Chitin and chitinases in SARS-CoV-2 infection

摘要 2019年严重急性呼吸系统综合征冠状病毒2（SARS-CoV-2）及其导致的冠状病毒疾病 （COVID-19）已造成全球健康危机，美国感染人数超过1亿。SARS- CoV-2感染的范围从无症状到呼吸衰竭和死亡，并可导致一系列长期的- 术语效应统称为SARS-CoV-2感染后急性后遗症（PASC）。的 这些影响的强度和持续时间的病理生物学机制和环境因素 目前尚不清楚，但一系列慢性肺损伤，类似于与年龄相关的并发症， 在严重的COVID-19中已经记录了肺纤维化，这表明环境驱动因素 与肺纤维化有关也可能影响SARS-CoV-2感染和PASC的过程。我们有 确定了环境成分几丁质作为持续性SARS-CoV-2的候选环境驱动因素， 诱导的疾病，与其先前描述的在肺纤维化中的作用一致。我们的初步研究显示 甲壳素在SARS-CoV-2感染小鼠的肺部自发积累，并伴随着 主要肺几丁质酶AMCase表达模式的改变，表明几丁质-几丁质酶 相互作用可能有助于SARS-CoV-2的发病机制。与野生型（WT）对照相比， 在感染SARS-CoV-2后，遗传上缺乏AMCase的患者表现出加重的肺部病理学， 以及在恢复期发生的病理后遗症中的几丁质酶。因此，我们假设， 环境甲壳素可以驱动COVID-19的严重程度、上皮失调和疾病持续， 上皮几丁质酶通过降解几丁质来减弱该过程。在这个项目中，我们利用最近开发的 SARS-CoV-2感染和几丁质暴露的小鼠模型，以描述宿主-环境相互作用， 可能导致SARS-CoV-2感染后持续性肺损伤。我们将测试我们的假设， 目的：（1）确定环境甲壳素对肺损伤的严重程度和持续性的影响 SARS-CoV-2感染后的病理学，以及（2）确定哺乳动物几丁质酶在SARS-CoV-2感染中的作用 和持续性肺病了解环境几丁质如何影响长期病理 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鉴定 与COVID-19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.