Mechanisms of Natural and Acquired Resistance to mousepox

病原体和其自然寄主之间的相互作用是极其复杂和微妙的，其中大部分是 错配的时候迷失了。鼠痘的病原体--鼠痘病毒(ECTV) 是为数不多的通过外周感染的天然老鼠病原体模型之一 通过淋巴系统传播成为全身性疾病。有两个主要的 预防鼠痘的机制。A)天生或天生的抵抗力，使一些品系的小鼠存活 第一次接触ECTV时没有出现重大的鼠痘症状。B)后天抵抗力，由此 对鼠痘敏感的小鼠通过以前接触ECTV或接种疫苗来保护。这是第二个项目 U19有两个广泛的目标。在目标1中，我们将研究I型IFN(TI-IFN)的机制 有助于自然抵抗致命的鼠痘。这一目标的实现将给我们带来广泛的 了解不同器官中TI-干扰素的产生和信号传递的动态， 干扰素亚型，诱生干扰素的途径，产生干扰素的细胞类型，其作用 局部干扰素信号在早期免疫应答建立中的作用及TI-IFN的保护作用 肝脏是病毒的主要靶器官。在目标2中，我们将研究记忆 CD8+T细胞和体液免疫提供获得性抵抗力。对于CD8+T细胞，我们将表征和 比较他们在VACV和ECTV感染后的休息状态和回忆反应，并确定他们的 保护机制。对于体液免疫，我们将确定记忆B细胞是否能够保护和 无论它们的作用是补充浆细胞室以产生循环抗体，反应迅速 以病毒挑战或充当APC。此外，我们还将描述和确定 ABS对病毒粒子和毒力因子具有保护作用。项目2的结果将与 具有高度互补性的项目1和项目3，以形成电子电视/鼠标的全面图景 活力四射。我们希望这张图片不仅能为项目提供未来的方向，还能提供洞察力 进入许多其他病毒/宿主关系，包括人类与其自然病原体的关系。

The interplay between a pathogen and its natural host is exquisitely complex and delicate and much of this is lost when mispaired. Ectromelia virus (ECTV), the causative agent of mousepox (the smallpox of the mouse) is one of the few models available of a natural mouse pathogen that infects through the periphery and spreads through the lymphatic system to become systemic and cause disease. There are two major mechanisms that prevent mousepox. A) Natural or innate resistance, whereby some mouse strains survive a first encounter with ECTV without major symptoms of mousepox. B) Acquired resistance, whereby mousepox susceptible mice are protected by previous exposure to ECTV or vaccination. Project 2 of this U19 has two wide Aims. In Aim 1 we will investigate the mechanisms whereby Type I IFNs (TI-IFNs) contribute to natural resistance to lethal mousepox. Completion of this Aim will give us a broad understanding about the dynamics of TI-IFN production and signaling in different organs, the importance of TI-IFN subtypes, the pathways whereby TI-IFNs are induced, the cell types that produce them, the role of local IFN signaling in the establishment of the early immune response, and the role of TI-IFNs in protecting the liver, a major target organ of the virus. In Aim 2 we will investigate the mechanisms whereby memory CD8+ T cells and humoral immunity provide acquired resistance. For CD8+ T cells, we will characterize and compare their resting state and recall response following VACV and ECTV infection and determine their mechanisms of protection. For humoral immunity, we will determine whether memory B cells can protect and whether their role is in replenishing the plasma cell compartment to generate circulating Abs, respond rapidly to virus challenge or act as APCs. In addition, we will characterize and determine the mechanisms whereby Abs to the virion and to virulence factors protect from disease. Results from Project 2 will be integrated with those of the highly complementary Projects 1 and 3 to form a comprehensive picture of the ECTV/mouse dynamic. We expect that this picture will not only provide future directions for the program, but also insight into many other virus/host relationships including that of humans with their natural pathogens.