C3-Dependent Intracellular Killing in Innate Immunity and Bacterial Pathogenesis

先天免疫和细菌发病机制中 C3 依赖性细胞内杀伤

基本信息

  • 批准号:
    9765616
  • 负责人:
  • 金额:
    $ 62.93万
  • 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:
    2019-03-05 至 2024-02-29
  • 项目状态:
    已结题

项目摘要

SUMMARY Bacterial infections remain a leading cause of morbidity and mortality worldwide and a critical public health issue due to increasing antibiotic resistance and limited vaccines. Many of the most consequential bacterial infections originate at mucosal surfaces, such as the gut, respiratory tract or skin, then disseminate to other tissues via the bloodstream. Two preeminent human pathogens causing both mucosal and invasive diseases are Gram- negative Salmonella enterica (e.g., serovar Typhimurium, STm) and Gram-positive group A Streptococcus (GAS). Pivotal to innate host defense against bloodstream infection is the function of complement system proteins and their activation cascades, especially opsonization by C3, coupled with the bactericidal activity of phagocytic cells including macrophages (MΦ) and neutrophils. Pathogenic strains of STm and GAS can subvert phagolysosome function to survive intracellularly in MΦ ex vivo and in vivo, whereupon the autophagy system emerges as a critical battleground for pathogen survival/killing. This project brings together two highly experienced and productive physician-scientist investigators with complementary expertise: Gram-negative bacterial pathogenesis, mucosal immunity and gnotobiotic mouse models (MPI, M. Raffatellu) coupled to Gram- positive bacterial pathogenesis, innate immunity, and bacterial-phagocyte interactions (MPI, V. Nizet). Together we have recently discovered a novel, essential intracellular function of C3: targeting of bacteria to the autophagy system for killing in MΦ – a discovery that may challenge conclusions of countless studies of MΦ-bacterial interactions performed in the absence of active serum. Further, we have discovered that the STm serine protease PgtE, the GAS serine protease SpyCEP, and the GAS cysteine protease SpeB allow the respective pathogens to inactivate C3 and to replicate intracellularly in MΦ. Our central hypothesis is that intracellular C3-dependent autophagy is critical to host innate defense, and that the ability of invasive pathogens such as STm and GAS to counteract this process substantially increases their disease-causing potential. Recent data also indicate the microbiome plays an essential role in skin and mucosal complement production, which may represent another crucial factor by which commensal microbes affect invasive bacterial infection risk. Here we propose to continue to investigate the role of intracellular C3 during infection, to understand the ramifications of this new principle of innate immunity on host-pathogen interactions and the outcome of two of the most important human infectious diseases. Our approaches are likely to reveal new virulence genes and host immune pathways that will connect mechanisms, resolve longstanding knowledge gaps, and lead to new avenues of investigation of broad relevance to bacterial pathogenesis including potential novel therapeutic targets and leads.
总结

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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Victor Nizet其他文献

Victor Nizet的其他文献

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{{ truncateString('Victor Nizet', 18)}}的其他基金

Identifying the Most Effective Adjuvant(s) for Leading Group A Streptococcal Vaccine Antigens in Preclinical Mouse and Nonhuman Primate Models
在临床前小鼠和非人灵长类动物模型中确定 A 组链球菌疫苗抗原最有效的佐剂
  • 批准号:
    10577066
  • 财政年份:
    2023
  • 资助金额:
    $ 62.93万
  • 项目类别:
The impact of ampicillin and breast milk oligosaccharides on the infant microbiome and immune functions
氨苄西林和母乳低聚糖对婴儿微生物组和免疫功能的影响
  • 批准号:
    10681295
  • 财政年份:
    2021
  • 资助金额:
    $ 62.93万
  • 项目类别:
The impact of ampicillin and breast milk oligosaccharides on the infant microbiome and immune functions
氨苄西林和母乳低聚糖对婴儿微生物组和免疫功能的影响
  • 批准号:
    10309710
  • 财政年份:
    2021
  • 资助金额:
    $ 62.93万
  • 项目类别:
The impact of ampicillin and breast milk oligosaccharides on the infant microbiome and immune functions
氨苄西林和母乳低聚糖对婴儿微生物组和免疫功能的影响
  • 批准号:
    10487500
  • 财政年份:
    2021
  • 资助金额:
    $ 62.93万
  • 项目类别:
Glycan-Lectin Receptor Regulation of Macrophage Maturation and Lung Innate Defenses in the Fetus and Newborn Infant
胎儿和新生儿巨噬细胞成熟和肺先天防御的聚糖-凝集素受体调节
  • 批准号:
    9979752
  • 财政年份:
    2019
  • 资助金额:
    $ 62.93万
  • 项目类别:
C3-Dependent Intracellular Killing in Innate Immunity and Bacterial Pathogenesis
先天免疫和细菌发病机制中 C3 依赖性细胞内杀伤
  • 批准号:
    9886202
  • 财政年份:
    2019
  • 资助金额:
    $ 62.93万
  • 项目类别:
C3-Dependent Intracellular Killing in Innate Immunity and Bacterial Pathogenesis
先天免疫和细菌发病机制中 C3 依赖性细胞内杀伤
  • 批准号:
    10579831
  • 财政年份:
    2019
  • 资助金额:
    $ 62.93万
  • 项目类别:
C3-Dependent Intracellular Killing in Innate Immunity and Bacterial Pathogenesis
先天免疫和细菌发病机制中 C3 依赖性细胞内杀伤
  • 批准号:
    10357760
  • 财政年份:
    2019
  • 资助金额:
    $ 62.93万
  • 项目类别:
Glycan-Lectin Receptor Regulation of Macrophage Maturation and Lung InnateDefenses in the Fetus and Newborn Infant
胎儿和新生儿巨噬细胞成熟和肺先天防御的聚糖-凝集素受体调节
  • 批准号:
    10360375
  • 财政年份:
    2019
  • 资助金额:
    $ 62.93万
  • 项目类别:
C3-Dependent Intracellular Killing in Innate Immunity and Bacterial Pathogenesis
先天免疫和细菌发病机制中 C3 依赖性细胞内杀伤
  • 批准号:
    10094189
  • 财政年份:
    2019
  • 资助金额:
    $ 62.93万
  • 项目类别:

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