Chitin and chitinases in SARS-CoV-2 infection

摘要 严重急性呼吸综合征冠状病毒2(SARS-CoV-2)及其引发的冠状病毒病2019 新冠肺炎(Alipay)引发了一场全球健康危机，美国感染人数已超过1亿。非典-- CoV-2感染范围从无症状到呼吸衰竭和死亡，并可导致一系列长期的 长期效应统称为SARS-CoV-2感染的急性后遗症(PASC)。这个 这些影响的强度和持续时间背后的病理生物学机制和环境因素 尚不清楚，但一系列慢性肺损伤类似于与年龄相关的并发症 肺纤维化已经在严重的新冠肺炎中被记录下来，这表明环境驱动因素 参与肺纤维化也可能影响SARS-CoV-2感染和PASC的病程。我们有 确定环境成分甲壳素是持续SARS-CoV-2的候选环境驱动因素- 诱导性疾病，与之前描述的其在肺纤维化中的作用一致。我们的初步研究表明 这种甲壳素自发地积聚在感染SARS-CoV-2的小鼠的肺部，并伴随着 肺主要几丁质酶AMCase表达模式的变化提示几丁质-几丁质酶 相互作用可能在SARS-CoV-2的发病机制中起作用。与野生型(WT)对照组相比， 遗传性缺乏AMCase显示感染SARS-CoV-2后肺部病理加重，与甲壳素有关 以及在恢复期出现的病理后遗症中的几丁质酶。因此，我们假设 环境甲壳素可以推动新冠肺炎的严重性、上皮细胞失调和疾病持久性，而且 上皮性几丁质酶通过降解几丁质来减弱这一过程。在这个项目中，我们利用最近开发的 SARS-CoV-2感染和甲壳素暴露的小鼠模型描述宿主与环境的相互作用 可能导致SARS-CoV-2感染后的持续性肺损伤。我们将通过以下方式验证我们的假设 解决两个目标：(1)确定环境甲壳素对肺的严重性和持久性的影响 SARS-CoV-2感染后的病理，以及(2)确定哺乳动物几丁质酶在SARS-CoV-2感染中的作用 和持续性肺部疾病。了解环境甲壳素如何影响长期病理 SARS-CoV-2感染后的反应可能导致新的生物标志物和治疗靶点的确定 与新冠肺炎和PASC的不同疾病结局相关。

ABSTRACT Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and resultant coronavirus disease 2019 (COVID-19) has caused a global health crisis, surpassing 100 million infections in the United States. SARS- CoV-2 infections range from asymptomatic to respiratory failure and death, and can result in an array of long- term effects collectively referred to as post-acute sequelae of SARS-CoV-2 infection (PASC). The pathobiological mechanisms and environmental factors underlying the intensity and duration of these effects remain unclear, but a range of chronic lung impairments that resemble complications associated with age-related pulmonary fibrosis have been documented in severe COVID-19, suggesting that environmental drivers implicated in pulmonary fibrosis may also influence the course of SARS-CoV-2 infection and PASC. We have identified the environmental constituent chitin as a candidate environmental driver of persistent SARS-CoV-2- induced disease, consistent with its previously described role in pulmonary fibrosis. Our preliminary studies show that chitin spontaneously accumulates in the lungs of SARS-CoV-2-infected mice, and is accompanied by alterations in the expression patterns of the major lung chitinase, AMCase, suggesting that chitin-chitinase interactions may contribute to SARS-CoV-2 pathogenesis. In comparison with wild-type (WT) controls, mice that genetically lack AMCase exhibit exacerbated lung pathology after infection with SARS-CoV-2, implicating chitin and chitinases in the pathologic sequelae that occur during the recovery phase. Thus, we hypothesize that environmental chitin can drive COVID-19 severity, epithelial dysregulation, and disease persistence, and that epithelial chitinases attenuate this process by degrading chitin. In this project, we leverage recently developed mouse models of SARS-CoV-2 infection and chitin exposure to delineate a host-environmental interaction that may contribute to persistent lung impairments following SARS-CoV-2 infection. We will test our hypothesis by addressing two Aims: (1) determine the influence of environmental chitin on the severity and persistence of lung pathology after SARS-CoV-2 infection, and (2) define the role of mammalian chitinases in SARS-CoV-2 infection and persistent lung disease. Understanding how environmental chitin influences long-lasting pathologic responses after SARS-CoV-2 infection may lead to the identification of new biomarkers and therapeutic targets associated with differential disease outcomes in COVID-19 and PASC.