The role of CD4+ Cell Responses in LCMV Infection

CD4 细胞反应在 LCMV 感染中的作用

• 批准号: 7342586
• 负责人: Bianca Romina Mothe
• 金额: $ 11.1万
• 依托单位: CALIFORNIA STATE UNIVERSITY SAN MARCOS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7342586
• 关键词: Acute; Address; Adult; Animals; Antigen-Presenting Cells; Antigens; Apoptosis; Appearance; Biological Assay; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; Cessation of life; Chronic; Containment; Cytotoxic T-Lymphocytes; Data; Development; Educational process of instructing; Epitopes; Failure; Functional disorder; Funding; Goals; Grant; HIV; Hepatitis C virus; Histocompatibility Antigens Class II; Immune response; Immunity; Immunization; Immunocompetent; Immunotherapy; Impairment; Infection; Interleukin-10; Lead; Lymphocytic choriomeningitis virus; Lymphokines; Maintenance; Mediating; Modeling; Mus; Mutation; Pathogenesis; Phase; Physiologic pulse; Pilot Projects; Play; Production; Protein Overexpression; Publications; Pulse taking; Research; Role; Score; Staging; Staining method; Stains; T-Lymphocyte; T-Lymphocyte Epitopes; Variant; Viral; Viremia; Virus; Virus Diseases; Work; anergy; cytokine; enzyme linked immunospot assay; exhaustion; insight; peer; programs; response

DESCRIPTION (provided by applicant): In recent years, tremendous advances have been made in understanding viral biology and immune responses to viral infection. In the majority of viral infections, the acute phase of infection is associated with successful immune responses leading to the containment of viremia and viral spread. However, certain viruses, such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV), are able to establish persistent infection. In this proposal, we are going to use the Lymphochoriomeningitis virus (LCMV) model of infection to probe why one set of immune responses is hampered in chronic infection. LCMV has been widely used as a murine model of host pathogenesis, and depending on the LCMV strain utilized, either self-resolving acute infection (e.g., LCMV Armstrong) or persistent infection (e.g., LCMV clone 13) can be obtained. The work we performed in our original SCORE pilot project has thus far lead to the characterization of a set of nine CD4+ T-cell epitopes after LCMV Armstrong infection, showing a broad repertoire of responses in the setting of successful control of viral replication. However, these responses were not detected in chronic infection with LCMV clone 13. Even though these responses could be elicited after immunization, subsequent LCMV clone 13 infection resulted in their suppression. It has also been recently shown by other groups that programmed death-1 (PD-1) is up-regulated in T-cells in chronic infection, resulting in their apoptosis. It remains to be seen whether this applies to CD4+ T-cells in persistent LCMV infection. We hypothesize that infection with persistent LCMV viral strains leads to impairment of LCMV-specific CD4+ T-cell immunity contributing to the establishment of persistent infection. The long-term goal of this proposal is to mechanistically define how CD4+ T-cells are impaired in chronic infection. To address this, our specific aims consist of the following: (1) to determine whether effective LCMV-specific CD4+ T-cell responses develop after persistent LCMV infection using virus-pulsed antigen presenting cells and CD4+ T-cells from infected animals in ELISPOT assays; (2) to understand whether CD4+ T-cell impairment is a result of deletion and/or dysfunction in persistent LCMV infection by following CD4+ T-cells with tetramer staining and lymphokine production; (3) to determine whether CD4+ T-cell responses can be rescued in the setting of LCMV persistent infection by investigating if CD4+ T-cells express high levels of PD-1 which can be blocked.

描述（由申请人提供）：近年来，在理解病毒生物学和对病毒感染的免疫反应方面取得了巨大进展。在大多数病毒感染中，感染的急性期与成功的免疫反应有关，从而导致病毒血症和病毒传播的遏制。然而，某些病毒，例如人类免疫缺陷病毒（HIV）和丙型肝炎病毒（HCV），能够建立持续感染。在本提案中，我们将使用淋巴组织脑膜炎病毒（LCMV）感染模型来探讨为什么一组免疫反应在慢性感染中受到阻碍。 LCMV 已被广泛用作宿主发病机制的小鼠模型，并且根据所使用的 LCMV 毒株，可以获得自消性急性感染（例如 LCMV Armstrong）或持续感染（例如 LCMV 克隆 13）。迄今为止，我们在最初的 SCORE 试点项目中所做的工作已经确定了 LCMV 阿姆斯特朗感染后一组九个 CD4+ T 细胞表位的特征，显示出在成功控制病毒复制的情况下的广泛反应。然而，在 LCMV 克隆 13 的慢性感染中未检测到这些反应。尽管这些反应可以在免疫后引发，但随后的 LCMV 克隆 13 感染导致其抑制。其他研究小组最近也发现，慢性感染时 T 细胞中的程序性死亡 1 (PD-1) 上调，导致细胞凋亡。这是否适用于持续 LCMV 感染中的 CD4+ T 细胞还有待观察。 我们假设持续性 LCMV 病毒株感染会导致 LCMV 特异性 CD4+ T 细胞免疫受损，从而导致持续性感染的建立。该提案的长期目标是从机制上定义 CD4+ T 细胞在慢性感染中如何受损。为了解决这个问题，我们的具体目标包括以下内容：(1) 在 ELISPOT 测定中，使用病毒脉冲的抗原呈递细胞和来自感染动物的 CD4+ T 细胞，确定持续 LCMV 感染后是否会产生有效的 LCMV 特异性 CD4+ T 细胞反应； (2) 通过四聚体染色和淋巴因子产生跟踪 CD4+ T 细胞，了解 CD4+ T 细胞损伤是否是持续 LCMV 感染中缺失和/或功能障碍的结果； (3) 通过研究 CD4+ T 细胞是否表达高水平的 PD-1（可被阻断），确定在 LCMV 持续感染的情况下是否可以挽救 CD4+ T 细胞反应。