asthma. We will establish primary cultures of EC from control and asthmatic individuals prior to RV infection and examine them for baseline- and RV infection- induced expression of cytokines central to anti-viral immunity (IFNs-α, -ß, and λ and IL-15). We expect that anti-viral mediator expression will correlate inversely with the susceptibility, tempo, and severity of RV infection.

描述（由申请方提供）：大多数儿童和年轻人的哮喘急性发作是由鼻病毒（RV）感染引起的。作为哮喘相关发病率的最重要原因，在人类中进行临床研究以确定潜在机制至关重要。我们假设哮喘患者鼻内产生的免疫反应是随后免疫系统系统调节的基础，并且在易感个体（先前存在哮喘的个体）中，这种改变的鼻环境是哮喘恶化的原因。具体来说，我们建议，这种修改产生了一个独特的模式，免疫反应RV在哮喘患者的上呼吸道，这触发了发展的Th 2细胞因子的“签名”状态，驱动RV感染的不良后果在哮喘患者的下呼吸道。此外，我们提出，这种Th 2诱导的鼻气道环境的强度在这些过敏性哮喘患者中被进一步夸大，在有效的抗RV免疫应答的发展和表达中伴随缺陷，导致对RV的更大易感性。确定鼻病毒引起的哮喘急性发作的病因将确定预防和治疗这些发作的特定靶点。具体目标1将解决这一假设，即在过敏性气道疾病的演变过程中，鼻上皮细胞（EC）发生表观遗传变化， 被编程以产生细胞因子，该细胞因子对于协调变应性炎症免疫应答至关重要。我们将主要确定过敏性哮喘患者的鼻上皮在感染RV时是否被编程为分泌促进Th 2细胞因子“签名”（IL-25、IL- 33和TSLP）的细胞因子。具体目标2将询问补充假设，即哮喘患者对RV的易感性增加和鼻腔感染程度放大了这种Th 2诱导偏倚的后果。具体来说，我们认为随着时间的推移，哮喘患者的鼻上皮细胞表观遗传学重新编程，导致EC对RV感染的易感性增加。最初，我们将分析鼻EC离体测试的假设，EC从哮喘患者将更容易RV感染表现为更大幅度的RV复制，更快的感染克里思和整体更大的RV感染细胞的死亡。然后，我们将通过用RV感染哮喘患者和对照组来证实这种体外分析与体内研究，监测病毒载量随时间的变化，作为感染速度的衡量标准。最重要的是，我们将在感染高峰期进行鼻活检，以确定病毒感染的程度，以及这是否代表细胞病变（坏死）或凋亡细胞死亡。最后，特异性目标3将解决哮喘抗病毒免疫缺陷的分子和细胞基础。我们将在RV感染前建立对照和哮喘个体EC的原代培养物，并检查其基线和RV感染诱导的抗病毒免疫核心细胞因子（IFN-α、IFN-γ和IFN-λ以及IL-15）的表达。我们预计，抗病毒介质的表达将与RV感染的易感性，克里思和严重程度呈负相关。

项目成果

Fatal Coxsackie meningoencephalitis in a patient with B-cell lymphopenia and hypogammaglobulinemia following rituximab therapy.

利妥昔单抗治疗后出现 B 细胞淋巴细胞减少和低丙种球蛋白血症的患者发生致命柯萨奇脑膜脑炎。

• DOI: 10.1016/j.anai.2015.05.007
• 发表时间: 2015
• 期刊: Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology
• 作者: Palacios,Thamiris;Bartelt,Luther;Scheld,William;Lopes,MBeatriz;Kelting,SarahM;Holland,Steven;Lipkin,WIan;Quan,Phenix-Lan;Borish,Larry;Lawrence,Monica
• 通讯作者: Lawrence,Monica

Nasal IgE production in allergic rhinitis: Impact of rhinovirus infection.

过敏性鼻炎中鼻 IgE 的产生：鼻病毒感染的影响。

• DOI: 10.1111/cea.13372
• 发表时间: 2019
• 期刊: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
• 作者: Hamed,Ahmed;Preston,DeVonC;Eschenbacher,Will;Khokhar,Dilawar;Workman,Lisa;Steinke,JohnW;Heymann,Peter;Lawrence,Monica;Soto-Quiros,Manuel;Platts-Mills,ThomasAE;Payne,Spencer;Borish,Larry
• 通讯作者: Borish,Larry