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

 描述（由申请方提供）：在粘膜组织中引发稳健记忆CD8+T细胞应答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启动感染。虽然中和抗体反应是保护的临床相关因素，但组织驻留记忆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，能够在靶粘膜组织中引发稳健的记忆性CD8+T细胞群体的粘膜免疫策略受到极大关注。然而，一个主要的限制因素，成功的粘膜疫苗的发展是缺乏有效和安全的免疫佐剂。在当前的项目中，我们将开发和研究自组装肽纳米材料用于引发保护性粘膜CD8+T细胞反应的功效结核分枝杆菌（Mtb），这是一个主要的全球健康负担。我们将利用从连接到结核分枝杆菌（Mtb）的抗原表位的自组装肽构建的肽纳米纤维，并研究小鼠鼻内免疫后的效应和记忆CD8+T细胞应答。在目标1中，我们将合成单独携带天然CD8+T细胞表位或与Mtb特异性CD4+T辅助表位共组装的肽纳米纤维，以在肺中引发强大的细胞免疫。具有强免疫原性特征的制剂将使用雾化Mtb攻击来测试针对感染的保护，以模拟 结核杆菌感染的自然途径。将测定肺、肝和其他器官中的细菌负荷以评估保护作用。在目标2中，我们将把合成的toll样受体（TLR）激动剂纳入目标1的保护性肽类疫苗制剂中，以扩大具有多功能回忆活性的记忆CD8+T细胞群。将在鼻内递送Mtb疫苗后确定粘液和全身效应器和记忆应答，并将使用雾化Mtb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，对人类健康产生重大影响。这些研究将为基于纳米材料的原型免疫平台奠定基础，以引发强大的粘膜CD8+T细胞免疫，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.