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

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)
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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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