Enhancing Collectin-Mediated Defense Against Influenza

增强集合素介导的流感防御

基本信息

  • 批准号:
    6824052
  • 负责人:
  • 金额:
    $ 32.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2001
  • 资助国家:
    美国
  • 起止时间:
    2001-12-12 至 2006-03-31
  • 项目状态:
    已结题

项目摘要

The collectins are collagenous lectins present in serum and lung secretions involved in innate immunity. Pulmonary surfactant proteins A and D (SP-A and SP-D), play important roles in defense against influenza A virus (IAV). Compared to controls, mice lacking SP-D due to gene-deletion (SP-D -/-) have markedly increased lung viral titers and inflammation after IAV infection. IAV infection of these mice will be characterized in more detail for this proposal. A better understanding of the mechanisms through which SP-D inhibits replication of IAV could elucidate why certain people are more susceptible to complications of IAV infection. This proposal will examine in vitro important functional aspects of SP-D relevant to its role in host defense against IAV, including its ability to bind to, aggregate and neutralize infectivity of IAV, and to modulate the interactions of phagocytic cells with IAV. In addition, the antiviral activities of recombinant preparations of polymorphic variants of SP-D will be tested. SP-D -/- have pulmonary lipidosis. Since phospholipid accumulation could play a role in the increased susceptibility SP-D -/- mice to IAV infection, relevant interactions of SP-D or IAV with surfactant phospholipids will also be examined. Another respiratory tract protein called gp340 binds to SP-D, and has cooperative antiviral effects when combined with SP-D. This proposal will examine further the antiviral activity of gp340 and the mechanisms through which it potentiates the antiviral effects of SP-D. Since SP-D binds to IAV, phagocytes, phospholipids and gp340, through its carbohydrate recognition domain (CRD), the contribution of specific parts of the CRD to these functional activities will be intensively examined. A series of recombinant constructs will be made in which parts of the SP-D CRD are replaced with analogous parts of serum collectins. Since several of the serum collectins have stronger ability to neutralize infectivity of IAV than SP-D, and probably differ from SP-D in terms of binding to phagocytes, phospholipids and gp340, this approach should identify more precisely which groups of amino acids on the CRD are critical for these functions. Based on prior experiments, it is likely that the modified forms of SP-D generated for this proposal will have greater ability to inhibit infectivity of IAV than wild type SP-D. This will be tested in vitro and in vivo by intranasal instillation or transgenic expression of some of these novel, recombinant SP-Ds in SP-D -/- mice. This proposal should not only increase our understanding of the complex mechanisms through which SP-D participates in host defense against IAV, but also provide evidence of the feasibility of restoring or enhancing collectin-mediated defense through use of recombinantly modified collectins.
胶原凝集素是存在于参与先天免疫的血清和肺分泌物中的胶原凝集素。 肺表面活性物质蛋白A和D(SP-A和SP-D)在抵抗甲型流感病毒(IAV)中起重要作用。 与对照组相比,由于基因缺失而缺乏SP-D(SP-D -/-)的小鼠在IAV感染后具有显著增加的肺病毒滴度和炎症。 这些小鼠的IAV感染将更详细地描述本提案。 更好地了解SP-D抑制IAV复制的机制可以阐明为什么某些人更容易出现IAV感染并发症。 该提案将在体外研究SP-D的重要功能方面,其在宿主防御IAV中的作用,包括其结合、聚集和中和IAV感染性的能力,以及调节吞噬细胞与IAV的相互作用。 此外,还将测试SP-D多态性变体重组制剂的抗病毒活性。 SP-D -/-有肺动脉硬化症。 由于磷脂蓄积可能在SP-D -/-小鼠对IAV感染的易感性增加中起作用,因此还将检查SP-D或IAV与表面活性剂磷脂的相关相互作用。 另一种称为gp 340的呼吸道蛋白与SP-D结合,当与SP-D结合时具有协同抗病毒作用。 该提案将进一步研究gp 340的抗病毒活性及其增强SP-D抗病毒作用的机制。由于SP-D通过其碳水化合物识别结构域(CRD)与IAV、吞噬细胞、磷脂和gp 340结合,因此将深入研究CRD的特定部分对这些功能活性的贡献。 将制备一系列重组构建体,其中SP-D CRD的部分被血清凝集素的类似部分替代。 由于几种血清凝集素具有比SP-D更强的中和IAV感染性的能力,并且可能在与吞噬细胞、磷脂和gp 340的结合方面不同于SP-D,因此这种方法应该更精确地鉴定CRD上哪些氨基酸组对这些功能至关重要。 基于先前的实验,很可能为该提议产生的SP-D的修饰形式将比野生型SP-D具有更大的抑制IAV感染性的能力。 这将通过在SP-D -/-小鼠中鼻内滴注或转基因表达这些新型重组SP-D中的一些来在体外和体内进行测试。 这一建议不仅应该增加我们的理解,通过SP-D参与宿主防御IAV的复杂机制,但也提供了证据的可行性,恢复或增强收集蛋白介导的防御,通过使用重组修饰收集蛋白。

项目成果

期刊论文数量(0)
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Kevan L Hartshorn其他文献

Kevan L Hartshorn的其他文献

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{{ truncateString('Kevan L Hartshorn', 18)}}的其他基金

Enhancing Collectin Mediated Defense Against Influenza
增强收集素介导的流感防御
  • 批准号:
    8318629
  • 财政年份:
    2001
  • 资助金额:
    $ 32.2万
  • 项目类别:
Collectin-Mediated Defense Against Influenza
集合素介导的流感防御
  • 批准号:
    7790615
  • 财政年份:
    2001
  • 资助金额:
    $ 32.2万
  • 项目类别:
Enhancing Collectin-Mediated Defense Against Influenza
增强集合素介导的流感防御
  • 批准号:
    6682313
  • 财政年份:
    2001
  • 资助金额:
    $ 32.2万
  • 项目类别:
Enhancing Collectin-Mediated Defense Against Influenza
增强集合素介导的流感防御
  • 批准号:
    6421509
  • 财政年份:
    2001
  • 资助金额:
    $ 32.2万
  • 项目类别:
Collectin-Mediated Defense Against Influenza
集合素介导的流感防御
  • 批准号:
    7100407
  • 财政年份:
    2001
  • 资助金额:
    $ 32.2万
  • 项目类别:
Enhancing Collectin Mediated Defense Against Influenza
增强收集素介导的流感防御
  • 批准号:
    9276089
  • 财政年份:
    2001
  • 资助金额:
    $ 32.2万
  • 项目类别:
Collectin-Mediated Defense Against Influenza
集合素介导的流感防御
  • 批准号:
    7571650
  • 财政年份:
    2001
  • 资助金额:
    $ 32.2万
  • 项目类别:
Enhancing Collectin Mediated Defense Against Influenza
增强收集素介导的流感防御
  • 批准号:
    8681493
  • 财政年份:
    2001
  • 资助金额:
    $ 32.2万
  • 项目类别:
Collectin-Mediated Defense Against Influenza
集合素介导的流感防御
  • 批准号:
    7193464
  • 财政年份:
    2001
  • 资助金额:
    $ 32.2万
  • 项目类别:
Enhancing Collectin Mediated Defense Against Influenza
增强收集素介导的流感防御
  • 批准号:
    8185932
  • 财政年份:
    2001
  • 资助金额:
    $ 32.2万
  • 项目类别:

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