IFNγ receptor down‐regulation facilitates Legionella survival in alveolar macrophages. Issue 2 (2nd December 2019)

• Record Type: Journal Article
• Authors: Yang, Chao; McDermot, Daniel S.; Pasricha, Shivani; Brown, Andrew S.; Bedoui, Sammy; Lenz, Laurel L.; van Driel, Ian R.; Hartland, Elizabeth L.
• Is Part Of: Journal of leukocyte biology. Volume 107:Issue 2(2020)
• Page Start: 273
• Page End: 284
• Publication Date: 2019-12-02
• Subjects: bacterial lung pathogen -- IFNγ -- L. pneumophila -- macrophages; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1002/JLB.4MA1019-152R
• Languages: English
• ISSNs: 0741-5400

Abstract

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. Abstract : NF‐κB activation following Legionella lung infection resulted in downregulation of IFNGR1 expression in alveolar macrophages contributing to intracellular bacterial survival.