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COVID-19于2019年12月首次出现，并正式被 世卫组织于2020年3月宣布大流行。在此期间，COVID-19已造成数百万病例， 世界各地的死亡。虽然大多数病例无症状或出现轻度呼吸道和流感样症状， 症状，很大一部分COVID-19患者会出现严重的肺部并发症， 炎症因子和其他表现的过度产生，在危急情况下导致多器官 功能障碍呼吸衰竭和死亡令人惊讶的是，最近的证据表明，除了典型的 严重的肺部病理，SARS-Cov-2感染还促进自身抗体的产生和其他自身免疫性疾病， 一些患者的症状。然而，为什么其他患者似乎受到保护， COVID-19相关的自身免疫性仍然未知。我们假设， SARS-Cov-2感染的患者取决于遗传易感性，但也取决于个人的病史。 暴露于环境触发因素，包括结晶二氧化硅，一种丰富的矿物质， 自身免疫为了测试这种可能性，在本补充申请中，我们提出了用小鼠进行实验 表达SARS-Cov-2的受体人ACE 2。这些小鼠将感染SARS-Cov-2， 诱导低水平COVID相关病理但无死亡的剂量，允许长期监测 自身免疫我们将测试SARS-Cov-2感染时间和气道暴露于晶体的影响， 二氧化硅对表达hACE 2的非自身免疫和狼疮易感小鼠模型中自身免疫表现的影响。 此外，我们将研究二氧化硅的剂量如何影响SARS-Cov-2感染者的自身免疫诱导。 小鼠结果将提供概念证明，暴露于环境因子可能会加剧 COVID-19相关的炎症和自身免疫反应，为未来的研究奠定了基础， 评估其他环境触发因素的影响，疾病发病机制和潜在的 治疗干预。

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.