Immunity and Virus Disease

免疫与病毒性疾病

• 批准号: 8239533
• 负责人: Raymond M Welsh
• 金额: $ 40.31万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-07-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239533
• 关键词: Acute; Antibodies; Antigens; Antiviral Agents; Apoptosis; Apoptotic; Attenuated; Biomedical Research; Bioterrorism; CD8B1 gene; Cell Count; Cell Death; Containment; Ebola virus; Environment; HIV; Hantavirus; Health; Hepatitis Viruses; Herpesviridae; Human; Immune; Immune system; Immunity; Infection; Life; Lymphocytic choriomeningitis virus; Lymphopenia; Maintenance; Measures; Mediating; Memory; Monkeypox; Mus; Papillomavirus; Peripheral; Phase; Pichinde; Public Health; Rest; SARS coronavirus; Signal Transduction; Site; Smallpox; Smallpox Viruses; Staging; T cell response; T memory cell; T-Lymphocyte; Tissues; Vaccines; Vaccinia virus; Virus; Virus Diseases; combat; cytokine; exhaustion; influenza virus strain; pathogen; response; vaccine development

Despite many advances in biomedical research, viral infections remain a major threat to human health. In the past 20 years we have witnessed either the emergence or the definition of acute and persistent viral infections caused by agents such as HIV, HTLV, hepatitis viruses, ebola virus, hantavirus, papillomavirus, herpesviruses 6-8, the SARS coronavirus, and monkeypox, and we continue to live with the specter of the re-emergence of a 1918-1ike strain of influenza virus or the release of variola (small pox) virus by bioterrorism. There are few effective antiviral drugs to combat these viruses, and protection from these agents mainly rests on public health containment measures and on the use and development of vaccines. It is now thought that attenuated viruses which induce CD8 T cell responses, as well as antibody, make better, longer lasting vaccines. Thus, it is important to understand factors contributing to the maintenance or loss of CD8 memory in an environment in which a host is continually challenged by pathogens that may sometimes become persistent. The CD8 T cell response to viral infections is highly dynamic, beginning with a cytokine- driven apoptotic loss (lymphopenia) in memory CD8 T cell number in the early stages of infection, followed by a dramatic expansion in number of virus-specific T cells and then by a second decline or silencing phase, associated with T cell apoptosis and dissemination into peripheral tissues. The activated CD8 T cells during the acute response also become sensitized to undergo Fas/FasL-mediated activation-induced cell death (AICD) on strong signaling through their TCR, and this may contribute to the transient immune deficiencies seen during viral infections and to the clonal exhaustion of T cells under conditions of antigen excess. My lab has made the unique observations that (1) there is a cytokine-driven apoptosis early in infection, that (2) apoptosis of CD8 T cells is differentially regulated, dependent on the tissue site, and that (3) there is substantial attrition of memory CD8 T cells occurring as a consequence of acute or persistent infections with unrelated viruses. Here we propose to continue our studies on CD8 T cell apoptosis in mice infected with LCMV, Pichinde, and vaccinia viruses, and determine (1) the mechanism and significance of the early cytokine-induced lymphopenia and apoptosis of memory CD8 T cells during viral infections, (2) the mechanisms regulating the tissue-dependent differences in apoptosis of virus-specific CD8 T cells, and (3) the mechanism and significance of memory T cell attrition following acute and persistent viral infections.

尽管生物医学研究取得了许多进步，但病毒感染仍然是对人类的主要威胁 健康。在过去的20年中，我们目睹了急性和持久的出现或定义 由HIV，HTLV，肝炎病毒，埃博拉病毒，汉坦病毒，诸如HIV，HTLV，Hantavirus，等引起的病毒感染。 乳头瘤病毒，疱疹病毒6-8，SARS冠状病毒和Monkeypox，我们继续与 1918年1月1日的流感病毒菌株的重新出现的幽灵或Variola（小痘）病毒的释放 由生物恐怖主义。很少有有效的抗病毒药物可以抵抗这些病毒，并保护这些病毒 代理商主要取决于公共卫生遏制措施以及疫苗的使用和开发。它 现在认为，诱导CD8 T细胞反应以及抗体的减弱病毒使得更好， 持续疫苗更长。因此，重要的是要了解导致维护或损失的因素 在宿主不断受到病原体挑战的环境中的CD8记忆，有时可能 变得持久。 CD8 T细胞对病毒感染的反应是高度动态的，从细胞因子开始 在感染的早期，记忆CD8 T细胞数中的驱动凋亡损失（淋巴细胞减少）随后 通过大量病毒特异性T细胞的急剧扩张，然后通过第二次下降或沉默阶段， 与T细胞凋亡和分散到周围组织有关。在 急性反应也敏感地接受FAS/FAS介导的激活诱导的细胞死亡 （AICD）通过其TCR强信号传导，这可能有助于瞬时免疫缺陷 在抗原过量的条件下，在病毒感染和T细胞的克隆耗尽期间可见。我的 实验室已经证明了（1）感染早期有细胞因子驱动的细胞凋亡，（2） CD8 T细胞的凋亡受差异调节，取决于组织部位，（3）有 记忆CD8 T细胞的大量损耗是由于急性或持续感染而发生的 无关病毒。在这里，我们建议继续对感染的小鼠CD8 T细胞凋亡的研究 LCMV，Pichinde和Vaccinia病毒，并确定（1）早期的机制和意义 细胞因子诱导的记忆CD8 T细胞在病毒感染过程中的淋巴细胞减少和凋亡，（2） 调节病毒特异性CD8 T细胞凋亡中组织依赖性差异的机制，（3） 急性和持续性病毒感染后记忆T细胞损耗的机制和意义。