Synergistic effects of silica exposure, virus infection and genetic predisposition in systemic autoimmunity

项目摘要 由新型冠状病毒SARS-CoV-2引起的新冠肺炎最早出现在2019年12月，并正式 世卫组织于2020年3月宣布大流行。在此期间，新冠肺炎引发了数以百万计的案件和 世界各地的死亡人数。虽然大多数病例没有症状或出现轻度呼吸道和流感样症状 症状，很大一部分新冠肺炎患者会出现严重的肺部并发症， 炎症因子和其他症状的过度产生，在危重病例中导致多器官 功能障碍，呼吸衰竭和死亡。引人注目的是，最近的证据表明，除了典型的 严重的肺部病理，SARS-CoV-2感染也促进自身抗体的产生和其他自身免疫 部分患者的临床表现。然而，为什么其他患者似乎受到保护，以及 新冠肺炎相关的自身免疫仍不清楚。我们假设自身免疫的发展是在 感染SARS-CoV-2的患者不仅取决于遗传易感性，还取决于个人的病史 暴露于环境诱因，包括结晶二氧化硅，一种丰富的矿物质，经常与 自身免疫力。为了测试这种可能性，在本补充应用程序中，我们建议用小鼠进行实验 表达SARS-CoV-2的受体人ACE2。这些小鼠将在以下时间感染SARS-CoV-2 导致低水平COVID相关病理但无死亡的剂量，允许长期监测 自身免疫力。我们将测试SARS-CoV-2感染时间和呼吸道接触水晶的影响 硅胶在表达hACE2的非自身免疫和狼疮易感小鼠模型中的自身免疫表现。 此外，我们还将研究二氧化硅剂量如何影响SARS-CoV-2感染患者的自身免疫诱导。 老鼠。这一结果将提供暴露于环境制剂可能加剧的概念证据 新冠肺炎相关的炎症和自身免疫反应，为未来的研究奠定了基础 评估其他环境诱因、疾病发病机制和潜在的影响 治疗性干预。

Project Summary COVID-19 caused by the novel coronavirus SARS-Cov-2 first emerged in December 2019 and was officially declared a pandemic by WHO in March 2020. During this time, COVID-19 has caused millions of cases and deaths across the world. While most cases are asymptomatic or present with mild respiratory and flu-like symptoms, a significant fraction of COVID-19 patients develop severe pulmonary complications, overproduction of inflammatory factors and other manifestations, leading in critical cases to multiorgan dysfunction, respiratory failure and death. Strikingly, recent evidence indicates that, besides the typical severe lung pathology, SARS-Cov-2 infection also promotes autoantibody production and other autoimmune manifestations in some patients. However, why other patients seem protected and the mechanisms for COVID-19-associated autoimmunity remain unknown. We hypothesize that autoimmunity development in SARS-Cov-2-infected patients depends on genetic predisposition but also on the history of the individual’s exposure to environmental triggers, including crystalline silica, an abundant mineral often associated with autoimmunity. To test this possibility, in this supplemental application we propose experiments with mice expressing human ACE2, the receptor for SARS-Cov-2. These mice will be infected with SARS-Cov-2 at doses that induce low-level COVID-related pathology but no mortality, allowing long-term monitoring for autoimmunity. We will test the effect of the time of SARS-Cov-2 infection and airway exposure to crystalline silica on autoimmune manifestations in hACE2-expressing non-autoimmune and lupus-prone mouse models. In addition, we will examine how the dose of silica affects induction of autoimmunity in SARS-Cov-2-infected mice. The results will provide proof of concept that exposure to environmental agents may exacerbate COVID-19-associated inflammatory and autoimmune responses, creating the foundation for future studies to assess the effect of other environmental triggers, mechanisms of disease pathogenesis, and potential therapeutic interventions.