| Influenza is a serious threat to human health that can infect a wide range of hosts. The annual epidemics result in about 600 million infections and 250 000 to 500 000 deaths major of which was caused influenza A virus. More threatening is that influenza A virus occasionally cause pandemics, resulting devastated catastrophes. In the past 100 years, four influenza pandemics occurred, including 1918 Spanish flu causing by H1N1, 1957 Asian influenza H2N2, and 1968 Hong Kong influenza H3N2, and each outbreak have caused millions of deaths. In 2009, a swine-origin influenza virus H1N1 infected people and transmitted to many countries within a few weeks. Though the mortality rate is low, its high transmission rate create great concerns to the world. All pandemics were due to several zoonotic transmissions in which animal influenza virus across the species barrier to infect humans. In addition, the zoonotic influenza virus, especially avian influenza, continuing challenge the host restriction, resulting in sporadic human infections, such as H5N1, H7N7, H7N9, H9N2. Although yet to cause a pandemic, these influenza and potential new emerging influenza has been a serious threat to human health. The “host jump” were mostly contributed by the rapid evolution of influenza A. The evolution of influenza A virus is mainly driven by two mechanisms. First, due to an error prone RNA dependent RNA polymerase, the mutation rate of influenza A is significant high so that it can continuing accumulate substitutions to evade host immunity and gain host adaptive mutations. Besides, the genome of influenza viruses comprised segmented RNAs. Thus, new hybrid virus may be created when mixed infection occurred, a process called "reassortment". These two mechanisms both contributed to the cross species transmission. Therefore, study the evolution of influenza A is of great significance to understanding its “host jump” mechanisms. Improvements in High-throughput sequencing, expanding influenza virus resource databases and development of sophisticated molecular evolutionary theory provide us to investigate the important long-standing questions in influenza virus evolution related host adaption, host range restrictions and "reassortment". Increasing such knowledge will help us better prepared endemics and epidemics as well as provide guidelines from epidemiology control. In this research paper, by using public available influenza virus resources including genetic, antigenic, phenotypic and epidemiological information as well as phylogenetic analysis, we did a comprehensive research on the evolution of influenza A virus, particularly concerned about the origin and formation of novel emerging virus, cross host range restriction, reassortment, and geographic spread. In the first part of this thesis, with a new angle, we created evolutionary panorama of influenza A virus using all public available whole genome sequences. This allows us to fully trace the trajectory of its evolution. O ur evolutionary panorama reveal the whole evolutionary history of influenza A, for example, the generation of 1957 H2N2 human influenza, 1968 H3N2, 2009 swine-origin influenza A H1N1. Although previous studies have confirmed human influenza H3N2 is a result of reassortment between avian influenza and human influenza H2N2. During the reassortment, H3N2 received HA and PB1 gene fragments from avian influenza. However, many mysterious still need to resolved. Thus, via using the panorama and other "coalescent" approach, we re- investigated the origin of Hong Kong flu H3N2. Besides, we reconstruct the ancestral sequences to gain the host adaptive mutations when H3N2 initially circulated in human population. Second, we analyze the continuing evolution of human H3N2. The rapid evolution of the human influenza A H3N2 virus induce substantial morbidity and mortality every seasonal epidemics. Most previous studies have concentrated on the hemagglutinin(HA) gene which is under strong immune selection. Few studies have concentrated on the adaptive evolution of other viral proteins and the evolutionary cooperation of positively selected sites within or between proteins remains unclear. In this study, we aim at analyzing the mutational events occurring on the positively selected sites and the association among them. We detected natural selection operating on all 11 viral proteins of H3N2 and investigate the patterns of amino acid substitutions on positively selected positions through time. Using mutual information, we studied the correlation of different sites under positive selection and we found mutations at these sites were co-evolving. Further analysis show that coevolving of sites on each individual proteins may own to functional or structural constraints, and inter- molecular co-evolving sites might be involved in protein-protein interaction and more complex functional cooperation. All these phenomena suggest that human H3N2 evolved in a cooperated and restricted manner and gain insight into the restriction of viral reassortment and crossing host species barriers. Third, we traced the origin of the new emerging avian H7N9 influenza virus in China. A novel H7N9 influenza virus emerged in eastern China in late March 2013, causing more than 100 cases of human infections. In this study, by applying phylogenetic analyses and comprehensive characteristic amino acid identification, we found that H7N9 were generated separately by various reassortment events. A gene pool consisting of avian H9N2 influenza viruses around the Yangtze River Delta had played an important role by providing the internal gene segments for the formation of the novel H7N9 viruses. Detailed phylogenetic timing estimations showed that the novel H7N9 viruses had been circ ulating for some time before detected in human and may have potentials to create more reassortant successors.O ur findings suggested that effective measures should be taken to cut the A(H7N9) viruses from continuing to reassort with H9N2 gene pool. In the last chapter, we study the geographic spread of the avian influenza H9N2 in C hina. At present, more evidence, for example, the formation of H7N9, have showed that the avian influenza H9N2 may an incubator of new emerging influenza A virus which can cause human infections. The avian influenza H9N2 virus was widely distributed in different regions of China and occasionally jumps hosts and reassorts with other subtype s of influenza virus, posing a severe public health threat. Despite the genetic and antigenic evolution of the H9N2 virus in C hina is well documented, the geographic diffusion of H9N2 in China is not fully understood. Understanding its geographic spread and migration patterns could help us better prepare for epidemics as well as endemics and provide useful guidelines for epidemiological control. In this study, through a Bayesian phylogeography approach, we determined the source, migration patterns, and corresponding demography history of the avian influenza A H9N2 virus that circulated in C hina. O ur analyses indicate that migratory birds, poultry trade and transportation have all contributed to the spreading of the H9N2 virus in C hina. The ongoing migration and evolution of H9N2, which poses a constant threat to the human population, highlights the need for a more comprehensive surveillance of wild birds and for the enhancement of biosafety for China’s poultry industry... |
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