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

在我们AADCRC计划的第一个周期，我们的项目主要集中在表面活性蛋白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。在这次更新中，我们 初步数据显示，SP-A与白细胞介素6受体结合并干扰白细胞介素6信号，相关事件 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- 相关冠状病毒2型(SARS-CoV-2)驱动的冠状病毒病2019年(新冠肺炎)大流行出现并已 从根本上改变了我们的世界。血清IL-6升高是与 严重的新冠肺炎急性呼吸窘迫和IL-6抑制剂显示出治疗的前景。我们的数据显示 SP-A通过抑制IL-6信号中间产物发挥与SARS-CoV-2感染相关的先天功能 也通过与SARS-CoV-2用来进入的受体血管紧张素转换酶-2(ACE2)结合 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 在新冠肺炎中并通过这一机制，可起到治疗SARS-CoV-2感染的作用。几个 慢性肺部合并症被证明会增加与以下疾病相关的严重性和死亡率 新冠肺炎--哮喘是个明显的例外。来自我们小组的证据表明，2型(T2)细胞因子 如IL-4和IL-13，它们是特应性哮喘的关键分子基础，减少ACE2的表达 T2哮喘的呼吸道上皮细胞。这些发现表明，特应性哮喘相关的T2细胞因子 通过调节感染来防御新冠肺炎。在这次AADCRC的更新中，我们将在这些基础上 初步数据和合并两个互补的、独特的调查路线，以扩大我们提案的重点 并研究了SP-A和T2细胞因子在SARS的起始和效应阶段的相互作用。 哮喘患者的CoV-2呼吸道感染。我们将测试SP-A有效限制COVID的新假设- 19通过直接受体结合和抑制IL-6信号来减少ACE2介导的事件 小路。在特应性哮喘的背景下，2型细胞因子可能会降低对SARS-CoV的易感性。 2通过抑制血管紧张素转换酶2的表达和功能感染。在目标1中，我们将确定SP-A对 限制人鼻、支气管和远端呼吸道上皮细胞感染SARS-CoV-2 其作用依赖于ACE2结合和对IL-6信号的调节。在目标2中，我们将评估ACE2的表达 正常特应性和非特应性对照及T2哮喘患者的鼻腔、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 ACE2在这些细胞中的表达与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 来自新冠肺炎。这一建议充分利用了哮喘、SP-A免疫反应、病毒学和上皮细胞方面的专业知识 项目内的生物学，并与项目1和项目2很好地协同，以更好地了解哮喘中的病毒侮辱。

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.