MMP-8 Deficiency Improves Host Responses to Influenza Viral Infections
MMP-8 缺乏可改善宿主对流感病毒感染的反应
基本信息
- 批准号:10260933
- 负责人:
- 金额:$ 5.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-05-15 至 2022-05-14
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAnimalsAntiviral AgentsB-LymphocytesBody Weight decreasedCD4 Positive T LymphocytesCell CountCessation of lifeCleaved cellDataDiagnosisEpithelialEpithelial CellsEpitheliumFellowshipFutureGoalsHealthcareHistocompatibility Antigens Class IIImmune responseIndividualInflammation MediatorsInflammatory ResponseInfluenzaInfluenza A Virus, H1N1 SubtypeInfluenza A virusInterferon Type IInterferonsLeukocytesLinkLungLung diseasesMatrix MetalloproteinasesMorbidity - disease rateMusNeutrophil CollagenaseOseltamivirPathogenesisPatientsPlasmaPopulationPre-Clinical ModelProteinsRegimenSeveritiesStimulusSystemTestingTherapeutic EffectTimeToxic effectTreatment EfficacyVaccinatedVaccinesViralViral Load resultViral ProteinsVirusVirus DiseasesVirus Replicationadaptive immune responseadverse outcomeairway epitheliumcare burdeneffective therapyhuman subjectimprovedimproved outcomeinfluenza virus vaccineinhibitor/antagonistinsightmacrophagemacrophage productmortalitynanobodiesnew therapeutic targetnovelpandemic diseasepreventresponsesafety testingseasonal influenzasmall moleculetherapeutic evaluationtherapeutic target
项目摘要
Project Summary/ Abstract
Seasonal influenza causes 0.25-0.5 million deaths/year world-wide and mortality increases substantially in
pandemic years. Although influenza vaccines are developed annually, only 49% of the US population was
vaccinated in 2010-2011, and not all subjects develop robust protective immune responses to these vaccines.
Current anti-viral drugs (e.g. oseltamivir) target only the virus and do not prevent influenza-associated mortality
in all individuals. Thus, there is an urgent need to develop more effective therapies that limit the mortality and
high health care burden that are associated with influenza A viral (IAV) infections. MMP-8 cleaves pro-
inflammatory mediators to regulate inflammatory responses to various stimuli, but its contributions to the
pathogenesis of IAV disease have not been evaluated. My novel preliminary data strongly link Matrix
metalloproteinase-8 (Mmp-8) to adverse outcomes in animals infected with IAV. Plasma MMP-8 levels are
significantly upregulated in patients diagnosed with pandemic H1N1 and seasonal IAV infections, and levels
correlate inversely with the PaO2/FiO2 ratio. Mmp-8 lung levels are also increased in the lungs of H1N1-
infected WT mice and localized to airway epithelial cells and airway macrophages. Compared with WT mice,
Mmp-8-/- mice have reduced H1N1 IAV-induced mortality; lower lung viral burdens; increased lung levels of
type I interferons (IFNs) and products of activated M1 macrophages, and increased necroptosis of virally-
infected epithelial cells. Thus, our data identifying MMP-8 for the first time as a novel therapeutic target during
serious IAV infections. The goal of this postdoctoral fellowship is to test the central hypotheses: Mmp-8
deficiency in leukocytes (macrophages) reduces lung viral burdens and improves outcomes in IAV-infected
mice by increasing: 1) M1 macrophage polarization to induce a more effective (Th1) adaptive immune
response to IAV; 2) the lung macrophage type I IFN response; and 3) type I IFN induced-necroptosis of IAV-
infected epithelial cells to limit IAV viral replication and spreading. Small molecule MMP-8 inhibitors are not
selective and have off-target toxic effects. Our studies will also determine the extent to which a novel nanobody
inhibitor (Nb14_NbAlb) that selectively inhibits this host protein has therapeutic efficacy in a pre-clinical model of
IAV infection. Successful completion of these studies will pave the way for future IND-enabling studies to test
the safety and efficacy of a “first in class” therapeutic targeting the host response to reduce the morbidity and
mortality associated with serious IAV infections.
项目摘要/摘要
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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Xiaoyun Wang其他文献
Xiaoyun Wang的其他文献
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{{ truncateString('Xiaoyun Wang', 18)}}的其他基金
Mechanistic Insights of TIMP-1 in Influenza Virus Infection
TIMP-1 在流感病毒感染中的机制见解
- 批准号:
10615782 - 财政年份:2022
- 资助金额:
$ 5.03万 - 项目类别:
Mechanistic Insights of TIMP-1 in Influenza Virus Infection
TIMP-1 在流感病毒感染中的机制见解
- 批准号:
10431082 - 财政年份:2022
- 资助金额:
$ 5.03万 - 项目类别:
MMP-8 Deficiency Improves Host Responses to Influenza Viral Infections
MMP-8 缺乏可改善宿主对流感病毒感染的反应
- 批准号:
9760647 - 财政年份:2019
- 资助金额:
$ 5.03万 - 项目类别:
MMP-8 Deficiency Improves Host Responses to Influenza Viral Infections
MMP-8 缺乏可改善宿主对流感病毒感染的反应
- 批准号:
10264958 - 财政年份:2019
- 资助金额:
$ 5.03万 - 项目类别:
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