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

• 批准号: 10614603
• 负责人: BRUCE Steven KLEIN
• 金额: $ 61.26万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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/10614603
• 关键词: Adjuvant; Agonist; Agreement; Animals; Antifungal Agents; Antigens; Binding; Blastomyces; C Type Lectin Receptors; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Collaborations; Combined Vaccines; Communicable Diseases; Cytoprotection; Development; Dinucleoside Phosphates; Fostering; Fungal Vaccines; Genetic Transcription; Glucans; Goals; Human; Immunity; Immunization; Immunologic Receptors; Immunologist; Infection; Influenza A virus; Inhalation; Interleukin-2; Licensing; Ligands; Lipid A; Lung; Maintenance; Memory; Mucous Membrane; Mycoses; PPBP gene; Pathway interactions; Periodicity; Polysaccharides; Primary Infection; Productivity; 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; 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; vaccine formulation

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：病毒和真菌的呼吸道感染在全球构成了主要的公共卫生问题。 除了流感病毒外，没有针对病毒或真菌的许可疫苗。普遍认为 T细胞记忆的诱导对于防御病毒和呼吸道中的真菌至关重要。我们和其他人 已经表明，诱导组织居民记忆（TRM）CD8和CD4 T细胞以及全身迁移记忆 CD4 T细胞分别针对防止流感病毒（IAV）和吸入真菌至关重要。然而， TRM细胞和全身存储器CD4 T细胞都会受损，导致短暂的免疫力，这是 对于TC1/TH1细胞尤其如此。因此，耐用T细胞免疫的诱导对 疫苗接种学家。与Th1细胞相比，Th17细胞显示出备受追捧的茎，耐用性和 功能可塑性。我们建议量身定制组合佐剂以利用T17编程并诱发耐用 以及保护性肺TRM细胞和迁移记忆CD4 T细胞针对病毒和真菌。 我们发现，与TLR4激动剂葡萄糖吡喃糖基合并时，Adjuplex，一种纳米乳液辅助剂 脂质A（GLA），唤起肺中抗原特异性CD8和CD4 T细胞反应：（i）耐用和 多方面（TC1/TC17/TH1/TH17），（ii）赋予持续> 400天的IAV的异源性免疫。 我们进一步发现，将这些佐剂与真菌CLR配体爆炸性葡萄糖酶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以及引发 迁移记忆T细胞可防止真菌肺炎。通过单细胞RNASEQ，我们发现我们的 联合佐剂诱导记忆抗病毒和抗真菌CD8和CD4 T细胞簇，表达ICOS （诱导T细胞共刺激剂），转录因子C-MAF和促进组织居住的转录组， 干细胞和非致病T17编程。周期性二核苷酸还促进了T17编程 肺。这，我们假设编程类似干细胞的，功能性塑性，非致病TC17/TH17 与我们的组合佐剂（参与TLR-4，Dectin-1/2和STING途径）的记忆单元将促进 对肺中病毒和真菌病原体的持久保护性免疫。我们的具体目标将测试三个 假设：目标1：唤起TC17/TH17干细胞的组合佐剂在功能上塑性trm或 全身迁移记忆将使呼吸道病毒和真菌病原体具有持久的免疫力；目标2： TC17/TH17记忆的功能可塑性对于对病毒和真菌的保护性免疫很重要。目标3： ICOS/C-MAF途径对于耐用疫苗诱导的保护性的建立和/或维护不可或缺 对呼吸道病毒和真菌感染的免疫力。拟议的工作很重要，并且具有很高的影响，因为 它有可能创建一个可拖动的辅助系统/工具套件，该套件将推动疫苗的配方：（i） 针对粘膜或肠胃外给药； （ii）旨在诱导TRM或全身T细胞内存； （iii） 量身定制的，可引起CD8和CD4 T细胞，以防止病毒和真菌等多种病原体。

项目成果

Vaccine-induced systemic and mucosal T cell immunity to SARS-CoV-2 viral variants.

• DOI: 10.1073/pnas.2118312119
• 发表时间: 2022-05-17
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Kingstad-Bakke, Brock;Lee, Woojong;Chandrasekar, Shaswath S.;Gasper, David J.;Salas-Quinchucua, Cristhian;Cleven, Thomas;Sullivan, Jeremy A.;Talaat, Adel;Osorio, Jorge E.;Suresh, M.
• 通讯作者: Suresh, M.

Polymeric Pathogen-Like Particles-Based Combination Adjuvants Elicit Potent Mucosal T Cell Immunity to Influenza A Virus.

• DOI: 10.3389/fimmu.2020.559382
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Kingstad-Bakke B;Toy R;Lee W;Pradhan P;Vogel G;Marinaik CB;Larsen A;Gates D;Luu T;Pandey B;Kawaoka Y;Roy K;Suresh M
• 通讯作者: Suresh M

Airway surveillance and lung viral control by memory T cells induced by COVID-19 mRNA vaccine.

• DOI: 10.1172/jci.insight.172510
• 发表时间: 2023-11-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Kingstad-Bakke, Brock;Cleven, Thomas;Bussan, Hailey;Yount Jr., Boyd L.;Uraki, Ryuta;Iwatsuki-Horimoto, Kiyoko;Koga, Michiko;Yamamoto, Shinya;Yotsuyanagi, Hiroshi;Park, Hongtae;Mishra, Jay S.;Kumar, Sathish;Baric, Ralph S.;Halfmann, Peter J.;Kawaoka, Yoshihiro;Suresh, M.
• 通讯作者: Suresh, M.

Localized and Systemic Immune Responses against SARS-CoV-2 Following Mucosal Immunization.

• DOI: 10.3390/vaccines9020132
• 发表时间: 2021-02-06
• 期刊: Vaccines
• 影响因子: 7.8
• 作者: Chandrasekar SS;Phanse Y;Hildebrand RE;Hanafy M;Wu CW;Hansen CH;Osorio JE;Suresh M;Talaat AM
• 通讯作者: Talaat AM

Vaccine adjuvants to engage the cross-presentation pathway.

• DOI: 10.3389/fimmu.2022.940047
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3