Protracted clinical and inflammatory response to rhinovirus challenge in human asthmatics

人类哮喘患者对鼻病毒攻击的持久临床和炎症反应

• 批准号: 10540527
• 负责人: LARRY C BORISH
• 金额: $ 32.3万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540527
• 关键词: Allergens; Allergic; Asthma; Biopsy; Bronchial Hyperreactivity; Cell Compartmentation; Cells; Clinical; Confocal Microscopy; Development; Epigenetic Process; Epithelial; Epithelial Cells; Flow Cytometry; Future; Generations; Goblet Cells; Human; Immune; Immunohistochemistry; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Interleukin-13; Interleukin-5; Interleukins; Location; Lymphocyte; Lymphoid; Mediating; Memory; Metaplasia; Modeling; Outcome; Pathway interactions; Phenotype; Physiological; Population; Predisposition; Process; Production; Recurrence; Respiratory Signs and Symptoms; Respiratory Tract Infections; Rhinovirus; Rhinovirus infection; Risk; Severities; Symptoms; TSLP gene; Tissues; adaptive immune response; airborne allergen; airway epithelium; airway inflammation; airway remodeling; associated symptom; asthma exacerbation; asthmatic; cell type; chemokine; cohort; cytokine; eosinophil; eosinophilic inflammation; gene discovery; inflammatory milieu; mast cell; novel; pulmonary function; receptor; recruit; respiratory virus; response; single-cell RNA sequencing; transcriptomics

Rhinovirus (RV) infections are the most common cause of asthma exacerbations and our previous studies with experimental RV-A16 inoculations demonstrate the ability of this model to recapitulate the physiological and immune consequences of natural infections. What has never previously been appreciated is that asthmatics consistently also demonstrate recurrence of upper and lower airway symptoms peaking 2-3 weeks post- inoculation. RV inoculation in asthmatics is associated with rapid development of an eosinophilic response in the airway that peaks at 2-4 days post-infection (dpi). This increase in eosinophilic inflammation evolves too rapidly to be explained by an adaptive immune response, however, the ability of the innate immune system to exacerbate an established type 2 inflammatory state is recognized. This reflects generation by a dysmatured epithelial cells (EpC) compartment of a type 2 inflammation-promoting milieu including release of the cytokines interleukin (IL)-25, IL-33, and TSLP. IL-25 has recently been recognized to be exclusively produced by a differentiated EpC termed the solitary chemosensory cell (SCC). All 3 cytokines activate immune cells of the airway, including innate lymphoid 2 cells (ILC2s). But other cells including mast cells express their receptors and will respond with secretion of IL-5 and IL-13. Along with enhanced expression of other epithelial-derived eosinophil-activating cytokines, this explains the exacerbation of eosinophilic inflammation and symptoms observed within 2-3 days of the inoculation. In the proposed studies, we are particularly eager to explore mechanisms responsible for the protracted worsening of airway symptoms and inflammation. The increase in IL-13 production will promote the further differentiation of goblet cells and SCCs and we predict that these will comprise an increasingly high proportion of airway EpCs over 2-3 weeks. SCC-derived IL-25 (and other cytokines) will then promote the expansion of mast cells and ILC2s. However, this late recurrence of asthma symptoms is occurring in the presence of ongoing aeroallergen exposure. Our studies have demonstrated the ability of RV to enhance adaptive immune responses to bystander aeroallergens. The interaction of allergens with expanded populations of mast cells and allergen-specific CD4+ tissue resident memory (TRM) lymphocytes will establish a milieu that we propose underlies the protracted worsening of inflammation and symptoms. In summary, we hypothesize that RV infection results in the rapid induction of an inflammatory response by a dysmatured epithelial compartment, which leads to the exacerbation of a type 2 inflammatory state that is responsible for the rapid development RV-induced asthma exacerbations. More importantly, we propose that this RV infection will lead to the delayed expansion of SCCs, ILC2s, CD4+ TRM lymphocytes, and mast cells, that leads to the recurrent/protracted worsening of respiratory symptoms and enhances susceptibility to further exacerbations. This feedforward loop thereby forms the basis for a severe asthma phenotype characterized by frequent exacerbations and, in some situations, to the irreversible loss of lung function. 1

