IFNΛ3/4 locus polymorphisms and IFNΛ3 circulating levels are associated with COPD severity and outcomes

Egli, Adrian; Mandal, Jyotshna; Schumann, Desiree M.; Roth, Michael; Thomas, Bradley; Tyrrell, D. Lorne; Blasi, Francesco; Κostikas, Κonstantinos; Boersma, Wim; Milenković, Branislava; Lacoma, Alícia; Rentsch, Katharina; Rohde, Gernot; Louis, Renaud; Aerts, Joachim; Welte, Tobias; Torres, Antoni; Tamm, Michael; Stolz, Daiana

doi:10.1186/s12890-018-0616-6

Cited by 14 publications

(13 citation statements)

References 46 publications

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“…Thus, it is also now important to investigate the impact of IFN-β on macrophage function in the context of respiratory viruses and secondary bacterial infections (30,31,34). (36)(37)(38)(39). We postulate that the mechanism underpinning the anti-viral benefits of prophylaxis over treatment is driven by delayed ISG expression, however eliciting the exact mechanism for this is complex not least due significant redundancy in signalling in parallel ISG associated pathways (40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Dynamics of IFN-β Responses during Respiratory Viral Infection. Insights for Therapeutic Strategies

Watson

Spalluto

McCrae

et al. 2020

Am J Respir Crit Care Med

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Viral infections are major drivers of exacerbations and clinical burden in patients with asthma and COPD. IFN-β is a key component of the innate immune response to viral infection. To date studies of inhaled IFN-β treatment have not demonstrated a significant effect on asthma exacerbations. OBJECTIVES: The dynamics of exogenous IFN-β activity were investigated to inform on future clinical indications for this potential anti-viral therapy. METHODS: Monocyte-derived macrophages (MDMs), alveolar macrophages (AMs) and primary bronchial epithelial cells (PBECs) were isolated from healthy controls and COPD patients and infected with influenza virus either prior to or after IFN-β stimulation. Infection levels were measured by % nucleoprotein 1 positive (NP1+) cells using flow cytometry. Viral RNA shedding and interferon stimulated gene expression were measured by qPCR. Production of inflammatory cytokines was measured using MSD. MEASUREMENTS AND MAIN RESULTS: Adding IFN-β to MDMs, AMs and PBECs prior to, but not after, infection reduced %NP1 + cells by 85%, 56% and 66%, respectively (p<0.05). Inhibition of infection lasted for 24h following removal of IFN-β and was maintained albeit reduced up to 1 week in MDMs and 72h in PBECs; 2 this was similar between health and COPD. IFN-β did not induce inflammatory cytokine production by MDMs or PBECs but reduced influenza-induced IL-1β production by PBECs. CONCLUSIONS: In vitro modelling of IFN-β dynamics highlights the potential for intermittent prophylactic doses of exogenous IFN-β to modulate viral infection. This provides important insights to aid the future design of clinical trials of IFN-β in asthma and COPD.

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Section: Discussionmentioning

confidence: 99%

Dynamics of IFN-β Responses during Respiratory Viral Infection. Insights for Therapeutic Strategies

Watson

Spalluto

McCrae

et al. 2020

Am J Respir Crit Care Med

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“…INFL3 is known to be a hallmark of the clearance of HCV infection and a predictor for the risk of developing fibrosis of the liver due to different hepatic diseases such chronic liver fibrosis and CF [ 42 ]. At the onset, IFNL3 possesses anti-tumorigenic and immune-modulatory effects and is primarily triggered by viral infections [ 43 ]. In addition, IFN-λ has critical immunomodulatory and anti-bacterial/viral roles across the respiratory tract.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, IFN-λ has critical immunomodulatory and anti-bacterial/viral roles across the respiratory tract. Importantly, the relationship between IFNL3 polymorphisms and circulating IFNL3 levels is dependent on the type of disease [ 43 ]. For instance, the levels of IFNL3 in serum have been found to be high in subjects with pulmonary fibrosis, resulting in the conclusion that this may be linked to both liver fibrosis and pulmonary fibrosis [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Similarities between the effect of SARS-CoV-2 and HCV on the cellular level, and the possible role of ion channels in COVID19 progression: a review of potential targets for diagnosis and treatment

