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Legionella pneumophila Outer Membrane Vesicles: Isolation and Analysis of Their Pro-inflammatory Potential on Macrophages
Published on: February 22, 2017
IFNγ receptor down-regulation facilitates Legionella survival in alveolar macrophages
Chao Yang1, Daniel S McDermot2, Shivani Pasricha1,3
1Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
Abstract:
Legionella pneumophila is an opportunistic human pathogen and causative agent of the acute pneumonia known as Legionnaire's disease. Upon inhalation, the bacteria replicate in alveolar macrophages (AM), within an intracellular vacuole termed the Legionella-containing vacuole. We recently found that, in vivo, IFNγ was required for optimal clearance of intracellular L. pneumophila by monocyte-derived cells (MC), but the cytokine did not appear to influence clearance by AM. Here, we report that during L. pneumophila lung infection, expression of the IFNγ receptor subunit 1 (IFNGR1) is down-regulated in AM and neutrophils, but not MC, offering a possible explanation for why AM are unable to effectively restrict L. pneumophila replication in vivo. To test this, we used mice that constitutively express IFNGR1 in AM and found that prevention of IFNGR1 down-regulation enhanced the ability of AM to restrict L. pneumophila intracellular replication. IFNGR1 down-regulation was independent of the type IV Dot/Icm secretion system of L. pneumophila indicating that bacterial effector proteins were not involved. In contrast to previous work, we found that signaling via type I IFN receptors was not required for IFNGR1 down-regulation in macrophages but rather that MyD88- or Trif- mediated NF-κB activation was required. This work has uncovered an alternative signaling pathway responsible for IFNGR1 down-regulation in macrophages during bacterial infection.
Insights
Legionella pneumophila evades immune cells by down-regulating the IFNγ receptor 1 (IFNGR1) in alveolar macrophages. Restoring IFNGR1 expression enhances bacterial clearance, revealing a new immune evasion strategy.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Legionella pneumophila causes Legionnaires' disease by replicating within alveolar macrophages (AM).
- Interferon-gamma (IFNγ) aids clearance by monocyte-derived cells (MC) but not AM during infection.
- IFNγ receptor subunit 1 (IFNGR1) is downregulated in AM during L. pneumophila infection.
Purpose of the Study:
- To investigate the mechanism of L. pneumophila evasion of immune responses in AM.
- To determine the role of IFNGR1 downregulation in AM's inability to restrict bacterial growth.
- To identify signaling pathways involved in IFNGR1 downregulation.
Main Methods:
- Utilized genetically modified mice with constitutive IFNGR1 expression in AM.
- Assessed L. pneumophila replication in AM with and without IFNGR1 downregulation.
- Investigated the role of the Dot/Icm secretion system and NF-κB activation pathways.
Main Results:
- Preventing IFNGR1 downregulation in AM enhanced their ability to restrict L. pneumophila replication.
- IFNGR1 downregulation was independent of L. pneumophila's Dot/Icm secretion system.
- MyD88- or Trif-mediated NF-κB activation, not type I IFN signaling, was required for IFNGR1 downregulation.
Conclusions:
- IFNGR1 downregulation is a key mechanism by which L. pneumophila evades host immunity in AM.
- Restoring IFNGR1 expression in AM can improve bacterial clearance.
- A novel signaling pathway involving MyD88/Trif-mediated NF-κB activation regulates IFNGR1 levels in macrophages during infection.
