Salmonella pathogenicity island 2 triggers pore-induced intracellular trap formation to evade killing by neutrophils

Information

  • Research Project
  • 10405663
  • ApplicationId
    10405663
  • Core Project Number
    R21AI143929
  • Full Project Number
    7R21AI143929-03
  • Serial Number
    143929
  • FOA Number
    PA-18-590
  • Sub Project Id
  • Project Start Date
    2/1/2020 - 4 years ago
  • Project End Date
    1/31/2022 - 2 years ago
  • Program Officer Name
    ALEXANDER, WILLIAM A
  • Budget Start Date
    8/1/2021 - 2 years ago
  • Budget End Date
    1/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    03
  • Suffix
  • Award Notice Date
    8/2/2021 - 2 years ago
Organizations

Salmonella pathogenicity island 2 triggers pore-induced intracellular trap formation to evade killing by neutrophils

PROJECT SUMMARY Salmonella serovars can cause severe extraintestinal disease in humans. While neutrophils can kill extracellular bacteria using NADPH oxidase-dependent killing mechanisms, macrophages support growth of the pathogen in tissue. The main virulence factor promoting bacterial survival at extraintestinal sites, a type III secretion system (T3SS-2) encoded by Salmonella pathogenicity island (SPI)-2, functions in evading NADPH oxidase-dependent killing by host phagocytes. Paradoxically, T3SS-2-deficient mutants can grow within macrophages in the liver and spleen of mice, suggesting that the virulence factor does not evade NADPH oxidase-dependent killing by macrophages in vivo. Our central hypothesis is that entrapment of S. Typhimurium within the cellular debris of a dead macrophage (termed the pore-induced intracellular trap or PIT) protects the pathogen from neutrophil NADPH oxidase-dependent killing mechanisms during efferocytosis of cellular debris containing viable bacteria. Through this mechanism, T3SS- 2-dependent macrophage PIT formation enables S. Typhimurium to evade NADPH oxidase-dependent killing by neutrophils when the pathogen exits from infected cells to form new infection foci. We will test key aspects of our hypothesis by determining whether localization in macrophage PITs protects Salmonella from neutrophil ROS (Specific Aim 1) and by elucidating how Salmonella T3SS-2 enables complement to reach intracellular bacteria in PITs (Specific Aim 2). Successful completion of the proposed experiments will establish the novel concept that macrophage PIT formation is a virulence strategy of intracellular pathogens to evade neutrophil-mediated host defenses.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R21
  • Administering IC
    AI
  • Application Type
    7
  • Direct Cost Amount
    125000
  • Indirect Cost Amount
    10000
  • Total Cost
    135000
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:135000\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    NAGASAKI UNIVERSITY
  • Organization Department
  • Organization DUNS
    697438752
  • Organization City
    NAGASAKI
  • Organization State
  • Organization Country
    JAPAN
  • Organization Zip Code
    8528521
  • Organization District
    JAPAN