Harnessing Natural Killer T cells to counteract swine influenza

尽管对流感如何在人类和动物群体中传播的认识有所提高，但全球流感大流行的威胁仍然很高。这是因为流感病毒继续以不断增加的速度进化，并且因为流感疫苗不能提供针对当前分离株的强的持久的交叉保护。因此，迫切需要探索创新策略，以减少流感病毒在人类和动物物种（如猪）之间的传播，这些动物物种是新毒株的天然宿主。一种可能性是利用一种称为自然杀伤T（NKT）细胞的T淋巴细胞免疫调节亚群，该细胞在小鼠中诱导预防或减少流感感染的保护性免疫反应。该提案旨在确定NKT细胞如何应对猪和人的流感病毒，并可能针对猪和人的流感病毒，因为这种病原体对商业猪肉生产商的重要性，并防止流感病毒从猪传播给人。猪也提供了一个很好的模型来了解人类NKT细胞如何对流感感染做出反应和靶向流感感染。因此，本申请寻求对利用NKT细胞通过三个重叠目标保护人和猪免受流感的双重目的的支持。在具体目标1中，我们将探索NKT细胞是否有助于保护猪免受流感病毒感染。我们将确定缺乏NKT细胞的CD 1d敲除猪是否比NKT细胞充足的CD 1d完整猪更容易感染流感。这一目标将为NKT细胞是否有助于保护人类免受流感感染提供有价值的见解，因为猪和人类NKT细胞在表型上非常相似。具体目标2将建立NKT细胞的治疗性活化改善SI病毒疫苗的功效的参数。我们已经表明，NKT细胞激动剂诱导深刻的佐剂效应，提高疫苗介导的免疫同源挑战。在目标2中，我们将扩展这些发现，以确定NKT细胞激动剂是否可以增强灭活或修饰的活病毒疫苗，以提供针对异源和异亚型病毒株的交叉保护。最后，具体目标3将确定NKT细胞激动剂的抗病毒作用是否可用于降低已建立的流感感染的严重程度和传播性，以改善猪和人类的病程。这些独立但相互关联的目标提供了更好地了解自然宿主物种中流感病毒感染背景下NKT细胞功能的机会;这些知识可用于人类和猪，以限制当前猪-人流感病毒传播的周期。我们的目标与此次资助机会的使命高度一致：通过推进与农业和生物医学研究高度相关的基础和转化研究，利用农业上重要的家畜物种来改善人类健康。

Despite an improved understanding about how influenza spreads within human and animal populations, the threat of global influenza pandemics remains high. This is because influenza viruses continue to evolve at an ever-increasing pace and because influenza vaccines fail to provide strong long lasting cross-protection against current isolates. Thus, there is an urgent need to explore innovative strategies to reduce transmission of influenza viruses between humans and animal species that serve as natural reservoirs for novel strains, such as swine. One possibility is to harness an immunoregulatory subset of T lymphocytes called natural killer T (NKT) cells that in mice induce protective immune responses that prevent or reduce influenza infections. This proposal seeks to identify how NKT cells respond to and may be targeted against influenza viruses for pigs and humans, because of the importance of this pathogen for commercial pork producers and to prevent the transmission of influenza viruses from pigs to people. Pigs also provide an excellent model to understand how human NKT cells might respond to and be targeted against influenza infections. Thus, the current application seeks support for the dual purpose of harnessing NKT cells to protect both humans and swine from influenza through three overlapping aims. In Specific Aim 1 we will explore whether NKT cells help protect pigs from influenza virus infections. We will determine if CD1d-knockout swine that lack NKT cells are more susceptible to influenza infection compared to CD1d-intact pigs that are NKT cell sufficient. This aim will provide valuable insight into whether NKT cells help protect humans from influenza infections, because pig and human NKT cells are phenotypically very similar. Specific Aim 2 will establish the parameters whereby therapeutic activation of NKT cells improves the efficacy of SI virus vaccines. We have already shown that NKT cell agonists induce profound adjuvant effects that boost vaccine-mediated immunity against homologous challenge. In Aim 2 we will extend these findings to determine whether NKT cell agonists can enhance killed or modified live virus vaccines to provide cross-protection against heterologous and heterosubtypic virus strains. Finally, Specific Aim 3 will determine if the antiviral effects of NKT cell agonists can be used to reduce the severity and transmissibility of established influenza infections to improve the course of disease in pigs and humans. These independent but interconnected aims offer the opportunity to better understand NKT cell function in the context of an influenza virus infection in a natural host species; this knowledge can be utilized in both humans and swine to limit the current cycle of swine-to-human transmission of influenza viruses. Our objectives strongly align with the mission of this funding opportunity: to utilize an agriculturally important domestic animal species to improve human health through the advancement of basic and translational research deemed highly relevant to both agricultural and biomedical research.