Deciphering microbial virulence mechanisms during Legionella pneumophila infection

破译嗜肺军团菌感染期间微生物的毒力机制

基本信息

项目摘要

The bacterium Legionella pneumophila is the causative agent of a potentially life-threatening pneumonia called Legionnaires' disease. Upon inhalation by humans, L. pneumophila enters the human lung where it can infect and replicate within alveolar macrophages, specialized immune cells. Instead of being degraded by macrophages, L. pneumophila uses the infected cell for its intracellular replication cycle. If not treated promptly, this respiratory infection ends fatal in up to 30 percent of all cases. The number of Legionnaires' disease cases in the U.S. has increased four-fold over the past 15 years, making L. pneumophila a significant health threat and a considerable economic burden. We are committed to studying how Legionella can escape our immune system so that we can develop better ways to prevent this from happening. Legionella is ubiquitously found in freshwater habitats such as cooling towers, faucets and shower heads, or water fountains. Major outbreaks of Legionnaires' disease occur when water from contaminated sources is aerosolized and subsequently inhaled by humans. Immune-compromised individuals, infants, or the elderly are at an elevated risk of contracting an infection. Like many other microbial pathogens, L. pneumophila have developed a variety of strategies to infect their human host and to cause disease. They use a specialized protein complex called Type IV Secretion System to inject an abundance of proteins, or effectors, into the infected host cell. The effectors modulate signaling events within the host in order to create conditions favorable for L. pneumophila. Obtaining a detailed understanding of Legionella's effectors and itsvirulence strategies is essential for the development of novel therapeutics capable of preventing and treating this dangerous pneumonia and will profoundly improve people's lives and wellbeing. Over the past funding period, we have made significant progress in deciphering some of the virulence strategies of L. pneumophila. One intriguing finding was that L. pneumophila exploits the human Hippo signaling pathway. The Hippo pathway is highly conserved in all eukaryotic life forms where it is best known for its role in controlling cell development and differentiation. Yet, our finding now suggests that this pathway also plays an important role during microbial infection. Specifically, we discovered that L. pneumophila encodes an effector called LegK7 that mimics the human Hippo kinase, thereby taking control of the Hippo signaling route with the goal of causing changes in host cell physiology that promotes intracellular bacterial growth. Pharmacological interference with this molecular mimicry rendered human cells less susceptible to L. pneumophila growth, providing us with a new way to treat infections by this pathogen. Another notable finding was the existence of a previously undescribed membrane targeting domain in one of the Legionella effectors. This protein, called SidD, localizes to a specific membranes within infected cells in order to properly execute its function. Not only did we reveal at a mechanistic and structural level how this domain can accomplish membrane targeting of SidD, but we also developed strategies to interfere with the targeting process and thus with the function of the Legionella effector. In a third project, we have taken the first step towards the development of smarter antibiotics that selectively target pathogens. Multi-drug-resistant pathogens are an emerging threat to human health. Since conventional antibiotics target not only the pathogen but also eradicate the beneficial human microbiota, they often cause additional clinical complications. Thus, there is an urgent need for the development of therapeutics that selectively target pathogens without affecting beneficial commensals. The bacterial type IV secretion system (T4SS) is essential for the virulence of a variety of pathogens but dispensable for bacterial viability in general and can, thus, be considered a pathogens Achilles heel. By identifying small molecules that interfere with the function of the T4SS from Legionella pneumophila and another important human pathogen, Coxiella burnetii, our study represents the first step in our pursuit towards precision medicine by developing pathogen-selective therapeutics capable of treating the infections without causing harm to commensal bacteria.
嗜肺军团菌是一种可能危及生命的肺炎(称为军团病)的病原体。人类吸入后,嗜肺军团菌进入人类肺部,在那里它可以感染肺泡巨噬细胞(专门的免疫细胞)并在其中复制。嗜肺军团菌不会被巨噬细胞降解,而是利用受感染的细胞进行其细胞内复制周期。如果不及时治疗,这种呼吸道感染在所有病例中高达 30% 会导致致命。 过去 15 年来,美国退伍军人病病例数量增加了四倍,使得嗜肺军团菌成为重大健康威胁和相当大的经济负担。 我们致力于研究军团菌如何逃避我们的免疫系统,以便我们能够开发出更好的方法来防止这种情况的发生。 军团菌普遍存在于冷却塔、水龙头、淋浴喷头或喷泉等淡水栖息地中。当来自受污染水源的水被雾化并随后被人类吸入时,就会发生军团病的大规模爆发。免疫功能低下的个体、婴儿或老年人感染感染的风险较高。 与许多其他微生物病原体一样,嗜肺军团菌已经开发出多种策略来感染人类宿主并引起疾病。他们使用一种称为 IV 型分泌系统的特殊蛋白质复合物,将大量蛋白质或效应物注入受感染的宿主细胞中。效应器调节宿主内的信号事件,以创造有利于嗜肺军团菌的条件。详细了解军团菌的效应子及其毒力策略对于开发能够预防和治疗这种危险肺炎的新型疗法至关重要,并将深刻改善人们的生活和福祉。 在过去的资助期间,我们在破译嗜肺军团菌的一些毒力策略方面取得了重大进展。 一项有趣的发现是嗜肺军团菌利用了人类 Hippo 信号通路。 Hippo 途径在所有真核生命形式中高度保守,以其在控制细胞发育和分化中的作用而闻名。然而,我们现在的发现表明,该途径在微生物感染过程中也发挥着重要作用。 具体来说,我们发现嗜肺军团菌编码一种名为 LegK7 的效应子,它模仿人类 Hippo 激酶,从而控制 Hippo 信号通路,目的是引起宿主细胞生理学的变化,促进细胞内细菌的生长。对这种分子拟态的药理干扰使人类细胞不易受嗜肺军团菌生长的影响,为我们提供了一种治疗这种病原体感染的新方法。 另一个值得注意的发现是在军团菌效应器之一中存在先前未描述的膜靶向结构域。这种蛋白质称为 SidD,定位于受感染细胞内的特定细胞膜,以便正确执行其功能。我们不仅在机制和结构水平上揭示了该结构域如何实现 SidD 的膜靶向,而且我们还开发了干扰靶向过程并从而干扰军团菌效应子功能的策略。 在第三个项目中,我们迈出了开发选择性针对病原体的更智能抗生素的第一步。多重耐药病原体是对人类健康的新威胁。由于传统抗生素不仅针对病原体,而且还根除有益的人类微生物群,因此它们通常会引起额外的临床并发症。因此,迫切需要开发选择性靶向病原体而不影响有益共生体的治疗方法。细菌 IV 型分泌系统 (T4SS) 对于多种病原体的毒力至关重要,但对于一般细菌的生存能力来说是可有可无的,因此可以被视为病原体的致命弱点。 通过识别干扰嗜肺军团菌和另一种重要人类病原体伯内氏立克次体 T4SS 功能的小分子,我们的研究代表了我们通过开发能够治疗感染而不造成伤害的病原体选择性疗法来追求精准医学的第一步到共生细菌。

