Reassortment of influenza viruses in a co-infected host

说明(申请人提供)：流感流行和大流行的复发性质是病毒的遗传和抗原变异性的结果。这种可变性反过来又源于容易出错的聚合酶引入的突变，以及在重新分类过程中病毒基因片段在菌株之间的洗牌。多年来，人们认识到人和动物流感病毒之间的重新分类对大流行性流感病毒株起源的重要性。最近的种系发生和流行病学研究进一步确立了季节性流感病毒之间的重新分类在产生新的流行毒株中的重要作用。然而，人们对同时感染两种流感病毒的宿主发生重新组合的效率和情况知之甚少。通过拟议的研究，我们计划解决这一知识差距。使用细胞培养和豚鼠模型，我们将首先确定在没有选择压力的情况下发生重新组合的频率。然后，我们将系统地引入一些变量，如先前存在的免疫或感染之间的时间间隔，并确定每个变量是增加还是减少由联合感染产生的重配后代的数量。通过这种方式，我们将建立管理流感病毒重新组合过程的参数。由于重组菌株只有在传播到更多宿主的情况下才具有流行病学意义，我们还将评估 流感病毒传播造成的瓶颈。因此，通过精心控制的实验研究，我们建议揭示控制流感病毒进化和流行毒株出现的机制的新见解。 与公共卫生的相关性：通过定期流行和罕见的大流行，流感每年影响相当大比例的人口。重组，即两种不同的流感病毒交换基因的过程，是能够导致这些爆发的抗原性新菌株出现的一种机制。通过定义可以进行重新分类的情况，我们拟议的研究将使旨在预测和限制新流感病毒株出现的公共卫生努力成为可能。！！

DESCRIPTION (provided by applicant): The recurring nature of influenza epidemics and pandemics is a consequence of the genetic and antigenic variability of the virus. This changeability in turn arises from mutations introduced by the error prone polymerase and the shuffling of viral gene segments among strains in the process of reassortment. The importance of reassortment among human and animal influenza viruses to the genesis of pandemic strains has been appreciated for many years. More recent phylogenic and epidemiological studies have furthermore established a significant role for reassortment between seasonal influenza viruses in the generation of novel epidemic strains. Nevertheless, little is known about how efficiently and under what circumstances reassortment occurs in a host co-infected with two influenza viruses. Through the proposed research we plan to address this gap in knowledge. Using both cell culture and guinea pig models, we will first determine the frequency with which reassortment occurs in the absence of selective pressures. We will then introduce systematically a number of variables, such as pre-existing immunity or a time interval between infections, and determine whether each increases or decreases the number of reassortant progeny arising from the co-infection. In this way, we will establish the parameters that govern the process of influenza virus reassortment. Since reassortant strains will be epidemiologically significant only if they are transmitted to additional hosts, we will also evaluate the size of the bottleneck created by influenza virus transmission. Thus, through carefully controlled experimental studies, we propose to reveal novel insights in the mechanisms governing influenza virus evolution and the emergence of epidemic and pandemic strains. PUBLIC HEALTH RELEVANCE: Through regular epidemics and infrequent pandemics, influenza affects a significant proportion of the population every year. Reassortment, the process by which two differing influenza viruses exchange genes, is one mechanism by which antigenically novel strains capable of causing these outbreaks arise. By defining the circumstances under which reassortment can proceed, our proposed research will enable public health efforts aimed at predicting and limiting the emergence of new influenza virus strains. !!