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: 10261957
• 负责人: Monica Kraft
• 金额: $ 37.12万
• 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/10261957
• 关键词: 2019-nCoV; ACE2; Adult 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 Airway 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; alveolar type II cell; asthmatic; cell type; chemokine; comorbidity; coronavirus disease; cytokine; cytokine release syndrome; epidemiology study; inhibitor/antagonist; 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.

在我们的AADCRC计划的第一个周期，我们的项目主要集中在表面活性剂蛋白A（SP-A）， 已知先天免疫调节剂，在哮喘中表现出重要的抗炎作用。在这次更新中，我们 显示SP-A结合白细胞介素（IL）-6受体并破坏IL-6信号传导的初步数据， 与特定的哮喘表型有关。在这项工作进行期间，严重急性呼吸系统综合症- 2019年冠状病毒病（COVID-19）大流行出现， 从根本上改变了世界升高的血清IL-6是“细胞因子风暴”的标志， 严重的COVID-19急性呼吸窘迫和IL-6抑制剂显示出作为治疗方法的希望。我们的数据表明 SP-A通过抑制IL-6信号传导中间体发挥与SARS-CoV-2感染相关的先天性功能 并通过与血管紧张素转换酶2（ACE 2）结合，ACE 2是SARS-CoV-2用于进入 进入宿主细胞这些发现表明SP-A可能减弱了不适当的先天免疫反应 在COVID-19中，并通过这种机制，可以在治疗SARS-CoV-2感染中发挥作用。几 慢性肺合并症已被证明会增加与以下疾病相关的严重程度和死亡率： COVID-19 -除了哮喘。我们小组的证据表明，2型（T2）细胞因子 如IL-4和IL-13，它们是特应性哮喘关键分子基础， T2哮喘的气道上皮细胞。这些发现表明，特应性哮喘相关的T2细胞因子 通过调节感染来预防COVID-19。在这次AADCRC更新中，我们将在这些基础上 初步数据，并合并两个互补的，独特的调查线，以扩大我们的建议的重点 并研究了SP-A和T2细胞因子在SARS的起始和效应阶段的相互作用， CoV-2呼吸道感染与哮喘我们将测试SP-A有效限制COVID的新假设， 通过直接受体结合和抑制IL-6信号传导减少ACE 2介导的事件 途径。在特应性哮喘的情况下，2型细胞因子可能降低对SARS-CoV的易感性， 2感染，通过抑制ACE 2的表达和功能。在目标1中，我们将确定SP-A在以下方面的影响： 限制SARS-CoV-2感染人鼻、支气管和远端气道上皮细胞，以及这些细胞是否 作用依赖于ACE 2结合和IL-6信号传导的调节。在目标2中，我们将评估ACE 2表达， 在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中， 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，以调节上皮细胞 ACE 2表达和SARS-CoV-2感染。我们假设SP-A和T2细胞因子可以 协同抑制SARS-CoV-2感染的起始和效应阶段，从而保护 从COVID-19该提案利用了哮喘，SP-A免疫反应，病毒学和上皮细胞 生物学在项目中，并协同项目1和2，以更好地了解哮喘病毒的侮辱。