Lethal influenza virus infection in macaques is associated with early dysregulation of inflammatory related genes.
Lethal influenza virus infection in macaques is associated with early dysregulation of inflammatory related genes.
复制标题
猕猴中致命的流感病毒感染与炎症相关基因的早期失调有关。
DOI：
10.1371/journal.ppat.1000604
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发表时间：
2009-10
期刊：
影响因子：
6.7
通讯作者：
Katze MG
中科院分区：
文献类型：
--
作者：
Cillóniz C;Shinya K;Peng X;Korth MJ;Proll SC;Aicher LD;Carter VS;Chang JH;Kobasa D;Feldmann F;Strong JE;Feldmann H;Kawaoka Y;Katze MG
1918 年至 1919 年西班牙流感大流行期间造成的巨大人员伤亡不断提醒我们流感病毒的潜在致命性。随着世界卫生组织宣布新的H1N1流感病毒大流行，以及人类高致病性H5N1禽流感病毒感染病例的持续出现，更好地了解宿主对高致病性流感病毒的反应至关重要。为此，我们比较了感染重建的 1918 年大流行病毒或高致病性禽 H5N1 病毒 A/Vietnam/1203/04 的猕猴支气管组织的病理学和整体基因表达谱。早在感染后 12 小时，就在 1918 年病毒感染动物的呼吸道组织中观察到严重的病理学变化，并且在以后的时间点病理学稳步增加。尽管感染 A/Vietnam/1203/04 的动物组织在早期也显示出明显的病理迹象，但在后期观察到的病理现象较少，并且有组织修复的证据。整体转录谱显示，与炎症和细胞死亡相关的特定基因组在感染 1918 病毒的动物的支气管组织中上调，但在感染 A/Vietnam/1203/04 的动物中下调。重要的是，1918 病毒上调了炎症小体、NLRP3 和 IL-1β 的关键成分，而这些基因在感染后早期就被 A/Vietnam/1203/04 下调。 TUNEL 检测显示，两种病毒均在肺部和支气管中引发细胞凋亡反应，尽管这种反应发生在 1918 年病毒感染期间较早。我们的研究结果表明，1918 年病毒感染的猕猴疾病的严重程度是细胞死亡和炎症相关基因早期上调的结果，其中累加或协同效应可能决定了组织损伤的严重程度。目前，全球正在经历一场由源自猪的新型 H1N1 流感病毒引起的大流行。尽管现在判断这种新病毒的毒力有多大还为时过早，但某些流感病毒可以引起严重的疾病。 1918 年的流感大流行也是由 H1N1 病毒引起，导致全球超过 5000 万人死亡。高致病性禽 H5N1 流感病毒正在世界多个地区传播，尽管人类感染的情况很少见，但该病毒经常引起致命疾病。为了确定高致病性流感病毒是否通过类似的方式引起疾病，我们使用猕猴感染模型来研究宿主对重建的 1918 病毒和称为 VN/1203 的禽类 H5N1 分离株的反应。我们发现，虽然这两种病毒都会引起严重的疾病，但感染 1918 病毒更有可能导致死亡，而感染 VN/1203 的动物则可以从感染中恢复。在感染 1918 病毒的动物中，与炎症相关的基因表达增加，并且这些基因早在感染后 12 小时就被开启。因此，限制早期炎症反应的药物可能有助于治疗高致病性流感病毒引起的感染。
The enormous toll on human life during the 1918–1919 Spanish influenza pandemic is a constant reminder of the potential lethality of influenza viruses. With the declaration by the World Health Organization of a new H1N1 influenza virus pandemic, and with continued human cases of highly pathogenic H5N1 avian influenza virus infection, a better understanding of the host response to highly pathogenic influenza viruses is essential. To this end, we compared pathology and global gene expression profiles in bronchial tissue from macaques infected with either the reconstructed 1918 pandemic virus or the highly pathogenic avian H5N1 virus A/Vietnam/1203/04. Severe pathology was observed in respiratory tissues from 1918 virus-infected animals as early as 12 hours after infection, and pathology steadily increased at later time points. Although tissues from animals infected with A/Vietnam/1203/04 also showed clear signs of pathology early on, less pathology was observed at later time points, and there was evidence of tissue repair. Global transcriptional profiles revealed that specific groups of genes associated with inflammation and cell death were up-regulated in bronchial tissues from animals infected with the 1918 virus but down-regulated in animals infected with A/Vietnam/1203/04. Importantly, the 1918 virus up-regulated key components of the inflammasome, NLRP3 and IL-1β, whereas these genes were down-regulated by A/Vietnam/1203/04 early after infection. TUNEL assays revealed that both viruses elicited an apoptotic response in lungs and bronchi, although the response occurred earlier during 1918 virus infection. Our findings suggest that the severity of disease in 1918 virus-infected macaques is a consequence of the early up-regulation of cell death and inflammatory related genes, in which additive or synergistic effects likely dictate the severity of tissue damage. The world is currently experiencing a pandemic caused by a new type of H1N1 influenza virus that originated in swine. Although it is too early to tell how virulent this new virus may be, some influenza viruses can cause severe disease. The 1918 pandemic, also caused by an H1N1 virus, resulted in over 50 million deaths worldwide. Highly pathogenic avian H5N1 influenza viruses are circulating in several parts of the world, and although human infection has been rare, the virus often causes a lethal illness. To determine whether highly pathogenic influenza viruses cause disease by similar means, we used a macaque infection model to study the host response to the reconstructed 1918 virus and an avian H5N1 isolate known as VN/1203. We found that although both viruses caused severe disease, infection with the 1918 virus was more likely to result in death, whereas animals infected with VN/1203 recovered from infection. In animals infected with the 1918 virus, there was increased expression of genes associated with inflammation, and these genes were turned on as early as 12 hours after infection. Drugs that limit the early inflammatory response may therefore be of benefit in treating infections caused by highly pathogenic influenza viruses.
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