Commensal bacteria as vehicles for robust mucosal vaccination against lung pathogens

共生细菌作为针对肺部病原体的强力粘膜疫苗接种的载体

• 批准号: 10749817
• 负责人: Layla Barkal
• 金额: $ 7.61万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10749817
• 关键词: Adjuvant; Anatomy; Antigens; Award; B-Lymphocytes; Biological Assay; Cells; Characteristics; Clinic; Data; Development; Dose; Economics; Effector Cell; Engineering; Flow Cytometry; Foundations; Genetic Engineering; Goals; Grant; Immune; Immune response; Immune system; Immunity; Immunology; Individual; Inflammation; Inflammatory; Influenza A virus; Inhalation; Intramuscular; K-Series Research Career Programs; Label; Lung; Lung infections; Mentorship; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Nasopharynx; Nose; Patients; Pattern; Physicians; Population; Prevalence; Research; Resources; Respiratory Mucosa; Respiratory Tract Infections; Safety; Scientist; Serum; Severities; Signal Transduction; Site; Skin; Staphylococcus epidermidis; Stimulus; Structure of mucous membrane of nose; Surface; T cell response; T-Cell Activation; Technology; Testing; Tissues; Training; Universities; Vaccinated; Vaccination; Vaccines; Viral Antigens; Viral Respiratory Tract Infection; Virus Diseases; Work; adaptive immune response; antigen-specific T cells; bacterial genetics; burden of illness; career; commensal bacteria; cytokine; cytotoxic CD8 T cells; host-microbe interactions; improved; influenza virus vaccine; interest; lung pathogen; microbial; mouse model; mucosal vaccination; mucosal vaccine; novel therapeutics; pathogenic virus; programs; recruit; respiratory; response; skills; skin vaccination; vaccination strategy; vaccine delivery; vaccine efficacy

PROJECT SUMMARY/ABSTRACT The prevalence and severity of respiratory infections is in part because vaccines struggle to elicit robust immunity at the nasal and lung mucosal barriers where early, strong defense is most needed. Specifically, vaccines delivered intramuscularly generate good serum responses but poor mucosal responses; alternatively, vaccinating the mucosa directly, such as with a nasal spray, requires high doses of adjuvants that cause local inflammation and resulting safety concerns. Commensal bacteria safely live at barrier surfaces such as the skin and nose where they generate antigen-specific immunity without any associated inflammation. The goal of this proposal is to investigate commensal bacteria as safe and effective vaccine vehicles. Preliminary data suggests that engineered strains of Staphylococcus epidermidis, a ubiquitous skin commensal, that express influenza A virus (IAV) antigens (S. epi-IAV) can be applied to the skin and function as partially protective vaccines. In the first aim of my proposal, I will elucidate the cells that respond in the skin and subsequently provide pulmonary protection. Specifically, I will use a T cell activation assay to assess for antigen-specific responding cells; I will also label and track immune cells originating in the skin using the ROSA mouse, which will allow me to profile innate cellular effectors too. In my second aim, I will evaluate for improved pulmonary protection in the case when vaccination on the skin is followed by subsequent antigen exposure at the respiratory mucosa. Finally, I will move to the nasopharynx. I will determine if commensal vaccination in the nose more effective than skin vaccination at eliciting pulmonary protection. My project will provide a deeper understanding of the immune- commensal interactions in the nasopharynx, how commensal-generate immunity is shared between barrier surfaces, and lay the foundation for using commensals to generate mucosal vaccines that are both safer and more effective than existing vaccines. This project builds off my expertise modeling host-microbe interactions in the lung from my graduate work and allows me to expand into the fields of mucosal immunology and microbial engineering. Support from the F32 program, the Fischbach lab, the Stanford Pulmonary Division, and the resources available at Stanford University will allow me to develop critical new skills in flow cytometry, bacterial genetic engineering, and mouse models. The training and mentorship I will receive during my F32 award will let me take a critical step towards my career goal of becoming an independent physician scientist engineering new therapies for my clinic and ICU patients with lung infections.

项目摘要/摘要 呼吸道感染的患病率和严重程度部分是因为疫苗难以引起强大的免疫力 在鼻粘膜和肺粘膜壁垒中，最需要强烈的防御能力。具体而言，疫苗 肌肉内提供的血清反应良好，但粘膜反应差；或者， 直接接种粘膜，例如用鼻喷雾剂，需要高剂量的佐剂来引起局部 发炎和由此产生的安全问题。共生细菌安全地生活在诸如皮肤之类的障碍表面 它们在没有任何相关炎症的情况下产生抗原特异性免疫。目标的目标 提案是将共生细菌作为安全有效的疫苗车进行研究。初步数据建议 葡萄球菌表皮（一种无处不在的皮肤共生）的设计菌株，表达流感 病毒（IAV）抗原（S. epi-iav）可以应用于皮肤，并作为部分保护性疫苗作用。在 我的提案的第一个目的，我将阐明在皮肤中反应的细胞，然后提供肺部 保护。具体而言，我将使用T细胞激活测定法评估抗原特异性响应细胞。我会 还使用Rosa小鼠标记和跟踪源自皮肤中的免疫细胞，这将使我能够概括 先天的细胞效应子。在我的第二个目标中，我将评估此案的改善肺部保护 当皮肤上的疫苗接种后，随后在呼吸道粘膜下暴露于抗原。最后，我 将移至鼻咽。我将确定鼻子中的共生疫苗是否比皮肤更有效 引起肺部保护时的疫苗接种。我的项目将为免疫提供更深入的了解 鼻咽的共生相互作用，屏障之间如何共享共生生成的免疫力 表面，并奠定基础，用于使用共生生成更安全的粘膜疫苗 比现有疫苗更有效。该项目建立了我的专业知识，以建模主机 - 微型互动 我的研究生工作中的肺部，使我能够扩展到粘膜免疫学和微生物的领域 工程。 F32计划，Fischbach实验室，斯坦福肺部和 斯坦福大学提供的资源将使我能够发展流式细胞术的关键新技能，细菌 基因工程和鼠标模型。我在F32奖上将获得的培训和指导将使 我朝着自己的职业目标迈出了关键的一步，成为一名独立的医师科学家工程新的 我的诊所和ICU患者肺部感染的疗法。