Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling

Kędzierski, Łukasz; Tate, Michelle D.; Hsu, Alan; Kolesnik, Tatiana B.; Linossi, Edmond M.; Dagley, Laura F.; Dong, Zhaoguang; Freeman, Sarah; Infusini, Giuseppe; Starkey, Malcolm R.; Bird, Nicola L.; Chatfield, Simon; Babon, Jeffrey J.; Huntington, Nicholas D.; Belz, Gabrielle T.; Webb, Andrew I.; Wark, Peter; Nicola, Nicos A.; Xu, Jianqing; Kedzierska, Katherine; Hansbro, Philip M.; Nicholson, Sandra E.

doi:10.7554/elife.20444

Cited by 67 publications

(51 citation statements)

References 62 publications

(91 reference statements)

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“…Previous data showed that, SOCS5 mRNA was significantly upregulated in response to H1N1, H3N2, H5N1, and H11N9. Suppressing SOCS signals improved influenza infection and inhibited HRSV replication [68,69]. CCR2 mRNA upregulation was correlated with HRSV-disease severity [70].…”

Section: Discussionmentioning

confidence: 99%

MERS-CoV infection is associated with downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated inflammatory innate immune response in the lower respiratory tract

et al. 2020

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A B S T R A C TMERS-CoV, a highly pathogenic virus in humans, is associated with high morbidity and case fatality. Inflammatory responses have a significant impact on MERS-CoV pathogenesis and disease outcome. However, CD4 + T-cell induced immune responses during acute MERS-CoV infection are barely detectable, with potent inhibition of effector T cells and downregulation of antigen presentation. The local pulmonary immune response, particularly the Th1 and Th2-related immune response during acute severe MERS-CoV infection is not fully understood. In this study, we offer the first insights into the pulmonary gene expression profile of Th1 and Th2related cytokines/chemokines (Th1 & Th2 responses) during acute MERS-CoV infection using RT 2 Profiler PCR Arrays. We also quantified the expression level of primary inflammatory cytokines/chemokines. Our results showed a downregulation of Th2, inadequate (partial) Th1 immune response and high expression levels of inflammatory cytokines IL-1α and IL-1β and the neutrophil chemoattractant chemokine IL-8 (CXCL8) in the lower respiratory tract of MERS-CoV infected patients. Moreover, we identified a high viral load in all included patients. We also observed a correlation between inflammatory cytokines, Th1, and Th2 downregulation and the case fatality rate. Th1 and Th2 response downregulation, high expression of inflammatory cytokines, and high viral load may contribute to lung inflammation, severe infection, the evolution of pneumonia and ARDS, and a higher case fatality rate. Further study of the molecular mechanisms underlying the Th1 and Th2 regulatory pathways will be vital for active vaccine development and the identification of novel therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

MERS-CoV infection is associated with downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated inflammatory innate immune response in the lower respiratory tract

et al. 2020

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“…Peptides were lyophilized to dryness using a Savant AES 1010 SpeedVac (GMI, Ramsey, MN, USA) and reconstituted in 150 μL 2% acetonitrile/0.1% trifluoroacetic acid. Mass spectrometry analysis was performed as previously described . Acidified peptide mixtures (2 μL) were analyzed by nanoflow reversed‐phase liquid chromatography tandem mass spectrometry on an EASYNano LC 1200 (Thermo Fisher, Bremen, Germany) coupled to a Q Exactive Orbitrap mass spectrometer (Thermo Fisher).…”

Section: Methodsmentioning

confidence: 99%

“…The FLAG‐tagged human Riplet construct was obtained from GenScript in a pcDNA 3.1 expression vector. Constructs for exogenous expression of TRIM25 and Riplet were similarly transfected into BCi‐NS1.1 cells 24 h prior to infection . IAV H1N1 (A/Auckland/1/2009) was diluted in the appropriate serum‐free media and added to cells at a multiplicity of infection of 5.…”

