Biological Effects of SARS-CoV Spike Polymorphisms

严重急性呼吸道综合征（SevereAcuteRespiratorysyndrome，SARS）是一种新近发现的流行性疾病，发病率高，死亡率近10%。病原体是一种有包膜的RNA冠状病毒。 冠状病毒在自然界中普遍存在，目前的研究结果表明SARS冠状病毒是从动物宿主进入人类的。大量研究表明，冠状病毒表面暴露的刺突糖蛋白参与冠状病毒与宿主细胞的结合，是流行病学和致病性的关键因素。因此，刺突蛋白可能在SARS-CoV感染患者的疾病中起主要作用。因此，该项目的中心目标是鉴定和表征SARS刺突蛋白的区域，这些区域赋予感染动物和人类的能力。作为这一目标的一部分，我们将使用可溶性刺突蛋白作为检测试剂来鉴定SARS-CoV所使用的宿主细胞受体。随着受体的发现，我们将继续确定刺突多态性是否改变动物或人类受体同源物的亲和力，因为这可能解释动物到人类的病毒传播。我们将专注于相关的人类气道细胞，并将确定刺突介导的合胞体形成的细胞和病毒决定因素，因为合胞体是冠状病毒细胞病理学的公认标志。冠状病毒可以容纳许多适应性突变的刺突蛋白，我们假设异嗜性和致病性SARS-CoV区分为这些突变形式的一个子集。我们将通过识别这些变异体并表征其受体结合和合胞体诱导特性来推进我们对SARS-CoV流行病学和发病机制的理解。

Severe Acute Respiratory Syndrome (SARS) is a recently recognized epidemic disease characterized by significant morbidity and nearly 10% mortality. The etiologic agent is an enveloped RNA coronavirus. Coronaviruses are prevalent in nature and current findings suggest that the SARS eoronavirus entered the human population from animal reservoirs. Numerous studies have shown that the surface-exposed spike glycoproteins involved in coronavirus binding to host cells are critical factors in epidemiology and pathogenicity. Thus, it is likely that the spike proteins will have a major role in the disease of SARS-CoV infected patients. Therefore, the central objective of this project is to identify and characterize regions of the SARS spike proteins that confer the ability to infect both animals and humans. As part of this objective, we will identify host cell receptors used by SARS-CoV, using soluble spike proteins as detection reagents. As receptors are found, we will proceed by determining whether spike polymorphisms alter affinities for animal or human receptor homologs, as this may explain animal-to-human virus transmissions. We will focus on relevant human airway cells and will identify both cellular and viral determinants of spike-mediated syncytial formation, as syncytia are a recognized hallmark of coronavirus cytopathology. Coronaviruses can accommodate many adaptive mutations in their spike proteins, and we hypothesize that xenotropic and pathogenic SARS-CoVs are distinguished as a subset of these mutant forms. We will advance our understanding of SARS-CoV epidemiology and pathogenesis by identifying these variants and characterizing their receptor binding and syncytium inducing properties.