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

• 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
• 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

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AADCRC计划的第一个周期中，我们的项目主要集中在表面活性剂蛋白A（SP-A），A 已知的先天免疫调节剂，在哮喘中表现出重要的抗炎作用。在这种续约中，我们 显示SP-A结合白介素（IL）-6受体并破坏IL-6信号，事件相关的初步数据 特定的哮喘表型。尽管这项工作正在进行，但严重的急性呼吸综合征 - 相关的冠状病毒2（SARS-COV-2）驱动冠状病毒疾病2019（Covid-19）大流行，已出现，并且已有 高架血清IL-6是与“细胞因子风暴”相关的标志 严重的Covid-19急性呼吸窘迫和IL-6抑制剂显示出有望作为治疗方法。我们的数据暗示 该SPA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 以及通过与血管紧张素转化酶-2（ACE2）结合，SARS-COV-2用于进入的接收器 进入宿主细胞。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，通过这种机制，可以在治疗SARS-COV-2感染中发挥作用。一些 已显示基于慢性肺的合并症会增加与之相关的严重性和死亡率 COVID -19-哮喘除外。我们小组的证据表明2型（T2）细胞因子 例如，是特应性哮喘的关键分子基础的IL-4和IL-13，降低了ACE2的表达 T2哮喘的气道上皮细胞。这些发现表明特应哮喘相关的T2细胞因子 通过调节感染来预防19号。在此AADCRC续约中，我们将基于这些 初步数据并合并两种完整性，独特的投资线，以扩大我们的提案的重点 并研究SARS-的倡议和效应子阶段的SP-A和T2细胞因子的相互作用 哮喘中的COV-2呼吸道感染。我们将测试新的假设，即SP-A有效地限制了共证 19通过直接受体结合和抑制IL-6信号传导减少ACE2介导的事件 途径。在特应性哮喘的情况下，2型细胞因子可能会降低对SARS-COV的敏感性 2通过抑制ACE2表达和功能感染。在AIM 1中，我们将确定SP-A在 限制人类鼻，支气管和远端气道上皮细胞的SARS-COV-2感染，以及这些是否是否 效果取决于IL-6信号传导的ACE2结合和调制。在AIM 2中，我们将评估ACE2表达 在鼻腔中，来自正常应对和非原子对照的支气管和不同的上皮细胞以及T2哮喘 参与者，并确定T2细胞因子和病毒诱导的干扰如何相互作用以调节上皮细胞 这些细胞中的ACE2表达和SARS-COV-2感染。我们假设SP-A和T2细胞因子可以 协同促进SARS-COV-2感染的倡议和效应阶段，从而保护 从Covid-19。该建议利用哮喘，SP-A免疫调查，病毒学和上皮的专业知识 项目中的生物学并与项目1和2协同效果，以更好地了解哮喘的病毒侮辱。