Viral Replication Rate Regulates Clinical Outcome and CD8 T Cell Responses during Highly Pathogenic H5N1 Influenza Virus Infection in Mice
Viral Replication Rate Regulates Clinical Outcome and CD8 T Cell Responses during Highly Pathogenic H5N1 Influenza Virus Infection in Mice
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DOI：
10.1371/journal.ppat.1001139
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发表时间：
2010-10-01
期刊：
影响因子：
6.7
通讯作者：
Suresh, M.
中科院分区：
文献类型：
--
作者：
Hatta, Yasuko;Hershberger, Karen;Suresh, M.
自1997年首次记录到人类感染禽源H5 N1病毒以来，散发性人类感染继续发生，死亡率惊人，> 60%。虽然持续的人际传播尚未发生，但人们越来越担心这些H5 N1病毒可能获得这种特征并引发大流行的幽灵。尽管在破译病毒致病性决定因素方面取得了进展，但我们仍然缺乏与人类H5 N1流感病毒感染相关的严重疾病和高死亡率有关的病毒/免疫系统相互作用的关键信息。使用两个人类分离的H5 N1病毒，在小鼠中的致病性不同，我们已经确定了机制之间的联系，病毒复制率，死亡率，CD 8 T细胞反应，和免疫病理学。H5 N1病毒的极端致病性与病毒快速复制的能力直接相关，并在感染后48小时内在肺部迅速达到高稳态滴度。高致病性H5 N1病毒的显著高复制率并没有阻止IFN-β的诱导或CD 8 T细胞的活化，但是CD 8 T细胞应答在控制肺中的病毒复制方面是无效的，并且CD 8 T细胞缺乏并不影响病毒滴度或死亡率。此外，BIM缺乏改善了肺病理学，抑制了T细胞凋亡，而不影响小鼠的生存。因此，快速复制、高致死性的H5 N1病毒可以简单地超过和压倒适应性免疫反应，并通过直接的细胞病变效应杀死宿主。然而，早期病毒复制的治疗抑制和相关的CD 8 T细胞反应的增强改善了致命H5 N1感染后小鼠的存活率。这些发现表明，抑制早期H5 N1病毒复制是有效的宿主反应程序的关键，这对人类感染的治疗有影响。
Since the first recorded infection of humans with H5N1 viruses of avian origin in 1997, sporadic human infections continue to occur with a staggering mortality rate of >60%. Although sustained human-to-human transmission has not occurred yet, there is a growing concern that these H5N1 viruses might acquire this trait and raise the specter of a pandemic. Despite progress in deciphering viral determinants of pathogenicity, we still lack crucial information on virus/immune system interactions pertaining to severe disease and high mortality associated with human H5N1 influenza virus infections. Using two human isolates of H5N1 viruses that differ in their pathogenicity in mice, we have defined mechanistic links among the rate of viral replication, mortality, CD8 T cell responses, and immunopathology. The extreme pathogenicity of H5N1 viruses was directly linked to the ability of the virus to replicate rapidly, and swiftly attain high steady-state titers in the lungs within 48 hours after infection. The remarkably high replication rate of the highly pathogenic H5N1 virus did not prevent the induction of IFN-beta or activation of CD8 T cells, but the CD8 T cell response was ineffective in controlling viral replication in the lungs and CD8 T cell deficiency did not affect viral titers or mortality. Additionally, BIM deficiency ameliorated lung pathology and inhibited T cell apoptosis without affecting survival of mice. Therefore, rapidly replicating, highly lethal H5N1 viruses could simply outpace and overwhelm the adaptive immune responses, and kill the host by direct cytopathic effects. However, therapeutic suppression of early viral replication and the associated enhancement of CD8 T cell responses improved the survival of mice following a lethal H5N1 infection. These findings suggest that suppression of early H5N1 virus replication is key to the programming of an effective host response, which has implications in treatment of this infection in humans.