Lethality of H5N1 Influenza Virus is Linked to TGF-beta

描述（由申请方提供）：目前在亚洲爆发的H5 N1流感与32例人类感染有关，死亡率约为70%。 鉴于整个亚洲家禽中的疫情未得到控制，人类感染可能继续增加。 1997年，香港发生了第一例人类感染H5 N1病毒的记录，该病毒是由纯粹的禽类H5 N1病毒株引起的。 这些病毒的使用增加了我们对流感毒力的病毒遗传学基础的理解。 然而，异常严重程度的细胞，免疫学和病理学基础仍然未被探索。在动物模型中进行的有限研究表明，1997年H5 N1病毒的毒性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细胞/宿主机制的毒性增加。 我们证明了1997年H5 N1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。TGF-β是一种有效的免疫调节因子，可影响宿主对包括流感在内的多种感染性疾病的反应。 与人类致死性相关的H5 N1病毒不激活TGF-β。 此外，在非致死性H5 N1感染期间TGF-β的中和导致致死性疾病，其特征在于肺中细胞凋亡减少、病毒清除延迟和白细胞减少。 综合考虑，这些结果表明TGF-β诱导可能是流感发病机制中的关键因素。 因此，这些研究的长期目标是确定H5 N1病毒的毒力机制和TGF-β在保护中的作用。具体目标是：1.分离TGF-β激活所需的流感神经氨酸酶区域，并确定激活机制。 2.评估TGF-β在保护免受致命感染方面的需求。3.研究对H5 N1流感感染的先天性和适应性免疫反应，以确定增强毒力的机制。 这些研究为了解H5 N1流感病毒在哺乳动物中毒力的细胞和免疫学基础提供了独特的机会：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.