Cao Yingying, Huang Yaowei, Xu Ke, Liu Yuanhua, Li Xuan, Xu Ye, Zhong Wu, Hao Pei
Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, University of Chinese Academy of Sciences, Shanghai, China.
Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, University of Chinese Academy of Sciences, Shanghai, China.
BMC Med Genomics. 2017 Dec 21;10(Suppl 4):70. doi: 10.1186/s12920-017-0304-z.
Innate immunity provides first line of defense against viral infections. The interactions between hosts and influenza A virus and the response of host innate immunity to viral infection are critical determinants for the pathogenicity or virulence of influenza A viruses. This study was designed to investigate global changes of gene expression and detailed responses of innate immune systems in human and avian hosts during the course of infection with various subtypes of influenza A viruses, using collected and self-generated transcriptome sequencing data from human bronchial epithelial (HBE), human tracheobronchial epithelial (HTBE), and A549 cells infected with influenza A virus subtypes, namely H1N1, H3N2, H5N1 HALo mutant, and H7N9, and from ileum and lung of chicken and quail infected with H5N1, or H5N2.
We examined the induction of various cytokines and chemokines in human hosts infected with different subtypes of influenza A viruses. Type I and III interferons were found to be differentially induced with each subtype. H3N2 caused abrupt and the strongest response of IFN-β and IFN-λ, followed by H1N1 (though much weaker), whereas H5N1 HALo mutant and H7N9 induced very minor change in expression of type I and III interferons. Similarly, differential responses of other innate immunity-related genes were observed, including TMEM173, MX1, OASL, IFI6, IFITs, IFITMs, and various chemokine genes like CCL5, CX3CL1, and chemokine (C-X-C motif) ligands, SOCS (suppressors of cytokine signaling) genes. Third, the replication kinetics of H1N1, H3N2, H5N1 HALo mutant and H7N9 subtypes were analyzed, H5N1 HALo mutant was found to have the highest viral replication rate, followed by H3N2, and H1N1, while H7N9 had a rate similar to that of H1N1 or H3N2 though in different host cell type.
Our study illustrated the differential responses of innate immunity to infections of different subtypes of influenza A viruses. We found the influenza viruses which induced stronger innate immune responses replicate slower than those induces weaker innate immune responses. Our study provides important insight into links between the differential innate immune responses from hosts and the pathogenicity/ virulence of different subtypes of influenza A viruses.
固有免疫为抵御病毒感染提供了第一道防线。宿主与甲型流感病毒之间的相互作用以及宿主固有免疫对病毒感染的反应是甲型流感病毒致病性或毒力的关键决定因素。本研究旨在利用从感染甲型流感病毒亚型（即H1N1、H3N2、H5N1 HALo突变体和H7N9）的人支气管上皮（HBE）、人气管支气管上皮（HTBE）和A549细胞，以及感染H5N1或H5N2的鸡和鹌鹑的回肠和肺中收集的和自行生成的转录组测序数据，研究人类和禽类宿主在感染各种甲型流感病毒亚型过程中基因表达的整体变化以及固有免疫系统的详细反应。
我们检测了感染不同亚型甲型流感病毒的人类宿主中各种细胞因子和趋化因子的诱导情况。发现I型和III型干扰素在每种亚型感染时的诱导情况存在差异。H3N2引起IFN-β和IFN-λ的突然且最强反应，其次是H1N1（尽管弱得多），而H5N1 HALo突变体和H7N9诱导I型和III型干扰素表达的变化非常小。同样，观察到其他固有免疫相关基因的差异反应，包括TMEM173、MX1、OASL、IFI6、IFITs、IFITMs，以及各种趋化因子基因，如CCL5、CX3CL1和趋化因子（C-X-C基序）配体、细胞因子信号抑制因子（SOCS）基因。第三，分析了H1N1、H3N2、H5N1 HALo突变体和H7N9亚型的复制动力学，发现H5N1 HALo突变体的病毒复制率最高，其次是H3N2和H1N1，而H7N9的复制率与H1N1或H3N2相似，尽管是在不同的宿主细胞类型中。
我们的研究阐明了固有免疫对不同亚型甲型流感病毒感染的差异反应。我们发现诱导较强固有免疫反应的流感病毒复制速度比诱导较弱固有免疫反应的病毒慢。我们的研究为宿主的差异固有免疫反应与不同亚型甲型流感病毒的致病性/毒力之间的联系提供了重要见解。
