Harnessing Natural Killer T cells to counteract swine influenza

利用自然杀伤 T 细胞对抗猪流感

• 批准号: 10183275
• 负责人: John Driver
• 金额: $ 12.61万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-04 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183275
• 关键词: Adaptive Immune System; Address; Adjuvant; Affect; Agonist; Agriculture; American; Animals; Antigens; Antiviral Agents; Basic Science; Biomedical Research; Cell physiology; Cells; Cellular Immunity; Cessation of life; Communicable Diseases; Cytotoxic T-Lymphocytes; Disease; Disease Outbreaks; Domestic Animals; Economic Burden; Family suidae; Frequencies; Funding; Funding Opportunities; Future; Glycolipids; Goals; Health; Hospitalization; Human; Immune; Immune response; Immunity; Industry; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Knock-out; Knowledge; Ligands; Lung diseases; Major Histocompatibility Complex; Mediating; Methods; Microbe; Mission; Modeling; Mus; Phenotype; Population; Porcine Influenza A Virus; Predisposition; Reagent; Regulatory T-Lymphocyte; Research; Resistance; Resources; Respiratory Tract Infections; Risk; Rodent; Severities; T cell response; T-Lymphocyte Subsets; Therapeutic; Translational Research; United States National Institutes of Health; Vaccines; Virus; Virus Diseases; Zoonoses; cross reactivity; cross-species transmission; dosage; flu transmission; human model; immunoreaction; immunoregulation; improved; influenza infection; influenza outbreak; influenza virus vaccine; influenzavirus; innovation; insight; interest; novel; pandemic disease; pandemic influenza; pathogen; pathogenic microbe; porcine model; prevent; swine influenza; transmission process; vaccine efficacy

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.

尽管对人类和动物种群中流感的传播如何传播有了更深刻的了解，但全球流感大流感的威胁仍然很高。这是因为流感病毒继续以不断增长的速度进化，并且流感疫苗未能针对当前的分离株提供强烈的持久交叉保护。因此，迫切需要探索创新的策略，以减少人类和动物物种之间的流感病毒传播，这些策略是新型菌株（例如猪）的天然储层。一种可能性是利用称为天然杀伤剂T（NKT）细胞的T淋巴细胞的免疫调节子集，该细胞在小鼠中诱导保护性免疫反应，以预防或减少流感感染。该提案旨在确定NKT细胞如何应对猪和人类的流感病毒的反应和靶向，因为这种病原体对商业猪肉生产者的重要性，并防止流感病毒从猪向人传播。猪还提供了一个出色的模型，以了解人类NKT细胞如何反应并针对流感感染。因此，当前的应用寻求支持双重目的，即通过三个重叠的目标来利用NKT细胞保护人类和猪免受流感。在特定目标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的影响。我们将确定与NKT细胞足够的CD1D-Intact Pig相比，缺乏NKT细胞的CD1D敲除猪更容易受到流感感染的影响。该目标将为NKT细胞是否有助于保护人类免受流感感染的影响，为您提供宝贵的见解，因为猪和人类NKT细胞在表型上非常相似。特定的目标2将建立参数，从而在其中NKT细胞的治疗激活提高了Si病毒疫苗的功效。我们已经表明，NKT细胞激动剂会诱导深刻的辅助作用，从而增强疫苗介导的免疫力对同源挑战。在AIM 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或修饰的活病毒疫苗，以提供针对异源和异源性和异源性病毒菌株的交叉保护。最后，特定的目标3将确定是否可以使用NKT细胞激动剂的抗病毒作用来降低已建立的流感感染的严重性和可传播性，以改善猪和人类的疾病进程。这些独立但相互联系的目的为在天然宿主物种的流感病毒感染的背景下提供了更好地了解NKT细胞功能的机会。这些知识都可以在人类和猪中都用于限制流感病毒的猪到人类传播的当前周期。我们的目标与这一资金机会的使命非常吻合：利用农业重要的家畜种种来改善与农业和生物医学研究高度相关的基本和转化研究的发展。