Reassortment of influenza viruses in a co-infected host

描述（由申请人提供）：流感流行和大流行的反复发生性质是病毒遗传和抗原性变异的结果。这种可变性反过来又源于易出错聚合酶引入的突变和病毒基因片段在重组过程中在菌株之间的改组。多年来，人们一直认识到人流感病毒和动物流感病毒重新组合对大流行毒株起源的重要性。最近的系统发育和流行病学研究进一步确定了季节性流感病毒之间的重组在产生新的流行毒株中的重要作用。然而，在两种流感病毒共同感染的宿主中，重组的效率如何以及在什么情况下发生，人们知之甚少。通过提出的研究，我们计划解决这方面的知识差距。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重排发生的频率。然后，我们将系统地引入一些变量，如预先存在的免疫力或感染之间的时间间隔，并确定每个变量是否增加或减少由共同感染引起的重组后代的数量。通过这种方式，我们将建立控制流感病毒重组过程的参数。由于重组菌株只有在传播到其他宿主时才具有流行病学意义，因此我们也将评估其大小

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.