Establishing a relevant mouse model with susceptibility to non-adapted influenza viruses for vaccine challenge studies

摘要 流感病毒感染是世界范围内的一个主要健康问题。我们对季节性流感的最好防御 病毒感染是接种疫苗，但目前的疫苗策略并不完全有效，可能无法提供保护 对抗从动物身上冒出的病毒。开发更好的疫苗的一个障碍是缺乏 一种用于测试新疫苗技术的易驯服且具有成本效益的小动物模型。老鼠无处不在 用于研究，但感染人类的流感病毒通常需要适应才能感染和引起 小鼠的病理学。这种对病毒适应的要求限制了小鼠模型用于测试人类 相关未适应人类病毒的挑战研究中的候选疫苗。但是我们发现， 转基因小鼠缺乏一种关键的抗病毒限制因子，即干扰素诱导的跨膜蛋白 3(IFITM3)显示对各种流感病毒株的敏感性增加，包括 否则不会对野生型小鼠造成明显的病理改变。我们认为IFITM3基因敲除小鼠可能 因此可以作为长期寻求的流感病毒疫苗测试的小鼠模型。我们将测试这些老鼠是否 具备临床前测试模型所需的两个特征：1)IFITM3基因敲除小鼠 有能力在接种疫苗后产生保护性适应性免疫反应，以及2)IFITM3是否 基因敲除小鼠对广泛的人类和动物来源的流感病毒非常敏感。在……里面 除了允许对新的季节性和普遍的流感病毒进行更快、更具成本效益的测试之外 疫苗方面，这项研究还将为拥有IFITM3缺陷的人类提供病毒方面的见解 易感性和通过接种疫苗抵消这种免疫缺陷的能力。

SUMMARY Influenza virus infection is a major health concern worldwide. Our best defense against seasonal influenza virus infections is vaccination, but current vaccine strategies are not fully effective and may not offer protection against viruses that emerge from animals. One impediment to the development of better vaccines is the lack of a tractable and cost-effective small animal model for testing new vaccine technology. Mice are ubiquitously used in research, but influenza viruses that infect humans often require adaptation in order to infect and cause pathology in mice. This requirement for virus adaptation limits the utility of the mouse model for testing human vaccine candidates in challenge studies with relevant non-adapated human viruses. However, we found that mice engineered to lack a critical antiviral restriction factor known as interferon-induced transmembrane protein 3 (IFITM3) show increased susceptibility to a variety of influenza virus strains, including human isolates that otherwise do not cause significant pathology in wild type mice. We propose that IFITM3 knockout mice may thus serve as a long-sought mouse model for influenza virus vaccine testing. We will test whether these mice possess the two characteristics needed in a pre-clinical testing model: 1) Whether IFITM3 knockout mice possess the ability to mount protective adaptive immune responses upon vaccination, and 2) Whether IFITM3 knockout mice are fully susceptible to a wide breadth of human and animal-derived influenza viruses. In addition to allowing more rapid and cost-effective testing of new seasonal and universal influenza virus vaccines, this research will also provide insights into humans who possess IFITM3 defects in terms of virus susceptibility and the ability to counteract this immunodeficiency with vaccination.