Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

Stifter, Sebastian A.; Feng, Carl G.

doi:10.4049/jimmunol.1402794

Cited by 74 publications

(72 citation statements)

References 206 publications

(220 reference statements)

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“…Compared with WT BMDCs, the production of IFN-b, which is critical for viral clearance, 39 was lower in Beclin-1 +/À BMDCs. Autophagy, which is deficient in Beclin-1…”

Section: Discussionmentioning

confidence: 82%

Autophagy is involved in regulating the immune response of dendritic cells to influenza A (H1N1) pdm09 infection

Zang¹,

Chen

Lin

et al. 2016

Immunology

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SummaryAutophagy can mediate antiviral immunity. However, it remains unknown whether autophagy regulates the immune response of dendritic cells (DCs) to influenza A (H1N1) pdm09 infection. In this study, we found that infection with the H1N1 virus induced DC autophagy in an endocytosis-dependent manner. Compared with autophagy-deficient Beclin-1 +/À mice, we found that bone-marrow-derived DCs from wild-type mice (WT BMDCs) presented a more mature phenotype on H1N1 infection. Wildtype BMDCs secreted higher levels of interleukin-6 (IL-6), tumour necrosis factor-a ( Our data indicate that autophagy is important in the regulation of the DC immune response to H1N1 infection, thereby extending our understanding of host immune responses to the virus.

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“…Compared with WT BMDCs, the production of IFN-b, which is critical for viral clearance, 39 was lower in Beclin-1 +/À BMDCs. Autophagy, which is deficient in Beclin-1…”

Section: Discussionmentioning

confidence: 82%

Autophagy is involved in regulating the immune response of dendritic cells to influenza A (H1N1) pdm09 infection

Zang¹,

Chen

Lin

et al. 2016

Immunology

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“…Detrimental roles for IFN-␤ and/or its receptor IFNAR1 have been described during sepsis (15)(16)(17), bacterial infections including Listeria and Mycobacterium spp. (18), parasitic infections caused by Trypanosoma and Leishmania spp. (18), chronic viral infection (8,19), and in the transmission of neuropathic pain (20).…”

Section: Discussionmentioning

confidence: 99%

“…(18), parasitic infections caused by Trypanosoma and Leishmania spp. (18), chronic viral infection (8,19), and in the transmission of neuropathic pain (20). It has been hypothesized that a targeted reduction in IFN-␤-IFNAR1 signals may be sufficient to protect the host against the lethality of experimental sepsis (21).…”

Section: Discussionmentioning

confidence: 99%

A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling

Weerd

Matthews

Pattie

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillThe interaction of IFN-␤ with its receptor IFNAR1 (interferon ␣/␤ receptor subunit 1) is vital for host-protective anti-viral and anti-proliferative responses, but signaling via this interaction can be detrimental if dysregulated. Whereas it is established that IFNAR1 is an essential component of the IFNAR signaling complex, the key residues underpinning the IFN-␤-IFNAR1 interaction are unknown. Guided by the crystal structure of the IFN-␤-IFNAR1 complex, we used truncation variants and site-directed mutagenesis to investigate domains and residues enabling complexation of IFN-␤ to IFNAR1. We have identified an interface on IFNAR1-subdomain-3 that is differentially utilized by IFN-␤ and IFN-␣ for signal transduction. We used surface plasmon resonance and cell-based assays to investigate this important IFN-␤ binding interface that is centered on IFNAR1 residues Tyr 240 and Tyr The type I IFNs, including 14 IFN-␣ and lone IFN-␤, IFN-⑀, and IFN-, have critical roles in response to viral and bacterial infections and cancers (1, 2). They are also applied clinically for the treatment of hepatitis virus B and C (1), cancers including melanoma (3), and multiple sclerosis (4). Although they show clinical efficacy, their use is restricted by dose-limiting toxicities, including leukopenia, nausea, fatigue, neurological disorders (3), and localized cutaneous effects (5). All type I IFNs engage their cognate receptors, IFNAR1 and IFNAR2, to activate the canonical JAK-STAT signaling pathway, but ligand engagement can also activate alternative signaling pathways (6). Despite sharing these receptor components, there are IFN subtype-specific elements to signaling; compared with IFN-␣, IFN-␤ has specific roles in osteoclastogenesis (7), control of chronic viral infection (8), the potent induction of apoptotic pathways required for control of tumor cell growth, and the development of B cells and myelopoiesis (9).Structural insight into the IFN-IFNAR 5 interactions has been gleaned from the crystal structures of a human IFN-␣2 variant and human IFN-in complex with both IFNAR1 and IFNAR2 (10). Furthermore, specific insight into the mode of IFN-␤-mediated activation of IFNAR1 was obtained from the crystal structure of the murine IFN-␤-IFNAR1 complex (11). Comparison of these structures and evidence from the literature (12) suggests that the minimal ligand binding domains for human and mouse IFNAR1 are similar and sit broadly across the three membrane distal SDs (SD1-3) of the receptor with limited involvement of the membrane proximal subdomain, SD4 (Fig. 1A). It has also been shown that key residues discriminate between ligands and that there is potential for ligand-specific interaction interfaces (10, 11).

