Cameron Mark J, Ran Longsi, Xu Luoling, Danesh Ali, Bermejo-Martin Jesus F, Cameron Cheryl M, Muller Matthew P, Gold Wayne L, Richardson Susan E, Poutanen Susan M, Willey Barbara M, DeVries Mark E, Fang Yuan, Seneviratne Charit, Bosinger Steven E, Persad Desmond, Wilkinson Peter, Greller Larry D, Somogyi Roland, Humar Atul, Keshavjee Shaf, Louie Marie, Loeb Mark B, Brunton James, McGeer Allison J, Kelvin David J
Division of Experimental Therapeutics, University Health Network, MaRS Centre, 3-916 TMDT, 101 College Street, Toronto, Ontario, Canada.
J Virol. 2007 Aug;81(16):8692-706. doi: 10.1128/JVI.00527-07. Epub 2007 May 30.
It is not understood how immune inflammation influences the pathogenesis of severe acute respiratory syndrome (SARS). One area of strong controversy is the role of interferon (IFN) responses in the natural history of SARS. The fact that the majority of SARS patients recover after relatively moderate illness suggests that the prevailing notion of deficient type I IFN-mediated immunity, with hypercytokinemia driving a poor clinical course, is oversimplified. We used proteomic and genomic technology to systematically analyze host innate and adaptive immune responses of 40 clinically well-described patients with SARS during discrete phases of illness from the onset of symptoms to discharge or a fatal outcome. A novel signature of high IFN-alpha, IFN-gamma, and IFN-stimulated chemokine levels, plus robust antiviral IFN-stimulated gene (ISG) expression, accompanied early SARS sequelae. As acute illness progressed, SARS patients entered a crisis phase linked to oxygen saturation profiles. The majority of SARS patients resolved IFN responses at crisis and expressed adaptive immune genes. In contrast, patients with poor outcomes showed deviated ISG and immunoglobulin gene expression levels, persistent chemokine levels, and deficient anti-SARS spike antibody production. We contend that unregulated IFN responses during acute-phase SARS may culminate in a malfunction of the switch from innate immunity to adaptive immunity. The potential for the use of the gene signatures we describe in this study to better assess the immunopathology and clinical management of severe viral infections, such as SARS and avian influenza (H5N1), is therefore worth careful examination.
目前尚不清楚免疫炎症如何影响严重急性呼吸综合征（SARS）的发病机制。一个存在激烈争议的领域是干扰素（IFN）反应在SARS自然病程中的作用。大多数SARS患者在病情相对较轻后康复，这一事实表明，关于I型干扰素介导的免疫缺陷、高细胞因子血症导致临床病程不佳的主流观点过于简单化。我们使用蛋白质组学和基因组技术，系统分析了40例临床特征明确的SARS患者从症状出现到出院或死亡的不同疾病阶段的宿主固有免疫和适应性免疫反应。早期SARS后遗症伴随着高干扰素-α、干扰素-γ和干扰素刺激趋化因子水平以及强大的抗病毒干扰素刺激基因（ISG）表达的新特征。随着急性疾病的进展，SARS患者进入与血氧饱和度相关的危机阶段。大多数SARS患者在危机时解决了干扰素反应并表达适应性免疫基因。相比之下，预后较差的患者表现出ISG和免疫球蛋白基因表达水平异常、趋化因子水平持续升高以及抗SARS刺突抗体产生不足。我们认为，急性期SARS期间不受调控的干扰素反应可能最终导致从固有免疫向适应性免疫转换的功能障碍。因此，我们在本研究中描述的基因特征用于更好地评估严重病毒感染（如SARS和禽流感（H5N1））的免疫病理学和临床管理的潜力值得仔细研究。
