Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: the role of cytokines and B- and T-cell responses
Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: the role of cytokines and B- and T-cell responses
复制标题
DOI：
10.1099/vir.0.80663-0
复制
发表时间：
2005-04-01
影响因子：
3.8
通讯作者：
Sangster, MY
中科院分区：
文献类型：
--
作者：
Lipatov, AS;Andreansky, S;Sangster, MY
H5 N1流感病毒在人类中引起的疾病的严重性仍然无法解释。香港H5 N1/97病毒的NS基因被证明有助于在猪模型中的高致病性。然而，这种现象背后的分子发病机制和宿主免疫反应仍不清楚。在此，在小鼠模型中，研究了含有H5 N1/97 NS基因、H5 N1/01 NS基因或编码NS 1中Glu（92）-> Asp取代的改变的H5 N1/97 NS基因的H1N1 A/波多黎各/8/34（PR/8）抵抗体。表征了呼吸道病毒的致病性、细胞因子的诱导、肺中的趋化因子CXCL 1（KC）以及特异性B-和T-细胞应答。用含有H5 N1/97 NS基因的重组病毒感染小鼠，小鼠致死量（50%）和肺病毒滴度与对小鼠具有高致病性的PR/8相似。从受感染小鼠的肺中清除这种抗性病毒比PR/8多需要两天。含有改变的H5 N1/97 NS基因或H5 N1/01 NS基因的抑制剂在小鼠中表现出减弱的致病性和较低的肺滴度。特异性3-和T-细胞应答与病毒致病性一致，不能解释H5 N1/97 NS抑制剂的延迟清除。抑制剂诱导炎性细胞因子IL 1 α、IL 1 β、IL 6、IFN-γ和趋化因子KC的肺浓度升高，并降低抗炎细胞因子IL 10的浓度。这种细胞因子失衡让人想起了两名死于H5 N1/97感染的人的临床发现，并可能解释这种疾病的异常严重性。
The severity of disease caused in humans by H5N1 influenza viruses remains unexplained. The NS gene of Hong Kong H5N1/97 viruses was shown to contribute to high pathogenicity of reassortants in a pig model. However, the molecular pathogenesis and host immune response underlying this phenomenon remain unclear. Here, in a mouse model, H1N1 A/Puerto Rico/8/34 (PR/8) reassortants that contained the H5N1/97 NS gene, the H5N1/01 NS gene, or an altered H5N1/97 NS gene encoding a Glu(92)-> Asp substitution in NS1 was studied. The pathogenicity of reassortant viruses, the induction of cytolkines; and chemokine CXCL1 (KC) in the lungs and specific B- and T-cell responses was characterized. In mice infected with reassortant virus containing the H5N1/97 NS gene, the mouse lethal dose (50%) and lung virus titres were similar to those of PR/8, which is highly pathogenic to mice. This reassortant virus required two more days than PR/8 to be cleared from the lungs of infected mice. Reassortants containing the altered H5N1/97 NS gene or the H5N1/01 NS gene demonstrated attenuated pathogenicity and lower lung titres in mice. Specific 3- and T-cell responses were consistent with viral pathogenicity and did not explain the delayed clearance of the H5N1/97 NS reassortant. The reassortant induced elevated pulmonary concentrations of the inflammatory cytokines; IL1 alpha, IL1 beta, IL6, IFN-gamma and chemokine KC, and decreased concentrations of the anti-inflammatory cytolkine IL10. This cytokine imbalance is reminiscent of the clinical findings in two humans who died of H5N1/97 infection and may explain the unusual severity of the disease.