et al. 2020

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The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has prompted an urgent need to identify effective medicines for the prevention and treatment of the disease. A comparative analysis between SARS-CoV-2 and Hepatitis C Virus (HCV) can expand the available knowledge regarding the virology and potential drug targets against these viruses. Interestingly, comparing HCV with SARS-CoV-2 reveals major similarities between them, ranging from the ion channels that are utilized, to the symptoms that are exhibited by patients. Via this comparative analysis, and from what is known about HCV, the most promising treatments for COVID-19 can focus on the reduction of viral load, treatment of pulmonary system damages, and reduction of inflammation. In particular, the drugs that show most potential in this regard include ritonavir, a combination of peg-IFN, and lumacaftor-ivacaftor. This review anaylses SARS-CoV-2 from the perspective of the role of ion homeostasis and channels in viral pathomechanism. We also highlight other novel treatment approaches that can be used for both treatment and prevention of COVID-19. The relevance of this review is to offer high-quality evidence that can be used as the basis for the identification of potential solutions to the COVID-19 pandemic.

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“…NLRs directly trigger inflammasome assembly and caspase-1 activation, leading to interleukin (IL)-1β and IL-18 processing (25). Type III interferons, also termed IFN-λ, have been recently identified as regulators of immunity and homeostasis in the respiratory tract (26) during infections, as well as during chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD) (27). Alveolar macrophages and dendritic cells (DC) have an important role sensing microbes and thus activating lung epithelial cells and neutrophils.…”

Section: Immune Response To Respiratory Tract Infectionsmentioning

confidence: 99%

“…Other disorders include ciliopathies and disorders of humoral immunity. Alpha 1-antitrypsin is a circulating serine protease inhibitor (serpin) made in the liver that plays an important role in modulating immunity, inflammation, apoptosis, and possibly cellular senescence programs and its deficiency is considered the genetic cause of COPD, but there are other genetic factors that may affect disease activity and outcomes, even in patients without this deficiency (27).…”

Section: Genetic Susceptibility To Respiratory Tract Infectionsmentioning

confidence: 99%

Impact of Host Genetics and Biological Response Modifiers on Respiratory Tract Infections

et al. 2019

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Host susceptibility to respiratory tract infections (RTI) is dependent on both genetic and acquired risk factors. Repeated bacterial and viral RTI, such as pneumonia from encapsulated microorganisms, respiratory tract infections related to respiratory syncytial virus or influenza, and even the development of bronchiectasis and asthma, are often reported as the first symptom of primary immunodeficiencies. In the same way, neutropenia is a well-known risk factor for invasive aspergillosis, as well as lymphopenia for Pneumocystis , and mycobacterial infections. However, in the last decades a better knowledge of immune signaling networks and the introduction of next generation sequencing have increased the number and diversity of known inborn errors of immunity. On the other hand, the use of monoclonal antibodies targeting cytokines, such as tumor necrosis factor alpha has revealed new risk groups for infections, such as tuberculosis. The use of biological response modifiers has spread to almost all medical specialties, including inflammatory diseases and neoplasia, and are being used to target different signaling networks that may mirror some of the known immune deficiencies. From a clinical perspective, the individual contribution of genetics, and/or targeted treatments, to immune dysregulation is difficult to assess. The aim of this article is to review the known and newly described mechanisms of impaired immune signaling that predispose to RTI, including new insights into host genetics and the impact of biological response modifiers, and to summarize clinical recommendations regarding vaccines and prophylactic treatments in order to prevent infections.

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IFNΛ3/4 locus polymorphisms and IFNΛ3 circulating levels are associated with COPD severity and outcomes

Cited by 14 publications

References 46 publications

Dynamics of IFN-β Responses during Respiratory Viral Infection. Insights for Therapeutic Strategies

Dynamics of IFN-β Responses during Respiratory Viral Infection. Insights for Therapeutic Strategies

Similarities between the effect of SARS-CoV-2 and HCV on the cellular level, and the possible role of ion channels in COVID19 progression: a review of potential targets for diagnosis and treatment

Impact of Host Genetics and Biological Response Modifiers on Respiratory Tract Infections

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