Avian and human receptor binding by hemagglutinins of influenza A viruses

An understanding of the structural determinants and molecular mechanisms involved in influenza A virus binding to human cell receptors is central to the identification of viruses that pose a pandemic threat. To date, only a limited number of viruses are known to have infected humans even sporadically, and this has recently included the virulent H5 and H7 avian viruses. We compare here the 3-dimensional structures of H5 and H7 hemagglutinins (HA) complexed with avian and human receptor analogues, to highlight regions within the receptor binding domains of these HAs that might prevent strong binding to the human receptor.     

Fate of 130 hemagglutinins from different influenza A viruses

In this study, we use our probabilistic models to analyze 130 hemagglutinins from different influenza A virus in order to gain the insight into their fate. The results provide three lines of evidence regarding the H5, H6, and H9 hemagglutinins: (i) the H5 hemagglutinins are more sensitive to mutations, this is the current state of the H5, H6, and H9 hemagglutinins; (ii) the H5 hemagglutinins had experienced more mutations in the past, this is the history of the H5, H6, and H9 hemagglutinins; and (iii) the H6 hemagglutinins has a bigger potential towards future mutations, this is the future of the H5, H6, and H9 hemagglutinins. Furthermore, this study gives two clues on the mutation tendency that is a degeneration process and the species susceptibility that is the chickens and ducks.     

甲型流感病毒非结构蛋白NS1功能研究进展

甲型流感病毒(influenza A virus,IAV)是每年季节性流感的主要病原体,也是全球儿童急性呼吸道感染的重要病毒性病原。非结构蛋白1(nonstructural protein 1,NS1)是由病毒基因组编码的蛋白,表达于被感染的细胞中,但不存在于病毒颗粒中。近年来,大量研究表明NS1是IAV的重要毒力因素,通过NS1-RNA之间、NS1-蛋白之间的相互作用,在拮抗宿主抗病毒反应、抑制宿主细胞凋亡、调节宿主及自身基因表达等多方面发挥作用。深入研究NS1与宿主细胞的相互作用,不仅可加深对IAV致病机制的理解,还可为预防和控制IAV的传播甚至暴发奠定理论基础,在新型抗病毒药物及疫苗研制中有着重要的应用价值。     

Comparative pathology of the diseases caused by Hendra and Nipah viruses

Information on the pathogenesis and transmissibility of Hendra and Nipah viruses was obtained by comparing their histopathology. Both viruses induced syncytial cells in vascular tissues and they were primarily vasotropic and/or neurotropic, generating interstitial pneumonia or encephalitis. Nipah virus in pigs was also epitheliotropic in respiratory epithelium and thus contagious.     

Prediction of mutation trend in hemagglutinins and neuraminidases from influenza A viruses by means of cross-impact analysis

In this study, we use the cross-impact analysis to define the relationship among impact, mutation, and outbreak of bird flu. Then we use the distribution rank, which is developed by us over last several years, to quantify the mutations from amino acid sequences of 134 hemagglutinins and 97 neuraminidases. With the help of Bayesian equation, we calculate the probability of occurring of mutation in H5, H6, and H9 hemagglutinins, and N1 and N2 neuraminidases. Finally, we estimate the probability of occurring of mutation with different intensities of an impact. Although we have no means to predict an impact, which is severe enough to lead to the mutations in hemagglutinins and neuraminidases resulting in the outbreak of bird flu, we can in principle monitor the changes in distribution rank along the time course, and predict the trend of mutations, even to predict the degree of outbreak of bird flu.     

Prediction of antiviral peptides derived from viral fusion proteins potentially active against herpes simplex and influenza A viruses

There are very few antiviral drugs available to fight viral infections and the appearance of viral strains resistant to these antivirals is not a rare event. Hence, the design of new antiviral drugs is important. We describe the prediction of peptides with antiviral activity (AVP) derived from the viral glycoproteins involved in the entrance of herpes simplex (HSV) and influenza A viruses into their host cells. It is known, that during this event viral glycoproteins suffer several conformational changes due to protein-protein interactions, which lead to membrane fusion between the viral envelope and the cellular membrane. Our hypothesis is that AVPs can be derived from these viral glycoproteins, specifically from regions highly conserved in amino acid sequences, which at the same time have the physicochemical properties of being highly exposed (antigenic), hydrophilic, flexible, and charged, since these properties are important for protein-protein interactions. For that, we separately analyzed the HSV glycoprotein H and B, and influenza A viruses hemagglutinin (HA), using several bioinformatics tools. A set of multiple alignments was carried out, to find the most conserved regions in the amino acid sequences. Then, the physicochemical properties indicated above were analyzed. We predicted several peptides 12-20 amino acid length which by docking analysis were able to interact with the fusion viral glycoproteins and thus may prevent conformational changes in them, blocking the viral infection. Our strategy to design AVPs seems to be very promising since the peptides were synthetized and their antiviral activities have produced very encouraging results.     

