Association of Increased Pathogenicity of Asian H5N1 Highly Pathogenic Avian Influenza Viruses in Chickens with Highly Efficient Viral Replication Accompanied by Early Destruction of Innate Immune Responses
Association of Increased Pathogenicity of Asian H5N1 Highly Pathogenic Avian Influenza Viruses in Chickens with Highly Efficient Viral Replication Accompanied by Early Destruction of Innate Immune Responses
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DOI：
10.1128/jvi.01434-08
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发表时间：
2009-08-01
影响因子：
5.4
通讯作者：
Tsukamoto, Kenji
中科院分区：
文献类型：
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作者：
Suzuki, Koutaro;Okada, Hironao;Tsukamoto, Kenji
自1996年以来，亚洲H5 N1高致病性禽流感（HPAI）病毒在各种鸟类中的致病性一直在增加，目前在亚洲、欧洲和非洲国家广泛传播。为了更好地了解最近亚洲H5 N1高致病性禽流感病毒在鸡中致病性增加的基础，我们使用无线温度传感器比较了感染亚洲H5 N1 A/chicken/Yamaguchi/7/04（CkYM 7）毒株和感染H5 N1 Duck/Yokohama/aq 10/03（DkYK 10）毒株的鸡的发热和平均死亡时间（MDT）。亚洲H5 N1 CkYM 7在引起发热之前就引起了鸡的急性死亡，而DkYK 10病毒引起了高热，并且有很长的MDT。细胞因子mRNA表达的实时PCR分析显示，CkYM 7在感染后24小时（hpi）迅速诱导抗病毒和促炎细胞因子mRNA表达，在32 hpi突然下降。与此相反，这些细胞因子mRNA的表达增加，在24 hpi的DkYK 10组，但从48 hpi向前下降到与低致病性H5 N2 A/鸡/茨木/1/2004株感染所产生的水平相似。肺、脾和肾中病毒的连续滴定表明，CkYM 7在感染的鸡中快速有效地复制，并且病毒滴度比DkYK 10的病毒滴度高两倍以上。CkYM 7在巨噬细胞和血管内皮细胞中优先有效地复制，而DkYK 10在巨噬细胞中适度生长。这些结果表明，最近的亚洲H5 N1高致病性禽流感病毒在鸡的致病性增加可能与病毒在巨噬细胞和血管内皮细胞中的极其快速和高复制有关，这导致了体温调节系统和先天免疫应答的破坏。
The Asian H5N1 highly pathogenic avian influenza (HPAI) viruses have been increasing in pathogenicity in diverse avian species since 1996 and are now widespread in Asian, European, and African countries. To better understand the basis of the increased pathogenicity of recent Asian H5N1 HPAI viruses in chickens, we compared the fevers and mean death times (MDTs) of chickens infected with the Asian H5N1 A/chicken/Yamaguchi/7/04 (CkYM7) strain with those infected with the H5N1 Duck/Yokohama/aq10/03 (DkYK10) strain, using a wireless thermosensor. Asian H5N1 CkYM7 caused peracute death in chickens before fever could be induced, whereas DkYK10 virus induced high fevers and had a long MDT. Real-time PCR analyses of cytokine mRNA expressions showed that CkYM7 quickly induced antiviral and proinflammatory cytokine mRNA expressions at 24 h postinfection (hpi) that suddenly decreased at 32 hpi. In contrast, these cytokine mRNA expressions increased at 24 hpi in the DkYK10 group, but decreased from 48 hpi onward to levels similar to those resulting from infection with the low-pathogenicity H5N2 A/chicken/Ibaraki/1/2004 strain. Sequential titrations of viruses in lungs, spleens, and kidneys demonstrated that CkYM7 replicated rapidly and efficiently in infected chickens and that the viral titers were more than twofold higher than those of DkYK10. CkYM7 preferentially and efficiently replicated in macrophages and vascular endothelial cells, while DkYK10 grew moderately in macrophages. These results indicate that the increased pathogenicity in chickens of the recent Asian H5N1 HPAI viruses may be associated with extremely rapid and high replication of the virus in macrophages and vascular endothelial cells, which resulted in disruption of the thermoregulation system and innate immune responses.