REOVIRUSES AS PROBES OF GUT MUCOSAL T-CELL RESPONSE

呼肠孤病毒作为肠道粘膜 T 细胞反应的探针

• 批准号: 3136597
• 负责人: JOHN J CEBRA
• 金额: $ 14.91万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1991-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3136597
• 关键词: Orthoreovirus; Peyer's patches; Reoviridae disease; T lymphocyte; antibody dependent killer cell; cellular immunity; communicable disease control; helper T lymphocyte; humoral immunity; laboratory mouse; microorganism immunology; tissue /cell culture; virus cytopathogenic effect; virus genetics; virus infection mechanism; virus replication

Reovirus will be used as a probe of the possible roles of murine gut associated lymphoid tissues (GALT) in resistance to and resolution of viral infections commencing via the intestinal route. We will focus on local priming in Peyer's patches (PP) of specific T-helper (TH) and T-cytotoxic (TC) lymphocyte populations and on any special propensity these may display for selective circulation through and/or lodging in the rest of the intestines in lamina propria (LPL) or intraperitoneal (IEL) effector T cell compartments. Thus the efficacies of various virus-specific TH- and TC-populations from different tissues primed by different routes at limiting and containing reovirus (type 3 hemagglutinin) in the gut and protecting vs. ordinarily lethal brain infection will be tested. Further, the possible potentiation by enterically delivered reovirus of non-specific naturally occurring cytotoxicity in PP, LPL, and IEL cell populations will be assayed since perturbations in natural killer and/or naturally cytotoxic cell populations may also have significance in both viral infections and oncogenic processes in the gut. A library of serotypes of reovirus and their genetic reassortants that differ in tissue tropisms, resistance to intestinal digestive enzymes, and sites of replication will be utilized to try to correlate particular viral polypeptides with efficacy of specific T cell priming in PP and the generation of protective immunity. Particular variants of reovirus, for instance one with the neurotropism of type 3 and the resistance to intestinal digestion of type 1, will be chosen to produce model infections for assay of functional activity of specific T cells in vivo. Identification of particular viral polypeptides with effective priming of PP lymphocytes may eventually lead to the construction of more general and effective gut mucosal vaccines. Two of our recent main findings that lend encouragement to our proposed program are: 1) the novel finding of sharply elevated numbers of precursors for viral-specific TC-lymphocytes in PP following an enteric virus infection; and 2) the dramatic rise in PP viral-specific precursors for antibody-secreting clones and in a high incidence of these becoming committed to secretory antibody (IgA) production. Both these perturbations followed intraduodenal infection with type 1 reovirus, a serotype with a special propensity to adhere to dome epithelium of PP, and support the potency of reovirus as a gut mucosal antigenic stimulus of both T- and B-cell compartments.

呼肠孤病毒将被用作小鼠肠道可能作用的探针 相关淋巴组织 (GALT) 在抵抗和消除病毒方面的作用 通过肠道途径开始的感染。 我们将专注于本地 派尔氏集结 (PP) 中特定 T 辅助细胞 (TH) 和 T 细胞毒性的启动 (TC) 淋巴细胞群以及这些细胞可能表现出的任何特殊倾向 用于选择性循环通过和/或住宿于其余部分 肠道固有层 (LPL) 或腹膜内 (IEL) 效应 T 细胞 隔间。 因此，各种病毒特异性 TH 和 来自不同组织的 TC 群体通过不同途径引发 限制和抑制肠道中的呼肠孤病毒（3 型血凝素）， 将测试保护性脑部感染与通常致命的脑部感染的比较。 更远， 肠内传递的呼肠孤病毒可能增强非特异性 PP、LPL 和 IEL 细胞群中自然发生的细胞毒性将 由于自然杀伤剂和/或天然细胞毒性的扰动而进行测定 细胞群在病毒感染和 肠道中的致癌过程。 呼肠孤病毒血清型库和 它们的基因重配体在组织趋向性、抗性等方面有所不同 肠道消化酶和复制位点将被用来 尝试将特定病毒多肽与特定 T 的功效相关联 PP 中的细胞启动和保护性免疫的产生。 特别的 呼肠孤病毒的变种，例如具有 3 型和 1型肠道消化抵抗力，将被选择产生 用于测定特定 T 细胞功能活性的模型感染 体内。 有效鉴定特定病毒多肽 PP淋巴细胞的启动可能最终导致更多的构建 通用且有效的肠粘膜疫苗。 我们最近的两个主要 鼓励我们提出的计划的发现是：1）新颖 发现病毒特异性前体的数量急剧增加 肠道病毒感染后 PP 中的 TC 淋巴细胞；和 2） 抗体分泌克隆的 PP 病毒特异性前体急剧增加 并且这些人中发生分泌抗体的几率很高 (IgA) 产生。 这两种扰动均发生在十二指肠内 1 型呼肠孤病毒感染，这是一种具有特殊倾向的血清型 粘附在 PP 的圆顶上皮上，并支持呼肠孤病毒作为病毒的效力 T 细胞和 B 细胞区室的肠粘膜抗原刺激。