Gene Expression Analysis of Host Innate Immune Responses during Lethal H5N1 Infection in Ferrets
Gene Expression Analysis of Host Innate Immune Responses during Lethal H5N1 Infection in Ferrets
复制标题
DOI：
10.1128/jvi.00691-08
复制
发表时间：
2008-11-15
影响因子：
5.4
通讯作者：
Kelvin, David J.
中科院分区：
文献类型：
--
作者：
Cameron, Cheryl M.;Cameron, Mark J.;Kelvin, David J.
病毒和宿主因素如何导致H5N1亚型禽流感病毒感染在人类中的严重致病性尚不清楚。我们通过寡核苷酸芯片分析，从H5N1(A/越南/1203/04)流感病毒感染的雪貂的肺中鉴定了三组差异表达的先天性免疫反应基因。在H5N1感染的雪貂肺中，干扰素反应基因的表达比在致病性较低的H3N2亚型感染的雪貂的肺中更强。特别是，CXCL10基因在感染H5N1病毒的雪貂中的强劲表达使我们测试了CXCL10的S同源受体CXCR3在H5N1流感病毒感染过程中的致病作用。与载体治疗相比，使用CXCR3拮抗剂AMG487治疗感染H5N1病毒的雪貂，可以降低症状严重程度和延迟死亡率。我们认为，未受调控的宿主干扰素反应至少对H5N1感染的严重性负有部分责任，并提供了证据，表明减弱CXCR3信号通路可以改善雪貂H5N1感染的临床过程。
How viral and host factors contribute to the severe pathogenicity of the H5N1 subtype of avian influenza virus infection in humans is poorly understood. We identified three clusters of differentially expressed innate immune response genes in lungs from H5N1 (A/Vietnam/1203/04) influenza virus-infected ferrets by oligonucleotide microarray analysis. Interferon response genes were more strongly expressed in H5N1-infected ferret lungs than in lungs from ferrets infected with the less pathogenic H3N2 subtype. In particular, robust CXCL10 gene expression in H5N1-infected ferrets led us to test the pathogenic role of signaling via CXCL10's cognate receptor, CXCR3, during H5N1 influenza virus infection. Treatment of H5N1-infected ferrets with the drug AMG487, a CXCR3 antagonist, resulted in a reduction of symptom severity and delayed mortality compared to vehicle treatment. We contend that unregulated host interferon responses are at least partially responsible for the severity of H5N1 infection and provide evidence that attenuating the CXCR3 signaling pathway improves the clinical course of H5N1 infection in ferrets.