Novel mechanisms regulating immunity to respiratory virus infection
调节呼吸道病毒感染免疫力的新机制
基本信息
- 批准号:10753849
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-02 至 2023-08-11
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Respiratory Distress SyndromeAddressAnti-Inflammatory AgentsAntiviral AgentsAntiviral ResponseB-LymphocytesBacterial InfectionsBacterial PneumoniaCD80 geneCell physiologyCellsCessation of lifeCytotoxic T-LymphocytesDataDiseaseEpidemicGranzymeHealthHumanHyperimmunoglobulin M SyndromeHypoxiaImmuneImmune responseImmunityIn VitroInfectionInflammationInfluenzaInfluenza A virusInterferon Type IIInterleukin-10Knockout MiceKnowledgeLigandsLungLymphocyteLymphocyte FunctionMalignant NeoplasmsMediatingMorbidity - disease rateMultiple Organ FailureMusMutateNatural Killer CellsOutcomePDL1 pathwayPathway interactionsPersonsPhenotypePopulationPublic HealthPulmonary PathologyRNA VirusesRag1 MouseRoleSeasonsSeverity of illnessSignal PathwaySignal TransductionSliceStructure of parenchyma of lungSuspensionsT cell regulationT-LymphocyteTherapeuticViralViral PneumoniaVirusVirus DiseasesVirus ReplicationWild Type MouseWorkantiviral immunitycell typechronic infectioncytokineexhaustionfightinghumoral immunity deficiencyimmune cell infiltrateimmunopathologyimmunoregulationimprovedinfluenza infectioninfluenzavirusinterleukin-10 receptormast cellmortalityneutralizing antibodynovelnovel therapeuticspandemic potentialpharmacologicpreventprogrammed cell death ligand 1programmed cell death protein 1respiratory infection virusresponsetherapeutic targettumorvaccination outcomeviral resistance
项目摘要
Influenza viruses are rapidly mutating RNA viruses and are the causative agent of about one billion annual
respiratory virus infections and 500,000 deaths worldwide. Influenza-related deaths are generally attributable to
viral or bacterial pneumonia (from secondary bacterial infections); excessive inflammation resulting in acute
respiratory distress syndrome; and severe lung immunopathology, leading to hypoxia and multi-organ failure.
Influenza viruses have significant pandemic potential, seasonal epidemics burden the human population, and
viral resistance has developed to all available treatment options. Much emphasis is placed on the humoral
immune response to influenza, as neutralizing antibodies are the desired vaccine outcome. However, B cell-
deficient mice and humans with hyper-IgM syndrome clear influenza virus infections, while T cell-deficient mice
do not. Thus, B cell-independent mechanisms protect against influenza virus-related mortality. However, the
immune response to influenza virus infection remains poorly understood, and much-needed therapeutics
augmenting the antiviral immune response while preventing harmful immunopathology remain to be developed.
To address this knowledge gap, we recently generated novel and compelling evidence that Influenza A virus
(IAV) infection triggers lung mast cells (MCs) to produce the anti-inflammatory cytokine IL-10 (MC-IL-10). In wild-
type (WT) and T- and B-cell deficient (Rag1-KO) mice, IAV/MC-IL-10 induces the expression of the IL-10 receptor
(IL-10R) and programmed cell death ligand 1 (PD-L1) on Natural Killer (NK) cells. Notably, in Rag1-KO mice,
where NK cells are the sole virus-fighting lymphocytes, PD-L1 blockade, but not PD-1, PD-L2, or CD80 blockade,
significantly reduces IAV-related lethality. The IAV/MC-IL10/NK-PD-L1 pathway is also conserved in humans, at
least in vitro: IAV infection of human-lung tissue-derived single-primary-cell suspensions or intact human lung
tissue slices elicit MC-IL-10 and NK cell-expressed IL-10R and PD-L1. In mice and humans, T cells also
upregulate the IL-10R, PD-1, and PD-L1 upon IAV infection. Further, IAV-infected IL-10-KO/Rag-WT mice,
whose NK and T cells do not upregulate IL-10R, PD-1, PD-L1, or PD-L2, and IAV-infected WT mice in which
PD-L1 is blocked, develop prolonged immune infiltration and immunopathology after IAV clearance. Our findings
are novel and surprising. The induction of the PD/PD-L pathway is generally associated with lymphocyte
exhaustion (via T cell-expressed PD-1) in cancer or chronic infection rather than the modulation of lymphocyte
function in response to an acute viral illness. We hypothesize that influenza virus-induced MC-IL-10 balances
helpful antiviral responses with harmful immunopathology through PDL1 signaling in NK cells, and PD-1 and/or
PD-L1 signaling in T cells. We propose identifying the mechanisms of IAV/MC/IL-10/PD-L1-mediated NK cell
and IAV/MC/IL-10/PD-1 and/or PD-L1-mediated T cell regulation and each pathway's contribution to viral
clearance vs. lung tissue damage. Our proposal is highly significant to human health, as it has great potential to
identify therapeutic targets for alleviating IAV immunopathology-associated mortality and morbidity.
流感病毒是一种快速变异的RNA病毒,每年造成约10亿人死亡
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Silke Paust其他文献
Silke Paust的其他文献
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{{ truncateString('Silke Paust', 18)}}的其他基金
Novel mechanisms regulating immunity to respiratory virus infection
调节呼吸道病毒感染免疫力的新机制
- 批准号:
10931141 - 财政年份:2023
- 资助金额:
-- - 项目类别:
How antigen exposure shapes the subsequent NK cell response to HIV
抗原暴露如何影响随后的 NK 细胞对 HIV 的反应
- 批准号:
10924725 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Control of HIV-induced MDSC expansion and immunosuppression by cytotoxic lymphocytes
细胞毒性淋巴细胞控制 HIV 诱导的 MDSC 扩增和免疫抑制
- 批准号:
10559918 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Control of HIV-induced MDSC expansion and immunosuppression by cytotoxic lymphocytes
细胞毒性淋巴细胞控制 HIV 诱导的 MDSC 扩增和免疫抑制
- 批准号:
10674910 - 财政年份:2022
- 资助金额:
-- - 项目类别:
How antigen exposure shapes the subsequent NK cell response to HIV
抗原暴露如何影响随后的 NK 细胞对 HIV 的反应
- 批准号:
10561720 - 财政年份:2021
- 资助金额:
-- - 项目类别:
How antigen exposure shapes the subsequent NK cell response to HIV
抗原暴露如何影响随后的 NK 细胞对 HIV 的反应
- 批准号:
10374918 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Mechanisms of Protection of Universal Therapeutic Antibodies to Influenza A
甲型流感通用治疗抗体的保护机制
- 批准号:
10078587 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Harnessing NK Memory To Protect Against HIV Infection
利用 NK 记忆来预防 HIV 感染
- 批准号:
8996549 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Harnessing NK Memory To Protect Against HIV Infection
利用 NK 记忆来预防 HIV 感染
- 批准号:
9204387 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Harnessing NK Memory To Protect Against HIV Infection
利用 NK 记忆来预防 HIV 感染
- 批准号:
9430685 - 财政年份:2015
- 资助金额:
-- - 项目类别:
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