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:10614603
- 负责人:
- 金额:$ 61.26万
- 依托单位:
- 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:
- 关键词:AdjuvantAgonistAgreementAnimalsAntifungal AgentsAntigensBindingBlastomycesC Type Lectin ReceptorsCD4 Positive T LymphocytesCD8B1 geneCellsCollaborationsCombined VaccinesCommunicable DiseasesCytoprotectionDevelopmentDinucleoside PhosphatesFosteringFungal VaccinesGenetic TranscriptionGlucansGoalsHumanImmunityImmunizationImmunologic ReceptorsImmunologistInfectionInfluenza A virusInhalationInterleukin-2LicensingLigandsLipid ALungMaintenanceMemoryMucous MembraneMycosesPPBP genePathway interactionsPeriodicityPolysaccharidesPrimary InfectionProductivityPublic HealthReportingResidenciesRespiratory SystemRespiratory Tract InfectionsStructure of parenchyma of lungSystemT cell responseT memory cellT-LymphocyteTLR4 geneTestingTh1 CellsTimeTissuesVaccine AdjuvantVaccinesViralViral Respiratory Tract InfectionVirusWorkdectin 1designfactor Cfunctional plasticityfungal pneumoniafungushuman pathogeninfluenza A virus nucleoproteininfluenzavirusinnovationinsightmemory CD4 T lymphocytemouse dectin-2nanoemulsionparenteral administrationparticlepathogenpathogenic funguspathogenic microbepathogenic virusprogramsrespiratorysingle-cell RNA sequencingsoundstem cellsstem-like cellstemnesstooltranscription factortranscriptomevaccine developmentvaccine formulation
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:病毒和真菌引起的呼吸道感染是全球主要的公共卫生问题。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 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:
- 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:
- 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.
Vaccine adjuvants to engage the cross-presentation pathway.
疫苗佐剂可以接合交叉呈递途径。
- DOI:10.3389/fimmu.2022.940047
- 发表时间:2022
- 期刊:
- 影响因子:7.3
- 作者:
- 通讯作者:
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:
- 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
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BRUCE Steven KLEIN其他文献
BRUCE Steven KLEIN的其他文献
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{{ truncateString('BRUCE Steven KLEIN', 18)}}的其他基金
Mechanisms of vaccine immunity against coccidioidomycosis
球孢子菌病疫苗免疫机制
- 批准号:
10584260 - 财政年份:2023
- 资助金额:
$ 61.26万 - 项目类别:
Mechanisms of Vaccine Immunity against Coccidioidomycosis
球孢子菌病疫苗免疫机制
- 批准号:
10591641 - 财政年份:2022
- 资助金额:
$ 61.26万 - 项目类别:
Lung epithelial cell regulation of immunity to inhaled fungi
肺上皮细胞对吸入真菌免疫的调节
- 批准号:
10222492 - 财政年份:2018
- 资助金额:
$ 61.26万 - 项目类别:
Lung epithelial cell regulation of immunity to inhaled fungi
肺上皮细胞对吸入真菌免疫的调节
- 批准号:
10451274 - 财政年份:2018
- 资助金额:
$ 61.26万 - 项目类别:
Lung epithelial cell regulation of immunity to inhaled fungi
肺上皮细胞对吸入真菌免疫的调节
- 批准号:
9975090 - 财政年份:2018
- 资助金额:
$ 61.26万 - 项目类别:
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:
10224468 - 财政年份:2016
- 资助金额:
$ 61.26万 - 项目类别:
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:
10544356 - 财政年份:2016
- 资助金额:
$ 61.26万 - 项目类别:
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:
10448406 - 财政年份:2016
- 资助金额:
$ 61.26万 - 项目类别:
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