A novel multifunctional role of diverse substrate binding and import by the Haemophilus Sap transporter

嗜血杆菌汁液转运蛋白多种底物结合和输入的新型多功能作用

基本信息

  • 批准号:
    10092919
  • 负责人:
  • 金额:
    $ 50.01万
  • 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:
    2019-03-01 至 2024-02-29
  • 项目状态:
    已结题

项目摘要

Abstract Nontypeable Haemophilus influenzae (NTHI) is a Gram-negative nasopharyngeal commensal microbe, and opportunistic pathogen that mediates human airway diseases such as otitis media (OM), acute sinusitis, chronic bronchitis, pneumonia, and exacerbations in patients with cystic fibrosis and chronic obstructive pulmonary diseases. Commensals must adapt to various microenvironmental cues for long-term colonization of the host. Disruption of commensal-host homeostasis however, can potentiate disease development. Pathogenesis is a multifactorial and dynamic process that begins with NTHI migration to a privileged site and culminates with bacterial growth. Growth is dependent upon multiple complex and coordinated interactions between the microbe(s), the varied microenvironments encountered, and interactions with host immune effectors. Bacterial strategies to thwart innate immune mechanisms and acquisition of essential nutrients are critical for NTHI pathogenesis. The goals of my laboratory are to advance our understanding of NTHI commensal and pathogenic behaviors, determine host microenvironmental cues that dictate these behaviors, and target mechanisms of pathogenesis for development of novel therapies to treat disease. We defined an essential role for the sensitivity to antimicrobial peptide (Sap) transporter in the ability of NTHI to counter the lethal effects of host-derived antimicrobial peptides (AMPs). This novel mechanism of AMP recognition, import and bacterial cytoplasmic degradation is essential for NTHI to counter host AMP lethality in vivo. Additional data from our laboratory support a multi-functional role(s) for Sap transport activity, including the acquisition of essential heme-iron. These data support the first description of an ABC transporter to import more than one diverse substrate. Further, evidence indicates that differential assembly of Sap transporter complex proteins dictates these unique physiological functions. We therefore hypothesize that Sap transporter permease and ATPase proteins coordinate assembly of unique complexes to drive energetic import of AMP molecules, and that this functional complex differs from that assembled for import of additional substrates (heme-iron). We propose to differentiate the AMP and heme binding sites in the periplasmic binding protein, SapA, by point mutant analysis and determine how SapA uses the binding pocket to recognize structurally diverse AMPs (Aim 1). We will define the molecular mechanisms of complex assembly, kinetics of substrate transport, and investigate a role for these processes in bacterial nutrition (Aim 2). As part of both aims we will validate the impact of differential substrate acquisition on NTHI persistence in the preclinical model of OM. These studies will provide the necessary information for future studies to assess bacterial adaptation in response to these microenvironmental cues in vivo and to design small molecule peptide inhibitors or molecules to block Sap- dependent functions essential for NTHI survival.
摘要

项目成果

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Kevin M Mason其他文献

Kevin M Mason的其他文献

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{{ truncateString('Kevin M Mason', 18)}}的其他基金

Tryptophan metabolism in Haemophilus persistence and formation of intracellular communities
嗜血杆菌持久性和细胞内群落形成中的色氨酸代谢
  • 批准号:
    10408174
  • 财政年份:
    2021
  • 资助金额:
    $ 50.01万
  • 项目类别:
A novel multifunctional role of diverse substrate binding and import by the Haemophilus Sap transporter
嗜血杆菌汁液转运蛋白多种底物结合和输入的新型多功能作用
  • 批准号:
    9882943
  • 财政年份:
    2019
  • 资助金额:
    $ 50.01万
  • 项目类别:
A novel multifunctional role of diverse substrate binding and import by the Haemophilus Sap transporter
嗜血杆菌汁液转运蛋白多种底物结合和输入的新型多功能作用
  • 批准号:
    10343697
  • 财政年份:
    2019
  • 资助金额:
    $ 50.01万
  • 项目类别:
A novel multifunctional role of diverse substrate binding and import by the Haemophilus Sap transporter
嗜血杆菌汁液转运蛋白多种底物结合和输入的新型多功能作用
  • 批准号:
    10570899
  • 财政年份:
    2019
  • 资助金额:
    $ 50.01万
  • 项目类别:
The NTHI Sap Transporter: A Mechanism of Antimicrobial Peptide Resistance
NTHI 汁液转运蛋白:抗菌肽耐药性机制
  • 批准号:
    7314376
  • 财政年份:
    2007
  • 资助金额:
    $ 50.01万
  • 项目类别:
The NTHI Sap Transporter: A Mechanism of Antimicrobial Peptide Resistance
NTHI 汁液转运蛋白:抗菌肽耐药性机制
  • 批准号:
    7481172
  • 财政年份:
    2007
  • 资助金额:
    $ 50.01万
  • 项目类别:
Expression of sap Operon in NTHI-induced Otitis Media
NTHI诱导的中耳炎中SAP操纵子的表达
  • 批准号:
    6936560
  • 财政年份:
    2003
  • 资助金额:
    $ 50.01万
  • 项目类别:
Expression of sap Operon in NTHI-induced Otitis Media
NTHI诱导的中耳炎中SAP操纵子的表达
  • 批准号:
    6778272
  • 财政年份:
    2003
  • 资助金额:
    $ 50.01万
  • 项目类别:
Expression of sap Operon in NTHI-induced Otitis Media
NTHI诱导的中耳炎中SAP操纵子的表达
  • 批准号:
    6692403
  • 财政年份:
    2003
  • 资助金额:
    $ 50.01万
  • 项目类别:

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