Lethality of H5N1 Influenza Virus is Linked to TGF-beta

描述(申请人提供)：亚洲目前爆发的H5N1流感与32例人类感染和大约70%的死亡率有关。鉴于整个亚洲家禽疫情不受控制，人类感染可能会继续增加。首宗人类感染H5N1病毒纯禽流感病毒株个案于1997年在香港发生。这些病毒的使用增加了我们对流感毒力背后的病毒遗传学的理解。然而，这种不寻常的严重性的细胞、免疫学和病理学基础仍未被探索。在动物模型中的有限研究表明，1997年H5N1强毒病毒导致严重的呼吸道损伤和淋巴细胞抑制。需要进一步的研究来确定毒力增加的细胞/宿主机制。我们证明了1997年H5N1病毒之间的一个重要区别是激活转化生长因子-β(TGF-β)的能力。转化生长因子-β是一种强大的免疫调节因子，影响宿主对包括流感在内的多种传染病的反应。与人类致命性相关的H5N1病毒不会激活转化生长因子-β。此外，在非致命性H5N1感染期间，转化生长因子-β的中和导致了以肺部细胞凋亡减少、病毒清除延迟和白细胞减少为特征的致死性疾病。综合考虑，这些结果表明转化生长因子-β的诱导可能是流感发病机制中的一个关键因素。因此，这些研究的长期目标是确定H5N1毒力的机制和转化生长因子-β在保护中的作用。其具体目的是：1.分离转化生长因子-β激活所需的流感神经氨酸酶区域，并确定其激活机制。2.评价转化生长因子-β预防致死性感染的需要量。3.检查对H5N1流感感染的先天和获得性免疫反应，以确定毒力增强的机制。这些研究为了解H5N1流感病毒在哺乳动物中毒力的细胞和免疫学基础提供了一个独特的机会：目前，这是一个尚未探索的研究领域。

DESCRIPTION (provided by applicant): The current H5N1 influenza outbreak in Asia is associated with 32 human infections and approximately a 70% mortality rate. Human infections may continue to increase given the uncontrolled outbreak in poultry throughout Asia. The first documented instance of human H5N1 infection by a purely avian H5N1 strain occurred in Hong Kong in 1997. The use of these viruses increased our understanding of the viral genetics underlying influenza virulence. However, the cellular, immunological, and pathological basis for the unusual severity remains unexplored. Limited studies in animal models demonstrated that the virulent 1997 H5N1 viruses resulted in severe respiratory lesions and depression of lymphocytes. Further studies are required to determine the cellular/host mechanism of increased virulence. We demonstrated that an important difference amongst the 1997 H5N 1 viruses is the ability to activate transforming growth factor-beta (TGF-beta). TGF-beta is a potent immunomodulatory factor that influences the host response to numerous infectious diseases, including influenza. The H5N1 viruses associated with human lethality do not activate TGF-beta. Further, neutralization of TGF-beta during non-lethal H5N1 infection resulted in lethal disease characterized by decreased apoptosis in the lung, delayed viral clearance, and leukopenia. When considered together, these results suggested that TGF-beta induction might be a critical factor in influenza pathogenesis. Thus, the long-term goal of these studies is to define the mechanism of H5N1 virulence and the role of TGF-beta in protection. The specific aims are: 1. Isolate the region of influenza neuraminidase required for TGF-beta activation and determine the mechanism of activation. 2. Evaluate the requirement for TGF-beta in protection from lethal infection. 3. Examine the innate and adaptive immune responses to H5N1 influenza infection to define the mechanism of enhanced virulence. These studies provide a unique opportunity to understand the cellular and immunological basis of H5N1 influenza virus virulence in mammals: currently, an unexplored area of investigation.