Combination Adjuvants to Program Durable Immunity to Respiratory Viral and Fungal Pathogens

组合佐剂可对呼吸道病毒和真菌病原体产生持久免疫

基本信息

批准号：
10224468
负责人：
BRUCE Steven KLEIN
金额：
$ 59.95万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-17 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10224468
关键词：
Adjuvant Agonist Animals Antifungal Agents Antigens Antiviral Agents Binding Blastomyces C Type Lectin Receptors CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Combined Vaccines Communicable Diseases Development Dinucleoside Phosphates Fostering Fungal Vaccines Genetic Transcription Goals Human Immunity Immunization Immunologic Receptors Immunologist Influenza A virus Inhalation Interleukin-2 Ligands Lipid A Lung Maintenance Memory Mucous Membrane Mycoses PPBP gene Pathway interactions Periodicity Polysaccharides Primary Infection Public Health Reporting Residencies Respiratory System Respiratory Tract Infections Structure of parenchyma of lung System T cell response T memory cell T-Lymphocyte TLR4 gene Testing Th1 Cells Time Tissues Vaccine Adjuvant Vaccines Viral Viral Respiratory Tract Infection Virus Work base beta-Glucans dectin 1 design factor C functional plasticity fungal pneumonia fungus human pathogen influenza A virus nucleoprotein influenzavirus innovation insight memory CD4 T lymphocyte mouse dectin-2 nanoemulsion parenteral administration particle pathogen pathogenic fungus pathogenic microbe pathogenic virus programs respiratory single-cell RNA sequencing sound stem cells stem-like cell stemness tool transcription factor transcriptome vaccine development

项目摘要

ABSTRACT: Respiratory infections with viruses and fungi constitute major public health problems globally. Except for influenza virus, there are no licensed vaccines against viruses or fungi. It is generally agreed that induction of T-cell memory is critical for defense against viruses and fungi in the respiratory tract. We and others have shown that induction of tissue-resident memory (TRM) CD8 and CD4 T cells and systemic migratory memory CD4 T cells are essential for protection against influenza A virus (IAV) and inhaled fungi, respectively. However, both TRM cells and systemic memory CD4 T cells undergo attrition, leading to short-lived immunity, which is especially true for TC1/TH1 cells. Therefore, induction of durable T-cell immunity poses major challenges for vaccinologists. As compared to TH1 cells, TH17 cells display sought-after attributes of stem-ness, durability and functional plasticity. We propose to tailor combination adjuvants to harness T17 programming and induce durable and protective lung TRM cells and migratory memory CD4 T cells against viruses and fungi. We find that Adjuplex, a nano-emulsion adjuvant, when combined with the TLR4 agonist glucopyranosyl lipid A (GLA), evokes antigen-specific CD8 and CD4 T-cell responses in the lung that are: (i) durable and multifaceted (TC1/TC17/TH1/TH17), and (ii) confer heterosubtypic immunity against IAV that persists >400 days. We further find that combining those adjuvants with fungal CLR ligands Blastomyces endoglucanase 2 (Bl-Eng2; Dectin-2 agonist) and b-glucan particles (Dectin-1 agonist) augments antiviral TC17/TH17/TC1/TH1 and elicits migratory memory T cells that protect against fungal pneumonia. By single-cell RNAseq, we found that our combined adjuvants induce memory antiviral and antifungal CD8 and CD4 T-cell clusters that express ICOS (Inducible T Cell Co-stimulator), the transcription factor c-Maf, and a transcriptome that fosters tissue residency, stem cell-ness and non-pathogenic T17 programming. Cyclic dinucleotides also promote T17 programming in lungs. This, we postulate that programming stem cell-like, functionally plastic, non-pathogenic TC17/TH17 memory cells with our combination adjuvants (that engage TLR-4, Dectin-1/2 and STING pathways) will foster durable protective immunity to viral and fungal pathogens in the lung. Our specific aims will test three hypotheses: Aim 1: Combination adjuvants that evoke TC17/TH17 stem cell-like functionally-plastic TRM or systemic migratory memory will engender durable immunity to respiratory viral and fungal pathogens; Aim 2: Functional plasticity of TC17/TH17 memory is important for protective immunity to viruses and fungi; Aim 3: The ICOS/c-Maf pathway is integral to establishment and/or maintenance of durable vaccine-induced protective immunity to respiratory viral and fungal infections. The proposed work is significant and of high impact because it has the potential to create a tractable adjuvant system/tool kit that will advance the formulation of vaccines: (i) targeted for mucosal or parenteral administration; (ii) designed to induce TRM or systemic T-cell memory; and (iii) tailored to elicit CD8 and CD4 T cells that protect against diverse pathogens such as viruses and fungi.

