Role of host cytokine responses in the pathogenesis of avian H5N1 influenza viruses in mice
Role of host cytokine responses in the pathogenesis of avian H5N1 influenza viruses in mice
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DOI：
10.1128/jvi.02336-06
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发表时间：
2007-03-01
影响因子：
5.4
通讯作者：
Katz, Jacqueline M.
中科院分区：
文献类型：
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作者：
Szretter, Kristy J.;Gangappa, Shivaprakash;Katz, Jacqueline M.
高致病性H5 N1禽流感病毒目前在亚洲的家禽中广泛传播，最近已传播到一些非洲和欧洲国家。这些病毒在物种间传播给人类对公共卫生构成重大威胁。为了更好地理解H5 N1病毒的发病机制，我们研究了促炎细胞因子在白细胞介素-6（IL-6）、巨噬细胞炎性蛋白1 α（macrophage inflammatory protein 1 alpha）（MIP-1 α）、IL-1受体（IL-1 R）或肿瘤坏死因子受体1（TNFR 1），A/Hong Kong/483/97（HK/483）和A/Hong Kong/486/97（HK/486），分别在小鼠中表现出高和低致死率。在IL-6和MIP-1 α缺陷小鼠的病程和病毒复制和传播的程度与野生型小鼠在急性感染1,000 - 50%小鼠感染剂量的H5 N1病毒期间观察到的没有不同。然而，与HK/486病毒，IL-1 R缺陷小鼠表现出较高的发病率和死亡率由于感染，而没有观察到这样的差异与更致命的HK/483病毒。此外，TNFR 1缺陷小鼠表现出显着降低的发病率与H5 N1病毒的挑战，但没有差异，病毒复制和传播或最终的疾病结果与野生型小鼠相比。这些结果表明，TNF-α可能有助于在H5 N1流感病毒感染的发病率，而IL-1可能是重要的非致死性H5 N1疾病的有效病毒清除。
Highly pathogenic avian H5N1 influenza viruses are now-widespread in poultry in Asia and have recently spread to some African and European countries. Interspecies transmission of these viruses to humans poses a major threat to public health. To better understand the basis of pathogenesis of H5N1 viruses, we have investigated the role of proinflammatory cytokines in transgenic mice deficient in interleukin-6 (IL-6), macrophage inflammatory protein 1 alpha (MIP-1 alpha), IL-1 receptor (IL-1R), or tumor necrosis factor receptor 1 (TNFR1) by the use of two avian influenza A viruses isolated from humans, A/Hong Kong/483/97 (HK/483) and A/Hong Kong/486/97 (HK/486), which exhibit high and low lethality in mice, respectively. The course of disease and the extent of virus replication and spread in IL-6- and MIP-1 alpha-deficient mice were not different from those observed in wild-type mice during acute infection with 1,000 50% mouse infective doses of either H5N1 virus. However, with HK/486 virus, IL-1R-deficient mice exhibited heightened morbidity and mortality due to infection, whereas no such differences were observed with the more virulent HK/483 virus. Furthermore, TNFR1-deficient mice exhibited significantly reduced morbidity following challenge with either H5N1 virus but no difference in viral replication and spread or ultimate disease outcome compared with wild-type mice. These results suggest that TNF-alpha may contribute to morbidity during H5N1 influenza virus infection, while IL-1 may be important for effective virus clearance in nonlethal H5N1 disease.