鼻病毒（RV）感染是哮喘急性发作的最常见原因，我们先前的研究表明， 实验性RV-A16接种证明了该模型重现生理和 自然感染的免疫后果。以前从未被认识到的是， 也一致地表明上和下呼吸道症状的复发，在治疗后2-3周达到峰值。 接种。在哮喘患者中接种RV与快速发展的嗜酸性粒细胞反应相关， 在感染后2-4天（DPI）达到峰值的气道。这种嗜酸性粒细胞炎症的增加也会发展 然而，先天免疫系统的能力， 加重已建立的2型炎症状态。这反映了一个发育不良的 2型炎症促进环境的上皮细胞（EpC）区室，包括细胞因子的释放 白细胞介素（IL）-25，IL-33和TSLP。IL-25最近被认为是由一种 分化的EpC称为孤立的化学感受细胞（SCC）。所有3种细胞因子都激活了 气道，包括先天性淋巴样2细胞（ILC 2）。但其他细胞包括肥大细胞表达它们的受体 并将以IL-5和IL-13的分泌应答。沿着其他上皮源性 嗜酸性粒细胞激活细胞因子，这解释了嗜酸性粒细胞炎症和症状的恶化 在接种后2-3天内观察。在拟议的研究中，我们特别渴望探索 导致气道症状和炎症持续恶化的机制。的增加 IL-13的产生将促进杯状细胞和SCC的进一步分化，我们预测这些将促进SCC的分化。 包括在2-3周内越来越高比例的气道EPC。SCC衍生的IL-25（和其他 细胞因子）然后将促进肥大细胞和ILC 2的扩增。然而，这种迟发性哮喘 症状是在持续暴露于空气过敏原的情况下发生的。我们的研究表明， RV增强对旁观者空气变应原的适应性免疫应答的能力。过敏原的相互作用 肥大细胞和变应原特异性CD 4+组织驻留记忆（TRM）淋巴细胞的扩增群体 将建立一个环境，我们提出的基础上长期恶化的炎症和症状。在 综上所述，我们假设RV感染导致快速诱导炎症反应， 发育不良的上皮区室，这导致2型炎症状态的恶化， 导致RV引起的哮喘急性发作的快速发展。更重要的是，我们建议， 这种RV感染将导致SCC、ILC 2、CD 4 + TRM淋巴细胞和肥大细胞的延迟扩增， 这导致呼吸道症状的反复/持久恶化，并增加了对进一步呼吸道疾病的易感性。 加重因此，该前馈回路形成了严重哮喘表型的基础，其特征在于 频繁加重，在某些情况下，导致肺功能不可逆转的丧失。 1

项目成果

The Impact of CFTR Modulator Triple Therapy on Type 2 Inflammatory Response in Patients with Cystic Fibrosis.

CFTR 调节剂三联疗法对囊性纤维化患者 2 型炎症反应的影响。

• DOI: 10.21203/rs.3.rs-2846739/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Mehta,Ajay;Lee,Irene;Li,Galvin;Jones,Marieke;Hanson,Lydia;Lonabaugh,Kevin;List,Rhonda;Borish,Larry;Albon,Dana
• 通讯作者: Albon,Dana

Nasal polyposis: A neovascularization disorder?

• DOI: 10.1016/j.anai.2022.04.033
• 发表时间: 2022-07
• 期刊: Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology
• 作者: L. Borish;W. Eschenbacher

Rethinking the central role of mast cells in virally mediated asthma exacerbations.

重新考虑肥大细胞在病毒介导的哮喘恶化中的核心作用。

• DOI: 10.1016/j.anai.2022.03.029
• 发表时间: 2022-12
• 期刊: ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY
• 影响因子: 5.9
• 作者: Borish, Larry

Insights into mechanisms of immunotherapy circa 1943: "What has been will be again".

1943 年左右对免疫治疗机制的见解：“已有之事，必将再次发生”。

• DOI: 10.1016/j.anai.2023.01.035
• 发表时间: 2023
• 期刊: Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology
• 作者: Borish,Larry

Bronchoalveolar lavage cytokine patterns in children with severe neutrophilic and paucigranulocytic asthma.

• DOI: 10.1016/j.jaci.2020.05.039
• 发表时间: 2021-03
• 期刊: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
• 影响因子: 14.2
• 作者: Steinke, John W.;Lawrence, Monica G.;Teague, W. Gerald;Braciale, Thomas J.;Patrie, James T.;Borish, Larry
• 通讯作者: Borish, Larry