Epigenetic reprogramming mechanisms of immunity during influenza A virus infection

This paper reviews epigenetic mechanisms by which influenza viruses affect cellular gene activity to control their life cycles, aiming to provide new insights into the complexity of functional interactions between viral and cellular factors, as well as to introduce novel targets for therapeutic intervention and vaccine development against influenza infections.     

引发2009年流感暴发的H1N1新型流感病毒的研究进展

引起流感世界性大流行的主要原因与流感病毒表面抗原血凝素(HA)和神经氨酸酶(NA)频发的变异有很大关系,抗原的变异使得流感病毒可以逃逸机体的免疫防御,而且使许多应用中的疫苗失去防御效果。综述2009年世界暴发的H1N1新型流感病毒的结构在进化过程中发生的变异,有助于增加人们对流感病毒的了解,从而有效的治疗和预防流感大流行。     

The PDZ-binding motif of the avian NS1 protein affects transmission of the 2009 influenza A(H1N1) virus

By nature of their segmented RNA genome, influenza A viruses (IAVs) have the potential to generate variants through a reassortment process. The influenza nonstructural (NS) gene is critical for a virus to counteract the antiviral responses of the host. Therefore, a newly acquired NS segment potentially determines the replication efficiency of the reassortant virus in a range of different hosts. In addition, the C-terminal PDZ-binding motif (PBM) has been suggested as a pathogenic determinant of IAVs. To gauge the pandemic potential from human and avian IAV reassortment, we assessed the replication properties of NS-reassorted viruses in cultured cells and in the lungs of mice and determined their transmissibility in guinea pigs. Compared with the recombinant A/Korea/01/2009 virus (rK09; 2009 pandemic H1N1 strain), the rK09/VN:NS virus, in which the NS gene was adopted from the A/Vietnam/1203/2004 virus (a human isolate of the highly pathogenic avian influenza H5N1 virus strains), exhibited attenuated virulence and reduced transmissibility. However, the rK09/VN:NS-PBM virus, harboring the PBM in the C-terminus of the NS1 protein, recovered the attenuated virulence of the rK09/VN:NS virus. In a guinea pig model, the rK09/VN:NS-PBM virus showed even greater transmission efficiency than the rK/09 virus. These results suggest that the PBM in the NS1 protein may determine viral persistence in the human and avian IAV interface.     

Comparison of the evolution of recent and late phase of old influenza A (H1N1) viruses

A comparison of the evolutionary tree of new influenza A (H1N1) viruses to that of old H1N1 viruses which disappeared in 1957 was performed. The evolutionary trees of the hemagglutinin (HA) molecule based on amino acid sequences of the HA1 polypeptide were constructed with old and new H1N1 viruses isolated from 1947 to 1957 and 1986 to 2000, respectively. The evolutionary history of recent H1N1 viruses was similar to that of old H1N1 viruses just before the disappearance in two respects. Firstly, both viruses did not originate from the viruses of the previous H1N1 epidemic season but originated from the viruses branched off at the same point on the mainstream stem as the viruses of two H1N1 epidemic seasons earlier. Secondly, recent H1N1 viruses mainly circulating in Japan have a deletion at amino acid residue 134, located close to residue 131, which was deleted in old H1N1 viruses at the time of the disappearance. However, different from the evolutionary history of old H1N1 viruses, in the 1999/2000 H1N1 epidemic season, the H1N1 viruses which were located on the same lineage as the previous epidemic viruses were also isolated sporadically in Japan.     

