Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
PLoS Pathog. 2010 Oct 7;6(10):e1001139. doi: 10.1371/journal.ppat.1001139.
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-β 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.
自 1997 年首次记录到源自禽类的 H5N1 病毒感染人类以来，散发性人类感染仍在持续发生，死亡率高达惊人的>60%。尽管尚未发生持续的人际传播，但人们越来越担心这些 H5N1 病毒可能获得这种特性，并引发大流行的威胁。尽管在破译病毒致病性的决定因素方面取得了进展，但我们仍然缺乏有关病毒/免疫系统相互作用的关键信息，这些信息与人类 H5N1 流感病毒感染相关的严重疾病和高死亡率有关。使用在小鼠中致病性不同的两种人源 H5N1 病毒分离株，我们已经确定了病毒复制率、死亡率、CD8 T 细胞反应和免疫病理学之间的机制联系。H5N1 病毒的极端致病性与病毒快速复制的能力直接相关，并且在感染后 48 小时内迅速在肺部达到高稳态滴度。高致病性 H5N1 病毒的高复制率并没有阻止 IFN-β的诱导或 CD8 T 细胞的激活，但 CD8 T 细胞反应无法控制肺部的病毒复制，CD8 T 细胞缺失也不会影响病毒滴度或死亡率。此外，BIM 缺失可改善肺部病理并抑制 T 细胞凋亡，而不影响小鼠的存活。因此，快速复制、高度致命的 H5N1 病毒可能简单地超过并压倒适应性免疫反应，并通过直接细胞病变作用杀死宿主。然而，早期病毒复制的治疗性抑制以及相关的 CD8 T 细胞反应增强可提高感染致死性 H5N1 病毒后小鼠的存活率。这些发现表明，抑制早期 H5N1 病毒复制是编程有效宿主反应的关键，这对人类治疗这种感染具有重要意义。
