Harnessing Natural Killer T cells to counteract swine influenza

尽管人们对流感如何在人类和动物群体中传播的了解有所加深，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越来越快的速度进化，而且流感疫苗无法针对当前分离株提供强大而持久的交叉保护。因此，迫切需要探索创新策略来减少流感病毒在人类和动物物种之间的传播，动物物种是新毒株的天然储存库，例如猪。一种可能性是利用称为自然杀伤 T (NKT) 细胞的 T 淋巴细胞免疫调节子集，该细胞在小鼠体内诱导保护性免疫反应，从而预防或减少流感感染。该提案旨在确定 NKT 细胞如何响应猪和人类的流感病毒，并可能针对猪和人类的流感病毒，因为这种病原体对商业猪肉生产者很重要，并防止流感病毒从猪传播给人类。猪还提供了一个很好的模型来了解人类 NKT 细胞如何响应和针对流感感染。因此，当前的申请寻求对利用 NKT 细胞通过三个重叠目标保护人类和猪免受流感的双重目的的支持。在具体目标 1 中，我们将探讨 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 CD1d 敲除猪是否比 NKT 细胞充足的 CD1d 完整猪更容易受到流感感染。这一目标将为了解 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 将建立参数，通过 NKT 细胞的治疗性激活提高 SI 病毒疫苗的功效。我们已经证明 NKT 细胞激动剂可诱导深远的佐剂作用，增强疫苗介导的针对同源攻击的免疫力。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改良的活病毒疫苗，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确定的流感感染的严重性和传播性，从而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，以限制当前流感病毒从猪到人的传播周期。我们的目标与本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.