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“…IFNs work as antiviral molecules, immune modulators and antiproliferative molecules [171], and through the Jak/Stat signaling pathway they regulate gene expression [172] and recruit innate immune cells to the site of infection and have immune modulatory effects on the adaptive immune system. In the innate system the IFNs have three direct effects by i) transcription of RNases that can break down viral RNA, ii) arresting the protein synthesis machinery which prevents the assembly of new virus and iii) inducing apoptosis in the infected cell [172,173]. However, by replicating in non-antigen-presenting cells, fibroblasts and endothelial cells that can transfer the virus to the systemic circulation of the host, the virus may manage to overcome the immune system.…”

Section: Virusmentioning

confidence: 99%

Aquaporins in Infection and Inflammation

Holm¹

2016

Linköping University Medical Dissertations

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About the cover:The front cover displays a human, blood-derived macrophage stained for aquaporin 9.During the course of the research underlying this thesis, Angelika Holm was enrolled in Forum Scientium, a multidisciplinary doctoral programme at Linköping University Printed by LiU-Tryck, Linköping, Sweden, 2016 "Be brave, even if you're not, pretend to be. No one can tell the difference."To that young, awkward, tall girl who dared to dream of something else, something more:You did it. SUPERVISOR Elena VikströmDepartment of Clinical and Experimental Medicine Linköping University Linköping Sweden When cells of the innate immune system encounter pathogens they need to respond and prepare for migration and phagocytosis and do so through volume regulatory processes. The Gramnegative bacterium Pseudomonas aeruginosa utilizes a small molecule-based communication system, called quorum sensing (QS) to control the production of its virulence factors and biofilms. We found that P. aeruginosa with a complete QS system elicits a stronger phagocytic response in human blood-derived macrophages compared to its lasI-/rhlI-mutant lacking the production of the QS molecules N-butyryl-L-homoserine lactone (C4-HSL) and N-3-oxododecanoyl-L-homoserine lactone (3O-C12-HSL). Infection with P. aeruginosa further increases the expression of AQP9 and induces re-localisation of AQP9 to the front and trailing ends of macrophages. Moreover, the 3O-C12-HSL alone elevates the expression of AQP9, redistribute the water channel to the front and rear ends and increases the cell area and volume of macrophages. Both infection with the wild type P. aeruginosa and the treatment with 3O-C12-HSL change the nano-structural architecture of the AQP9 distribution in macrophages. ASSISTANT SUPERVISORS Karl-Eric MagnussonViruses use the intracellular machinery of the invaded cells to produce and assemble new viral bodies. Intracellular AQPs are localised in a membranes of cellular organelles to regulate their function and morphology. C3H10T1/2 fibroblasts transiently expressing green fluorescent protein (GFP)-AQP6 show a reduced expression of AQP6 after Hazara virus infection and an increased cell area. Overexpressing AQP6 in C3H10T1/2 cells reduces the infectivity of Hazara virus indicating that AQP6 expression has a protective role in virus infections.Ion and water channels in the epithelial cell lining tightly regulate the water homeostasis. In microscopic colitis (MC), patients suffer from severe watery diarrhoeas. For the first time, we have shown that the expression of AQP1, 8 and 11 and the sodium/hydrogen exchanger NHE1 are reduced in colonic biopsies from MC patients compared to healthy control individuals. Following treatment with the glucocorticoid budesonide the patients experienced a rapid recovery and we observed a restored or increased expression of the AQPs and NHE1 during treatment, suggesting a role for AQPs in the diarrhoeal mechanisms in MC.Taken together, this thesis provides new evidence on the importance of water homeostasis regulatio...

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Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

Cited by 74 publications

References 206 publications

Autophagy is involved in regulating the immune response of dendritic cells to influenza A (H1N1) pdm09 infection

Autophagy is involved in regulating the immune response of dendritic cells to influenza A (H1N1) pdm09 infection

A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling

Aquaporins in Infection and Inflammation

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