Surfactant Protein-A and Type 2 Asthma in SARS-CoV-2 Infection

SARS-CoV-2 感染中的表面活性蛋白 A 和 2 型哮喘

基本信息

批准号：
10473864
负责人：
Monica Kraft
金额：
$ 45.08万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10473864
关键词：
2019-nCoV ACE2 Acute Respiratory Distress Syndrome Antiinflammatory Effect Asthma Attenuated Binding Biology COVID-19 COVID-19 pandemic COVID-19 patient COVID-19 severity COVID-19 treatment Cells Chronic Chronic Obstructive Pulmonary Disease Collectins Communities Country Data Distal Epithelial Epithelial Cells Event Exhibits Extrinsic asthma Family Genetic Transcription Human IL-6 inhibitor Immune response Immunomodulators Infection Inflammation Mediators Inflammatory Response Influenza Innate Immune Response Interferons Interleukin 6 Receptor Interleukin-13 Interleukin-4 Interleukin-6 Investigation Mediating Modeling Molecular Natural Immunity Nose Participant Pathogenesis Phase Phenotype Play Predisposition Preparation Pulmonary Surfactant-Associated Protein A Receptor Inhibition Research Respiratory Tract Infections Role SARS-CoV-2 infection Serum Severities Signal Pathway Signal Transduction Testing Viral Virus Virus Diseases Vision Work airway epithelium airway immune response alveolar type II cell asthmatic cell type chemokine comorbidity coronavirus disease cytokine cytokine release syndrome epidemiology study inhibitor kidney epithelial cell lung basal segment member mortality mouse model novel programs protective effect receptor receptor binding respiratory virus response severe COVID-19 tocilizumab virology

项目摘要

During the first cycle of our AADCRC program, our project focused primarily on Surfactant Protein A (SP-A), a known innate immune modulator that exhibits important anti-inflammatory effects in asthma. In this renewal, we show preliminary data that SP-A binds the interleukin (IL)-6 receptor and disrupts IL-6 signaling, events relevant to specific asthma phenotypes. While this work was progressing, the Severe Acute Respiratory Syndrome- related Coronavirus 2 (SARS-CoV-2)-driven coronavirus disease 2019 (COVID-19) pandemic emerged and has fundamentally changed our world. Elevated serum IL-6 is a hallmark of the “cytokine storm” associated with severe COVID-19 acute respiratory distress and IL-6 inhibitors show promise as treatments. Our data suggest that SP-A exhibits innate functions relevant to SARS-CoV-2 infection by inhibiting IL-6 signaling intermediates and also by binding to angiotensin converting enzyme-2 (ACE2), the receptor used by SARS-CoV-2 for entry into host cells. These findings suggest that SP-A may attenuate the inappropriate innate immune responses in COVID-19 and by this mechanism, could play a role in the treatment of SARS-CoV-2 infection. Several chronic lung-based comorbidities have been shown to increase the severity and mortality associated with COVID-19 - with the notable exception of asthma. Evidence from our group suggests that type-2 (T2) cytokines such as IL-4 and IL-13, which are critical molecular underpinnings of atopic asthma, reduce ACE2 expression in airway epithelial cells from T2 asthma. These findings suggest that atopic asthma-associated T2 cytokines protect against COVID-19 by modulating infection. In this AADCRC renewal, we will build on these preliminary data and merge two complementary, unique lines of investigation to expand the focus of our proposal and investigate the interplay of SP-A and T2 cytokines at both the initiation and the effector stages of SARS- CoV-2 respiratory tract infection in asthma. We will test the novel hypothesis that SP-A effectively limits COVID- 19 by decreasing ACE2-mediated events through direct receptor binding and inhibition of IL-6 signaling pathways. In the setting of atopic asthma, type-2 cytokines may reduce the susceptibility to SARS-CoV- 2 infection by inhibiting ACE2 expression and function. In aim 1, we will determine the impact of SP-A in limiting SARS-CoV-2 infection of human nasal, bronchial and distal airway epithelial cells and whether these effects depend upon ACE2 binding and modulation of IL-6 signaling. In aim 2, we will assess ACE2 expression in nasal, bronchial and distal epithelial cells from normal atopic and non-atopic controls and T2 asthmatic participants, and determine how T2 cytokines and virus-induced interferons interact to regulate epithelial cell ACE2 expression and SARS-CoV-2 infection in these cells. We hypothesize that SP-A and T2 cytokines can synergize to dampen both the initiation and the effector phases of SARS-CoV-2 infection, thereby protecting from COVID-19. This proposal leverages expertise in asthma, SP-A immune responses, virology and epithelial biology within the project and synergizes well with Projects 1 and 2 to better understand viral insults in asthma.