摘要：病毒和真菌呼吸道感染构成全球主要公共卫生问题。除流感病毒外，尚无针对病毒或真菌的许可疫苗。人们普遍认为 T 细胞记忆的诱导对于防御呼吸道中的病毒和真菌至关重要。我们和其他人研究表明，组织驻留记忆 (TRM) CD8 和 CD4 T 细胞以及系统迁移记忆的诱导 CD4 T 细胞分别对于预防甲型流感病毒 (IAV) 和吸入性真菌至关重要。然而， TRM 细胞和系统性记忆 CD4 T 细胞都会发生损耗，导致短暂的免疫，这是对于 TC1/TH1 细胞尤其如此。因此，诱导持久的 T 细胞免疫对 T 细胞免疫提出了重大挑战。疫苗学家。与 TH1 细胞相比，TH17 细胞表现出干性、耐久性和功能可塑性。我们建议定制组合佐剂来利用 T17 编程并诱导持久以及针对病毒和真菌的保护性肺 TRM 细胞和迁移记忆 CD4 T 细胞。我们发现 Adjuplex（一种纳米乳剂佐剂）与 TLR4 激动剂吡喃葡萄糖结合使用脂质 A (GLA)，在肺部引起抗原特异性 CD8 和 CD4 T 细胞反应，这些反应是：(i) 持久且多方面（TC1/TC17/TH1/TH17），以及 (ii) 赋予针对 IAV 的异亚型免疫力，持续时间超过 400 天。我们进一步发现，将这些佐剂与真菌 CLR 配体芽生菌内切葡聚糖酶 2 (Bl-Eng2； Dectin-2 激动剂）和 b-葡聚糖颗粒（Dectin-1 激动剂）增强抗病毒 TC17/TH17/TC1/TH1 并引发能够预防真菌性肺炎的迁移记忆 T 细胞。通过单细胞RNAseq，我们发现我们的联合佐剂诱导表达 ICOS 的记忆抗病毒和抗真菌 CD8 和 CD4 T 细胞簇（诱导性 T 细胞共刺激剂）、转录因子 c-Maf 和促进组织驻留的转录组，干细胞性和非致病性 T17 编程。环状二核苷酸还促进 T17 编程肺。我们假设编程干细胞样、功能可塑、非致病性 TC17/TH17 记忆细胞与我们的组合佐剂（参与 TLR-4、Dectin-1/2 和 STING 通路）将促进对肺部病毒和真菌病原体具有持久的保护性免疫力。我们的具体目标将测试三个假设：目标 1：联合佐剂引发 TC17/TH17 干细胞样功能可塑性 TRM 或全身迁徙记忆将对呼吸道病毒和真菌病原体产生持久的免疫力；目标 2： TC17/TH17记忆的功能可塑性对于病毒和真菌的保护性免疫很重要；目标 3： ICOS/c-Maf 途径对于建立和/或维持持久的疫苗诱导保护作用是不可或缺的。对呼吸道病毒和真菌感染的免疫力。拟议的工作意义重大且影响深远，因为它有潜力创建一个易于处理的佐剂系统/工具包，以推进疫苗的配制：（i）用于粘膜或肠胃外给药； (ii) 旨在诱导 TRM 或全身 T 细胞记忆； (三) 专门针对诱导 CD8 和 CD4 T 细胞来防御病毒和真菌等多种病原体。