项目成果

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Matthias Machner其他文献

Matthias Machner的其他文献

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{{ truncateString('Matthias Machner', 18)}}的其他基金

Deciphering microbial virulence mechanisms during Legionella pneumophila infection
破译嗜肺军团菌感染期间的微生物毒力机制
  • 批准号:
    8941540
  • 财政年份:
  • 资助金额:
    $ 119.55万
  • 项目类别:
Deciphering microbial virulence mechanisms during Legionella pneumophila infection
破译嗜肺军团菌感染期间的微生物毒力机制
  • 批准号:
    9339261
  • 财政年份:
  • 资助金额:
    $ 119.55万
  • 项目类别:
Characterization of Legionella virulence mechanisms
军团菌毒力机制的表征
  • 批准号:
    8736927
  • 财政年份:
  • 资助金额:
    $ 119.55万
  • 项目类别:
Deciphering microbial virulence mechanisms during Legionella pneumophila infection
破译嗜肺军团菌感染期间微生物的毒力机制
  • 批准号:
    10908173
  • 财政年份:
  • 资助金额:
    $ 119.55万
  • 项目类别:
Deciphering microbial virulence mechanisms during Legionella pneumophila infection
破译嗜肺军团菌感染期间的微生物毒力机制
  • 批准号:
    9150158
  • 财政年份:
  • 资助金额:
    $ 119.55万
  • 项目类别:
Deciphering microbial virulence mechanisms during Legionella pneumophila infection
破译嗜肺军团菌感染期间的微生物毒力机制
  • 批准号:
    9550425
  • 财政年份:
  • 资助金额:
    $ 119.55万
  • 项目类别:
Characterization of Legionella virulence mechanisms
军团菌毒力机制的表征
  • 批准号:
    8351249
  • 财政年份:
  • 资助金额:
    $ 119.55万
  • 项目类别:
Characterization of Legionella virulence mechanisms
军团菌毒力机制的表征
  • 批准号:
    8553977
  • 财政年份:
  • 资助金额:
    $ 119.55万
  • 项目类别:
Characterization of Legionella effector proteins
军团菌效应蛋白的表征
  • 批准号:
    8149395
  • 财政年份:
  • 资助金额:
    $ 119.55万
  • 项目类别:
Deciphering microbial virulence mechanisms during Legionella pneumophila infection
破译嗜肺军团菌感染期间微生物的毒力机制
  • 批准号:
    10691795
  • 财政年份:
  • 资助金额:
    $ 119.55万
  • 项目类别:

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免疫治疗纳米粒子:对结核病和艾滋病毒治疗的影响
  • 批准号:
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