甲型流感病毒流行毒株检测和分型基因芯片的研制

【目的】研制一种可同时对甲型流感病毒H1N1、H1N2、H3N2、H5N1和H9N2等5种流行亚型进行检测和分型的基因芯片。【方法】根据National Center for Biotechnology Information中Influenza Virus Resource数据库,针对H1N1、H1N2、H3N2、H5N1和H9N2等5种亚型甲型流感病毒的HA和NA基因设计46条特异性寡核苷酸探针和1条质控探针,点制成基因芯片。利用通用引物扩增流感病毒HA和NA基因,使用Klenow酶对扩增产物进行荧光标记和片段化,将标记后产物和芯片杂交,清洗、扫描后根据荧光信号判定检测结果。用18株不同种属来源的甲型流感病毒分离毒株和186份咽拭子对芯片特异性、敏感性和临床应用进行初步评价。【结果】所有18株分离毒株均能被芯片准确检测并分型,芯片检测灵敏度能达约1×104个病毒基因拷贝。同时8份咽拭子检测结果为H1N1阳性,4份咽拭子为H3N2阳性。【结论】研究表明该芯片具有较高的特异性和灵敏度,可为甲型流感病毒的监测提供一种有效的方法。     

Epidemiological analysis of acute respiratory disease (ARD) and characteristics of the influenza epidemic in Bohemia during the season 1986/1987

The authors analyze the findings of epidemiological and virological surveillance of ARD in Bohemia during the season 1986/1987. In all, 57.5% of the Czech population was affected by acute respiratory disease (ARD). There were 5,950,832 cases reported, 124,444 complications (2.1% of the overall morbidity rate) and 5,374 deaths due to influenza, bronchitis, pneumonia and chronic pulmonary affection. The influenza epidemic commenced during the 48-th calendary week (CW) and lasted 5 weeks till the 52-nd CW. The epidemic was due to an influenza virus strain of the subtype A(H1N1) antigenically related to the drift variant A (Singapore) 6/86. Within an extremely short period of the epidemic, 1,094,865 influenza cases were reported and 22,313 cases of complications. 10.7% of the CSR population were affected during the epidemic in whose etiology noninfluenza respiratory viruses were significantly implicated, especially adenoviruses (41.7%) and the RS virus (26.9%). There was no excessive mortality in the course of the epidemic. The authors discuss the atypical nature of this particular influenza epidemic and the etiological role of respiratory viruses.     

IFIT家族基因抑制A型流感病毒WSN毒株的复制和转录

IFIT(Interferon induced proteins with tetratricopeptide repeats)家族基因是一组较早发现的干扰素刺激基因,它在抗病毒和免疫调节中发挥了重要作用。为研究IFIT家族基因抑制A型流感病毒复制的机理,利用高通量RNA深度测序(RNA-Seq)技术发现A型流感病毒A/WSN/33(WSN)毒株感染293T细胞后,IFIT家族基因均出现明显上调。同时发现在IFIT2、IFIT3过表达后,流感病毒的复制和转录均有明显下调,并对v RNP聚合酶活性具有剂量依赖型的抑制作用。进一步研究证明在感染IFIT2、IFIT3编码蛋白与流感病毒非结构蛋白(NS1)存在细胞内共定位,证明二者存在相互作用的可能。综上所述,IFIT家族基因可以抑制A型流感病毒的复制和转录,有助于进一步阐明宿主因子对流感病毒感染的调节机制。     

Induction of innate immunity and its perturbation by influenza viruses

Influenza A viruses (IAV) are highly contagious pathogens causing dreadful losses to human and animal, around the globe. IAVs first interact with the host through epithelial cells, and the viral RNA containing a 5′-triphosphate group is thought to be the critical trigger for activation of effective innate immunity via pattern recognition receptors-dependent signaling pathways. These induced immune responses establish the antiviral state of the host for effective suppression of viral replication and enhancing viral clearance. However, IAVs have evolved a variety of mechanisms by which they can invade host cells, circumvent the host immune responses, and use the machineries of host cells to synthesize and transport their own components, which help them to establish a successful infection and replication. In this review, we will highlight the molecular mechanisms of how IAV infection stimulates the host innate immune system and strategies by which IAV evades host responses.     

Secoiridoid analogues from the fruits of Ligustrum lucidum and their inhibitory activities against influenza A virus

A phytochemical study focusing on the secoiridoid components in the fruits of Ligustrum lucidum was carried out, which finally led to the isolation of nine secoiridoid glycosides (1–9) together with two secoiridoids (10, 11). The structures of all compounds were established mainly by NMR and MS experiments as well as the necessary chemical evidence, of which 1, 2, 4 (ligulucisides A–C), 10 and 11 (liguluciridoids A and B) were identified as new secoiridoid analogues. An in vitro antiviral bioassay indicated that 1, 4, 6, and 10 displayed the inhibitory activities against influenza A virus with the IC₅₀ values of 16.5, 12.5, 13.1, and 18.5?μM, respectively, which were better than the positive control Ribavirin (IC₅₀ 22.6?μM)..