IFNγ receptor down-regulation facilitates Legionella survival in alveolar macrophages

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, IFN 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 IFN 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-B activation was required. This work has uncovered an alternative signaling pathway responsible for IFNGR1 down-regulation in macrophages during bacterial infection.

Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway

“…Similarly, IFNγ may promote caspase-1-mediated cell killing ( Chin et al., 1997 ) or death receptor-induced apoptosis in some cancer-derived cell lines ( Takeda et al., 2002 ; Tanzer et al., 2017 ; Xu et al., 1998 ). Patients suffering from the pathogen-associated hyper-inflammatory condition, hemophagocytic lymphohistiocytosis (HLH), can benefit from IFNγ blockade ( Locatelli et al., 2020 ), while certain pathogens including Mycobacterium tuberculosis and Legionella pneumophilia have been reported to inhibit IFNγ receptor signaling ( Fortune et al., 2004 ; Kincaid and Ernst, 2003 ; Yang et al., 2020 ). While IFNγ may contribute to the death of infected cells ( Herbst et al., 2011 ; Janssen et al., 2002 ; Niedelman et al., 2013 ; Sedger et al., 1999 ), how IFNγ might invoke immune cell death and the consequences thereof remain incompletely understood.…”

CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes

“…#XP00140BOX) were used for electrophoresis of protein samples according to manufacturer’s instructions. Proteins were transferred to polyvinylidene difluoride membrane as previously reported 90 . Membranes were blocked in 5% (w/v) Bovine Serum Albumin in TBS (20 mm Tris, 50 mm NaCl, pH 8.0) with 0.1% (v/v) Tween-20 (TBST) at room temperature for at least 1 h with shaking at 60 rpm.…”

Costimulation of TLR8 responses by CXCL4 in Human Monocytes Mediated by TBK1-IRF5 Signaling and Epigenomic Remodeling

“…#XP00140BOX) were used for electrophoresis of protein samples according to manufacturer’s instructions. Proteins were transferred to polyvinylidene difluoride membrane was as previously reported 90 . Membranes were blocked in 5% (w/v) Bovine Serum Albumin in TBS (20 mm Tris, 50 mm NaCl, pH 8.0) with 0.1% (v/v) Tween 20 (TBST) at room temperature for at least 1 h with shaking at 60 rpm.…”