Exacerbated innate host response to SARS-CoV in aged non-human primates.
Exacerbated innate host response to SARS-CoV in aged non-human primates.
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DOI：
10.1371/journal.ppat.1000756
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发表时间：
2010-02-05
期刊：
影响因子：
6.7
通讯作者：
Haagmans BL
中科院分区：
文献类型：
--
作者：
Smits SL;de Lang A;van den Brand JM;Leijten LM;van IJcken WF;Eijkemans MJ;van Amerongen G;Kuiken T;Andeweg AC;Osterhaus AD;Haagmans BL
具有大流行潜力的病毒性呼吸道病原体的出现，如严重急性呼吸道综合征冠状病毒（SARS-CoV）和甲型流感H5 N1，迫切需要破译其发病机制，以制定新的干预战略。SARS-CoV感染导致急性肺损伤（ALI），其可发展为危及生命的急性呼吸窘迫综合征（ARDS），高龄与不良疾病结局呈正相关。然而，在老年个体中引起病毒诱导的ALI/ARDS的分子途径是不明确的。在这里，我们表明，SARS-CoV感染的老年猕猴发展更严重的病理比年轻的成年动物，即使病毒复制水平相似。全面的基因组分析表明，老年猕猴对病毒感染的宿主反应比年轻成年猕猴更强，与炎症相关的基因差异表达增加，NF-κB作为中心参与者，而I型干扰素（IFN）-β的表达减少。用I型IFN治疗SARS-CoV感染的老年猕猴，可减少病理学并减少促炎基因表达，包括白细胞介素-8（IL-8）水平，而不影响肺部病毒复制。因此，在SARS-CoV感染的老年猕猴中，ALI是先天宿主反应加剧的结果。I型IFN的抗炎作用揭示了病毒诱导的ALI的潜在干预策略。严重急性呼吸综合征冠状病毒（SARS-CoV）感染引起急性肺损伤，在大多数老年人中可发展为危及生命的急性呼吸窘迫综合征（ARDS）。虽然SARS-CoV感染可能是致命的，但大多数患者都能康复，这表明保护性宿主反应可以对抗病毒感染。因此，我们使用年龄作为易感因素，以了解SARS-CoV的发病机制。在这项研究中，我们发现，SARS-CoV感染的老年猕猴比年轻的成年动物发展出更多的病理学，这不能归因于病毒复制的差异。使用比较微阵列分析，结果表明，尽管老年和年轻成年猕猴对SARS-CoV感染的宿主反应的性质相似，但严重程度明显不同，老年猕猴显示与炎症相关的基因差异表达增加。有趣的是，I型IFN-β mRNA水平与大体病理学呈负相关。用I型干扰素治疗老年猕猴，在不影响病毒复制的情况下减少病理。然而，促炎基因表达显著减少。因此，调制主机响应I型干扰素提供了一个有前途的前景，新的干预策略。
The emergence of viral respiratory pathogens with pandemic potential, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza A H5N1, urges the need for deciphering their pathogenesis to develop new intervention strategies. SARS-CoV infection causes acute lung injury (ALI) that may develop into life-threatening acute respiratory distress syndrome (ARDS) with advanced age correlating positively with adverse disease outcome. The molecular pathways, however, that cause virus-induced ALI/ARDS in aged individuals are ill-defined. Here, we show that SARS-CoV-infected aged macaques develop more severe pathology than young adult animals, even though viral replication levels are similar. Comprehensive genomic analyses indicate that aged macaques have a stronger host response to virus infection than young adult macaques, with an increase in differential expression of genes associated with inflammation, with NF-κB as central player, whereas expression of type I interferon (IFN)-β is reduced. Therapeutic treatment of SARS-CoV-infected aged macaques with type I IFN reduces pathology and diminishes pro-inflammatory gene expression, including interleukin-8 (IL-8) levels, without affecting virus replication in the lungs. Thus, ALI in SARS-CoV-infected aged macaques developed as a result of an exacerbated innate host response. The anti-inflammatory action of type I IFN reveals a potential intervention strategy for virus-induced ALI. Severe acute respiratory syndrome coronavirus (SARS-CoV) infection causes acute lung injury that may develop into the life-threatening acute respiratory distress syndrome (ARDS) in mostly elderly individuals. Although SARS-CoV infection can be fatal, most patients recover, suggesting that protective host responses are operational to combat the viral infection. Therefore, we used age as predisposing factor to obtain insight into the pathogenesis of SARS-CoV. In this study, we show that SARS-CoV-infected aged macaques developed significantly more pathology than young adult animals, which could not be contributed to differences in viral replication. Using comparative microarray analyses, it was shown that although the nature of the host response to SARS-CoV infection was similar in aged and young adult macaques, the severity was significantly different, with aged macaques displaying an increase in differential expression of genes associated with inflammation. Interestingly, type I IFN-β mRNA levels correlated negatively with gross pathology. Therapeutic treatment of aged macaques with type I IFN reduced pathology without affecting virus replication. However, pro-inflammatory gene expression was significantly diminished. Thus, modulation of the host response by type I IFNs provides a promising outlook for novel intervention strategies.
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DOI：
10.1126/science.1179050
发表时间：
2009-10-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Amit I;Garber M;Chevrier N;Leite AP;Donner Y;Eisenhaure T;Guttman M;Grenier JK;Li W;Zuk O;Schubert LA;Birditt B;Shay T;Goren A;Zhang X;Smith Z;Deering R;McDonald RC;Cabili M;Bernstein BE;Rinn JL;Meissner A;Root DE;Hacohen N;Regev A
通讯作者：
Regev A
DOI：
10.1016/s0140-6736(03)13364-8
发表时间：
2003-05-17
期刊：
Lancet (London, England)
影响因子：
--
作者：
Hon KL;Leung CW;Cheng WT;Chan PK;Chu WC;Kwan YW;Li AM;Fong NC;Ng PC;Chiu MC;Li CK;Tam JS;Fok TF
通讯作者：
Fok TF
影响因子：
7.6
作者：
Billiau A
通讯作者：
Billiau A
影响因子：
15.9
作者：
FOLKESSON, HG;MATTHAY, MA;BROADDUS, VC
通讯作者：
BROADDUS, VC
影响因子：
12.7
作者：
Fang, Xiaonan;Gao, Jinrong;Ye, Linbai
通讯作者：
Ye, Linbai