Self-assembling Peptide Nanomaterials for Eliciting Mucosal CD8+ T cell Immunity

 描述(由申请人提供)：在粘膜组织中激发强大记忆CD8+T细胞反应的免疫策略对于促进早期遏制新生感染非常重要，因为据估计，70%的病原体通过粘膜表面发起感染。虽然中和抗体反应是临床上与保护相关的因素，但组织驻留的CD8+T细胞已被证明通过立即识别和杀死受感染的细胞来保护免受感染。因此，黏膜免疫策略能够在靶粘膜组织中诱导强大的记忆CD8+T细胞群是人们非常感兴趣的。然而，发展成功的粘膜疫苗的一个主要限制因素是缺乏有效和安全的免疫佐剂。在本项目中，我们将开发和研究自组装肽纳米材料诱导保护性粘膜CD8+T细胞反应结核分枝杆菌(Mtb)的有效性，Mtb是全球主要的健康负担。我们将利用与结核分枝杆菌(Mtb)抗原表位相连的自组装多肽构建多肽纳米纤维，并研究小鼠鼻腔免疫后的效应性和记忆性CD8+T细胞反应。在目标1中，我们将合成含有天然CD8+T细胞表位的多肽纳米纤维，或者与结核分枝杆菌特异性的CD4+T辅助表位共同组装，以在肺内诱导强大的细胞免疫。具有很强免疫原性的配方将使用雾化结核分枝杆菌模拟挑战进行预防感染测试 结核分枝杆菌自然感染途径。将测定肺、肝等器官的细菌载量，以评估保护作用。在目标2中，我们将在目标1的保护性多肽纳米纤维疫苗配方中加入合成的Toll样受体(TLR)激动剂，以扩大具有多功能回忆活性的记忆CD8+T细胞群。在鼻腔注射纳米纤维疫苗后，将确定粘膜和全身效应以及记忆反应，并将使用雾化结核分枝杆菌模型评估增强的保护。拟议工作的完成将整合合成化学、纳米技术、免疫学和感染预防等领域，以显著影响人类健康。这些研究将为基于纳米材料的原型免疫平台诱导强大的粘膜CD8+T细胞免疫奠定基础，该免疫平台可用于对抗多种粘膜病原体。

 DESCRIPTION (provided by applicant): Immunization strategies that elicit robust memory CD8+T cell responses in mucosal tissues are important to facilitate early containment of nascent infections, as it is estimated that 70% of pathogens initiate infection via mucosal surfaces. While neutralizing antibody responses are clinical correlates of protection, tissue-resident memory CD8+T cells have been shown to protect against infections by immediately recognizing and killing infected cells. Therefore mucosal immunization strategies capable of eliciting robust memory CD8+T cell populations in target mucosal tissue are of great interest. However, a major limiting factor to the development of successful mucosal vaccines is the lack of effective and safe immune adjuvants. In the current project, we will develop and investigate the efficacy of self-assembling peptide nanomaterials for eliciting protective mucosal CD8+T cell responses Mycobacterium tuberculosis (Mtb), which is a major global health burden. We will utilize peptide nanofibers constructed from self-assembling peptides linked to antigenic epitopes from Mycobacterium tuberculosis (Mtb) and investigate effector and memory CD8+T cell responses after intranasal immunization in mice. In aim 1, we will synthesize peptide nanofibers bearing native CD8+T cell epitopes alone or co-assembled with Mtb-specific CD4+T helper epitopes to elicit robust cellular immunity in the lung. Formulations with a strong immunogenicity profile will be tested for protection against infection using an aerosolized Mtb challenge to mimic natural route of Mtb infection. Bacterial load in the lung, liver, and other organs will be determined to assess protection. In Aim 2, we will incorporate synthetic toll-like receptor (TLR) agonists into protective peptide nanofiber vaccine formulations from Aim 1 to expand memory CD8+T cell populations with multifunctional recall activity. Mucosal and systemic effector and memory responses will be determined after intranasal delivery of nanofiber vaccines and enhanced protection will be assessed using an aerosolized Mtb model. Completion of the proposed work will integrate the fields of synthetic chemistry, nanotechnology, immunology, and infection prophylaxis to significantly impact human health. These studies will lay the foundation for prototypic nanomaterials-based immunization platforms to elicit robust mucosal CD8+T cell immunity, which can be adapted to combat numerous mucosal pathogens.