在我们 AADCRC 计划的第一个周期中，我们的项目主要关注表面活性剂蛋白 A (SP-A)，这是一种已知的先天免疫调节剂在哮喘中表现出重要的抗炎作用。显示初步数据表明 SP-A 结合白细胞介素 (IL)-6 受体并破坏 IL-6 信号传导、相关事件在这项工作取得进展的同时，严重急性呼吸综合征 - 相关的冠状病毒 2 (SARS-CoV-2) 驱动的 2019 年冠状病毒病 (COVID-19) 大流行已出现并已从根本上改变了我们的世界。血清 IL-6 升高是与“细胞因子风暴”相关的一个标志。我们的数据表明，严重的 COVID-19 急性呼吸窘迫和 IL-6 抑制剂作为治疗方法具有前景。 SP-A 通过抑制 IL-6 信号中间体表现出与 SARS-CoV-2 感染相关的先天功能还通过与血管紧张素转换酶-2 (ACE2) 结合，血管紧张素转换酶 2 是 SARS-CoV-2 用于进入的受体这些发现表明 SP-A 可能会减弱不适当的先天免疫反应。在 COVID-19 中，通过这种机制，可以在治疗 SARS-CoV-2 感染中发挥作用。慢性肺部合并症已被证明会增加与相关疾病相关的严重程度和死亡率 COVID-19 - 我们小组的证据表明 2 型 (T2) 细胞因子除外。例如 IL-4 和 IL-13 是特应性哮喘的关键分子基础，可降低 ACE2 的表达来自 T2 哮喘的气道上皮细胞这些发现表明与特应性哮喘相关的 T2 细胞因子。通过调节感染来预防 COVID-19 在本次 AADCRC 更新中，我们将以此为基础。初步数据并合并两个互补的、独特的调查路线，以扩大我们提案的重点并研究 SP-A 和 T2 细胞因子在 SARS 起始阶段和效应阶段的相互作用我们将测试 SP-A 有效限制 COVID-1 的新假设。 19 通过直接受体结合和抑制 IL-6 信号传导来减少 ACE2 介导的事件在特应性哮喘的情况下，2 型细胞因子可能会降低对 SARS-CoV-的易感性。 2 通过抑制 ACE2 表达和功能来感染在目标 1 中，我们将确定 SP-A 对感染的影响。限制人鼻腔、支气管和远端气道上皮细胞的 SARS-CoV-2 感染，以及这些是否效果取决于 ACE2 结合和 IL-6 信号传导的调节在目标 2 中，我们将评估 ACE2 表达。来自正常特应性和非特应性对照以及 T2 哮喘患者的鼻、支气管和远端上皮细胞参与者，并确定 T2 细胞因子和病毒诱导的干扰素如何相互作用来调节上皮细胞我们发现 SP-A 和 T2 细胞因子可以影响这些细胞中的 ACE2 表达和 SARS-CoV-2 感染。协同抑制 SARS-CoV-2 感染的起始阶段和效应阶段，从而保护该提案利用了哮喘、SP-A 免疫反应、病毒学和上皮细胞方面的专业知识。该项目内的生物学并与项目 1 和 2 很好地协同作用，以更好地了解哮喘中的病毒损伤。