Lethality of H5N1 Influenza Virus is Linked to TGF-beta

H5N1 流感病毒的致死率与 TGF-β 有关

• 批准号: 6866040
• 负责人: Stacey L Schultz-Cherry
• 金额: $ 24.52万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6866040
• 关键词: apoptosis; cellular immunity; cytotoxic T lymphocyte; edema; enzyme linked immunosorbent assay; enzyme mechanism; exo alpha sialidase; helper T lymphocyte; histopathology; influenza; influenzavirus A; laboratory mouse; microorganism immunology; natural killer cells; neutrophil; p53 gene /protein; respiratory epithelium; site directed mutagenesis; transforming growth factors; virulence; virus cytopathogenic effect; apoptosis; cellular immunity; cytotoxic T lymphocyte; edema; enzyme linked immunosorbent assay; enzyme mechanism; exo alpha sialidase; helper T lymphocyte; histopathology; influenza; influenzavirus A; laboratory mouse; microorganism immunology; natural killer cells; neutrophil; p53 gene /protein; respiratory epithelium; site directed mutagenesis; transforming growth factors; virulence; virus cytopathogenic effect

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.

描述（由申请人提供）：亚洲当前的H5N1流感爆发与32种人类感染和约70％的死亡率有关。 鉴于整个亚洲家禽爆发不受控制，人类感染可能会继续增加。 1997年，香港发生了纯粹的鸟类H5N1菌株的第一个被记录在人类H5N1感染的实例。这些病毒的使用增加了我们对流感毒素基于的病毒遗传学的理解。 然而，异常严重性的细胞，免疫学和病理基础仍未探索。动物模型中有限的研究表明，有毒的1997 H5N1病毒导致严重的呼吸病变和淋巴细胞抑郁症。 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，1997 H5N 1病毒之间的重要差异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素，它影响了包括流感在内的许多传染病的宿主反应。 与人致死性相关的H5N1病毒不会激活TGF-β。 此外，非致命性H5N1感染期间TGF-β的中和导致致死性疾病的特征是肺部凋亡减少，病毒释放延迟和白细胞减少症。 当一起考虑时，这些结果表明TGF-β诱导可能是流感发病机理的关键因素。 因此，这些研究的长期目标是定义H5N1毒力的机制和TGF-β在保护中的作用。具体目的是：1。隔离TGF-β激活所需的流感神经氨酸酶的区域，并确定激活的机理。 2。评估TGF-beta在保护免受致命感染的保护方面的要求。 3。检查对H5N1流感感染的先天和适应性免疫反应，以定义增强毒力的机制。 这些研究为了解哺乳动物中H5N1流感病毒毒力的细胞和免疫学基础提供了独特的机会：目前，这是一个未开发的研究领域。