Section: Methodsmentioning

confidence: 99%

“…Mass spectrometry analysis was performed as previously described. 46 Acidified peptide mixtures (2 lL) were analyzed by nanoflow reversed-phase liquid chromatography tandem mass spectrometry on an EASYNano LC 1200 (Thermo Fisher, Bremen, Germany) coupled to a Q Exactive Orbitrap mass spectrometer (Thermo Fisher). Peptides were loaded directly onto a C18 fused silica column (inner diameter 75 lm, outer diameter 360 lm 9 25 cm length) packed into an emitter tip (IonOpticks, Australia) at a constant flow rate of 400 nL min À1 with buffer A (99.9% MilliQ [Merek Millipore, Darmstadt, Germany] water, 0.1% formic acid) and eluted with a 90-min linear gradient from 2% to 34% buffer B (99.9% acetonitrile, 0.1% formic acid).…”

Section: Cytokine Analysesmentioning

confidence: 99%

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RIPLET, and not TRIM25, is required for endogenous RIG‐I‐dependent antiviral responses

et al. 2019

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The innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptors sense viral components and initiate immune signaling cascades that result in the production of an array of cytokines to combat infection. Retinoic acid–inducible gene‐I (RIG‐I) is a pattern recognition receptor that recognizes viral RNA and, when activated, results in the production of type I and III interferons (IFNs) and the upregulation of IFN‐stimulated genes. Ubiquitination of RIG‐I by the E3 ligases tripartite motif‐containing 25 (TRIM25) and Riplet is thought to be requisite for RIG‐I activation; however, recent studies have questioned the relative importance of these two enzymes for RIG‐I signaling. In this study, we show that deletion of Trim25 does not affect the IFN response to either influenza A virus (IAV), influenza B virus, Sendai virus or several RIG‐I agonists. This is in contrast to deletion of either Rig‐i or Riplet, which completely abrogated RIG‐I‐dependent IFN responses. This was consistent in both mouse and human cell lines, as well as in normal human bronchial cells. With most of the current TRIM25 literature based on exogenous expression, these findings provide critical evidence that Riplet, and not TRIM25, is required endogenously for the ubiquitination of RIG‐I. Despite this, loss of TRIM25 results in greater susceptibility to IAV infection in vivo, suggesting that it may have an alternative role in host antiviral defense. This study refines our understanding of RIG‐I signaling in viral infections and will inform future studies in the field.

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“…NF‐κB is also regulated by PHD (primarily PHD1), which reveals a common molecular pathway connecting hypoxia‐dependent regulation of HIF‐1 and NF‐κB . However, it remains unclear when CS‐induced HIF‐1α activation/overexpression and related pathology become important in the human disease course, which needs further investigation in experimental mouse models that recapitulate human disease features, and confirmed in prospective human studies …”

Section: Hypoxaemia and Hypoxia In Copdmentioning

confidence: 99%

Hypoxia‐inducible factor and bacterial infections in chronic obstructive pulmonary disease

et al. 2019

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COPD is a seriously disabling respiratory condition that inexorably progresses to disability and mortality. It affects approximately 10% of the population globally with a greater prevalence at advanced ages. Airway bacterial infections complicate the disease course in most COPD patients, leading to increased symptoms, more rapid decline in lung function, acute exacerbations and reduced quality of life. With increasing bacterial resistance to antibiotics and adverse effects of conventional treatments, new effective non‐antibiotic antimicrobial therapies are urgently needed to manage COPD. Hypoxia‐inducible factor (HIF)‐1α is an important transcriptional regulator of cellular responses to hypoxia, oxidants and inflammation, and is overexpressed in the lungs of COPD patients. Recent evidence shows that increased HIF‐1α expression can upregulate the platelet‐activating factor receptor (PAFR) on the airway epithelial surface that is increased in smokers and particularly COPD patients. The receptor is utilized by PAFR‐dependent bacteria (Streptococcus pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa) to induce infection in both the respiratory and gastrointestinal (GI) tracts. However, the importance and mechanism of HIF‐1α in augmenting PAFR‐dependent bacterial infections in COPD are poorly understood. Here, we review the evidence for the roles of local tissue hypoxia‐induced inflammation, HIF‐1α and PAFR in facilitating bacterial infections in COPD. Blocking PAFR may provide a novel antimicrobial approach to manage bacterial infections in COPD.

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Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling

Cited by 67 publications

References 62 publications

MERS-CoV infection is associated with downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated inflammatory innate immune response in the lower respiratory tract

MERS-CoV infection is associated with downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated inflammatory innate immune response in the lower respiratory tract

RIPLET, and not TRIM25, is required for endogenous RIG‐I‐dependent antiviral responses

Hypoxia‐inducible factor and bacterial infections in chronic obstructive pulmonary disease

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