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

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）：目前亚洲爆发的 H5N1 流感导致 32 人感染，死亡率约为 70%。 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。 第一个有记录的人类 H5N1 纯禽类 H5N1 病毒株感染病例于 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了解。 然而，这种异常严重程度的细胞、免疫学和病理学基础仍有待探索。有限的动物模型研究表明，1997 年 H5N1 病毒的剧毒会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 H5N 1 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传染病的反应。 与人类致死率相关的 H5N1 病毒不会激活 TGF-β。 此外，非致命性 H5N1 感染期间 TGF-β 的中和会导致致命性疾病，其特征是肺部细胞凋亡减少、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的关键因素。 因此，这些研究的长期目标是明确 H5N1 毒力机制以及 TGF-β 的保护作用。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 在防止致命感染方面的需求。 3. 检查对H5N1流感感染的先天性和适应性免疫反应，以确定毒力增强的机制。 这些研究为了解 H5N1 流感病毒对哺乳动物的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。