A chicken model to study hepatitis E virus pathogenesis

研究戊型肝炎病毒发病机制的鸡模型

• 批准号: 8782591
• 负责人: XIANG-JIN MENG
• 金额: $ 39.42万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8782591
• 关键词: Acute Disease; Adoptive Transfer; Animal Model; Animals; Antibody Response; Autopsy; B-Lymphocytes; Biochemical; Birds; CD8B1 gene; Cells; Chickens; Chronic; Chronic Hepatitis; Clinical; Defective Viruses; Development; Disease; Disease Progression; Event; Family suidae; Frequencies; Future; Goals; HIV; Health; Heavy-Chain Immunoglobulins; Hepatic; Hepatitis; Hepatitis A; Hepatitis E; Hepatitis E virus; Hepatocyte; Histologic; Human; Humoral Immunities; Immune; Immune Sera; Immune response; Immunity; Immunocompetent; Immunocompromised Host; Immunoglobulin Joining Region; Immunologic Factors; Immunosuppressive Agents; Impairment; Individual; Infection; Interferons; Interleukin-10; Interleukin-17; Interleukin-4; Intervention; Knock-out; Lead; Lesion; Liver; Lymphocyte Subset; Maps; Measures; Mediating; Modeling; Morbidity - disease rate; Organ Transplantation; Pathogenesis; Patients; Predictive Factor; Pregnant Women; Prevention strategy; Procedures; Public Health; Regulatory T-Lymphocyte; Role; T cell response; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Epitopes; T-Lymphocyte Subsets; Time; Transplant Recipients; Virus; Virus Diseases; Virus Replication; cytokine; cytotoxicity; immunosuppressed; leukemia/lymphoma; liver injury; mortality; response; treatment strategy; virus development; virus infection mechanism; virus pathogenesis

DESCRIPTION (provided by applicant): Hepatitis E is an important public health disease with a high mortality rate of up to 28% in infected pregnant women. Recently, chronic HEV infection has become an emerging and significant clinical problem worldwide in immunocompromised individuals such as organ transplant recipients and patients with HIV, lymphoma and leukemia with considerable morbidity and mortality. Approximately 58-92% of the HEV-infected organ transplant recipients developed chronic HEV infection but the mechanism leading to the progression into chronicity remains unknown. The long-term goal of this project is to develop an animal model for chronic hepatitis E to study the mechanisms of HEV immunopathogenesis and intervention strategies. In aim 1, we hypothesize that HEV infection in pigs under immunosuppressive conditions will mimic the course of chronic HEV infection in immunocompromised individuals, which will enable us to delineate the predictive immunological factors leading to the progression into chronicity. Pigs will be immunosuppressed to mimic the immunosuppressive conditions in organ transplant recipients and then experimentally infected with HEV. The immunological, pathological, biochemical, virological and clinical parameters of HEV infection and hepatitis will also be analyzed and compared to identify the broad predictive factors for progression into chronicity. In aim 2, we hypothesize that impairment of T-cell responses, particularly CD4+ and CD8+ T-cell responses, is responsible for the progression into chronicity in immunocompromised individuals. We will determine if depletion of specific CD4+ or CD8+ T cell subsets in chickens will lead to chronic infection and severe hepatitis in chickens infected with avian HEV. Chickens depleted of either CD4 or CD8 T cells will be experimentally infected with avian HEV, and assessed for pathological, biochemical, virological, immunological and clinical parameters of hepatitis. Adoptive transfer CD4+ or CD8+ T cells into immune cell-depleted chickens will also be performed. In aim 3, we hypothesize that the humoral immune response is a double-edged sword in that it is important in control of HEV infection but it also involves in immune-mediated hepatic damages. B cell- depleted chickens as well as immunoglobulin (Ig) heavy chain homozygous knockout (-/-) piglets and wild-type littermate (+/+) will be experimentally infected with HEV, hepatic lesions, immunological, biochemical and virological parameters of hepatitis will be assessed and compared. The Ig heavy chain(-/-) knockout piglets will also be passively transferred with a HEV-specific antiserum followed by HEV challenge. By completing this project, we anticipate that a unique animal model for chronic hepatitis E will be established, and that the predictive immunological factors leading to chronic infection will be identified, the T cell epitopes responding to HEV infection mapped, and the mechanisms of HEV immunopathogenesis and chronic infection delineated. The results will be important for devising effective prevention and treatment strategies against HEV.

描述（由申请人提供）：戊型肝炎是一种重要的公共卫生疾病，感染孕妇的死亡率高达28%。近年来，慢性戊型肝炎病毒（HEV）感染已成为世界范围内免疫功能低下者如器官移植受者、HIV、淋巴瘤和白血病患者的一个重要临床问题，其发病率和死亡率相当高。大约58-92%的HEV感染的器官移植受者发展为慢性HEV感染，但导致进展为慢性的机制仍然未知。本项目的长期目标是建立慢性戊型肝炎的动物模型，研究戊型肝炎的免疫发病机制和干预策略。在目标1中，我们假设免疫抑制条件下猪的HEV感染将模拟免疫功能低下个体的慢性HEV感染过程，这将使我们能够描述导致进展为慢性的预测性免疫因素。猪将被免疫抑制以模拟器官移植受体的免疫抑制条件，然后实验性感染HEV。还将分析和比较HEV感染和肝炎的免疫学、病理学、生物化学、病毒学和临床参数，以确定进展为慢性的广泛预测因素。在目标2中，我们假设T细胞应答，特别是CD 4+和CD 8 + T细胞应答的受损是免疫功能低下个体进展为慢性的原因。我们将确定是否耗尽特定的CD 4+或CD 8 + T细胞亚群在鸡感染禽戊型肝炎病毒将导致慢性感染和严重的肝炎。将用禽类HEV实验性感染耗尽CD 4或CD 8 T细胞的鸡，并评估肝炎的病理学、生物化学、病毒学、免疫学和临床参数。还将进行将CD 4+或CD 8 + T细胞连续转移到免疫细胞耗尽的鸡中。在目的3中，我们假设体液免疫应答是一把双刃剑，因为它在控制HEV感染方面很重要，但它也涉及免疫介导的肝损伤。B细胞耗竭的鸡以及免疫球蛋白（IG）重链纯合敲除（-/-）仔猪和野生型同窝仔（+/+）将实验性感染HEV，评估并比较肝炎的肝脏病变、免疫学、生化学和病毒学参数。IG重链（-/-）敲除仔猪也将被动转移HEV特异性抗血清，然后进行HEV攻毒。通过本项目的完成，我们期望建立一个独特的慢性戊型肝炎动物模型，并确定导致慢性感染的预测性免疫因素，定位HEV感染的T细胞表位，阐明HEV免疫发病机制和慢性感染机制。研究结果对制定有效的HEV预防和治疗策略具有重要意义。