Mechanisms of Influenza a Virus Transmission in Ferretts

描述（由申请人提供）：我们的长期目标是建立人类流感感染、发病机制、传播和进化的动物模型。特别令人关切的是，H5N1亚型禽流感病毒可能导致大流行。这些病毒直接从禽类传播给人类，尽管它们还不能维持持续的人际传播。我们建议研究禽流感病毒感染哺乳动物的机制，以及这些病毒在人与人之间传播的潜在进化，这是造成大流行所必需的。流感病毒在人类之间有效传播的分子基础尚不清楚，尽管已知气溶胶传播在这一过程中很重要。随着流感病毒从禽类直接传播给人类，但很少在人与人之间传播的出现，确定导致潜在大流行病毒在人类中有效传播的遗传特征至关重要。我们提出了两个具体的目标：1)人类H1、H2和H3病毒以及禽类H5、H7和H9病毒的传播潜力，这些病毒与鸟类对人类的感染有关。我们将确定颗粒大小对有效气溶胶传播的影响，以及病毒形态对在雪貂模型中建立自然传播链的影响。我们将比较流感感染对两种动物模型系统的影响，雪貂和棉鼠，这两种动物都可以表现出典型的流感症状，而不需要病毒适应。我们将使用无约束全身容积描记仪来测定呼吸频率、气道反应性（吸气与呼气的比率）和呼吸间隔时间，并将它们与雾化流感病毒颗粒的效果进行比较。我们将研究病毒在感染雪貂痰样本中的存活情况，以更好地了解可能影响病毒稳定性的自然条件及其对有效传播的影响。2)我们将通过反向遗传或将雪貂与禽类和人类毒株共同感染来产生禽/人重组流感病毒，以确定这种重组病毒是否可行，并更好地确定控制禽流感病毒在该动物模型系统中的传播的因素。

DESCRIPTION (provided by applicant): Our long term goal is to establish animal models for human influenza infection, pathogenesis, transmission and evolution. There is particular concern about the possibility that avian influenza viruses of the H5N1 subtype could lead to a pandemic. These viruses are transmitting directly from birds to humans, although they have been unable yet to maintain sustained human-to-human transmission. We propose to study the mechanisms that avian influenza viruses require to infect mammals as well as the potential evolution of those viruses to transmit human-to-human which is required to cause a pandemic. The molecular basis for the efficient transmission of influenza viruses from among humans is not well understood, although the aerosol transmission is known to be important in the process. With the emergence of direct transmission of influenza viruses from avian species to humans but little human-to-human transmission, it is crucial to determine the genetic traits that lead to efficient transmission of potentially pandemic viruses in humans. We propose two specific aims to address: 1) The transmissibility potential of human H1, H2, and H3 viruses as well as avian H5, H7, and H9 viruses that have been implicated in bird-to-human infections. We will determine the effect of particle size for efficient aerosol spread and the effect that virus morphology has to establish a natural chain of transmission in the ferret model. We will compare the effect of influenza infections in two animal model systems, the ferret and the cotton rat, both of which can display typical flu symptoms without requiring virus adaptation. We will use unrestrained whole body plethysmography to determine the frequency of respiration, airway responsiveness (ratio of inspiration to expiration) and time between breaths and compare them with the effect of aerosolization of influenza virus particles. We will study virus survival in sputum samples of infected ferrets to better understand the natural conditions that might affect the stability of the virus and its effect for efficient transmission. 2) We will generate avian/human reassortant influenza viruses by reverse genetics or by co-infection of ferrets with an avian and a human strain to determine whether such reassortants are viable and better define the factors that control transmission of avian influenza viruses in this animal model system.