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Selective Janus kinase inhibition preserves interferon-λ-mediated antiviral responses.

ABSTRACT: Inflammatory diseases are frequently treated with Janus kinase (JAK) inhibitors to diminish cytokine signaling. These treatments can lead to inadvertent immune suppression and may increase the risk of viral infection. Tyrosine kinase 2 (TYK2) is a JAK family member required for efficient type I interferon (IFN-α/β) signaling. We report here that selective TYK2 inhibition preferentially blocked potentially detrimental type I IFN signaling, whereas IFN-λ-mediated responses were largely preserved. In contrast, the clinically used JAK1/2 inhibitor baricitinib was equally potent in blocking IFN-α/β- or IFN-λ-driven responses. Mechanistically, we showed that epithelial cells did not require TYK2 for IFN-λ-mediated signaling or antiviral protection. TYK2 deficiency diminished IFN-α-induced protection against lethal influenza virus infection in mice but did not impair IFN-λ-mediated antiviral protection. Our findings suggest that selective TYK2 inhibitors used in place of broadly acting JAK1/2 inhibitors may represent a superior treatment option for type I interferonopathies to counteract inflammatory responses while preserving antiviral protection mediated by IFN-λ.

SUBMITTER: Schnepf D

PROVIDER: S-EPMC7610871 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Pharmacological inhibition of tyrosine kinase 2 preserves interferon-λ-mediated protection

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-04-09 | GSE146104 | GEO

Pharmacological inhibition of tyrosine kinase 2 preserves interferon-λ-mediated protection (neutrophils)

Project description:Treating inflammatory diseases with Janus kinase 1/2 (JAK1/2) inhibitors bears the risk that patients acquire viral infections due to unwanted immune suppression. Tyrosine kinase 2 (TYK2), a JAK family member, is required for type I interferon (IFN-α/β) signaling, but its role in type III IFN (IFN-λ) signaling is still under debate. We found that the selective TYK2 inhibitor BMS-986165 blocked potentially noxious type I IFN signaling without altering IFN-λ-mediated gene expression. We show that epithelial cells do not require TYK2 for IFN-λ-mediated signaling or antiviral protection. Lack of TYK2 diminished IFN-α-induced protection against lethal influenza virus infection of mice, but did not impair IFN-λ-mediated antiviral protection. Our findings suggest that selective TYK2 inhibitors likely represent a superior treatment option for type I interferonopathies than broadly acting JAK1/2 inhibitors, as selective TYK2 inhibitors may counteract inflammatory responses without abolishing the beneficial antiviral effects of IFN-λ.

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Pharmacological inhibition of tyrosine kinase 2 preserves interferon-λ-mediated protection

Project description:Pharmacological inhibition of tyrosine kinase 2 preserves interferon-λ-mediated protection

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Pharmacological inhibition of tyrosine kinase 2 preserves interferon-λ-mediated protection (neutrophils)

Project description:Pharmacological inhibition of tyrosine kinase 2 preserves interferon-λ-mediated protection (neutrophils)

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Pharmacological inhibition of tyrosine kinase 2 preserves interferon-λ-mediated protection (airway epithelial cells)

Project description:Pharmacological inhibition of tyrosine kinase 2 preserves interferon-λ-mediated protection (airway epithelial cells)

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Interferon lambda alleles predict innate antiviral immune responses and hepatitis C virus permissiveness.

| S-EPMC4104123 | biostudies-literature

Selective inhibition of phosphoinositide 3-kinase p110? preserves lymphocyte function.

Project description:Class IA phosphoinositide 3-kinase (PI3K) is essential for clonal expansion, differentiation, and effector function of B and T lymphocytes. The p110? catalytic isoform of PI3K is highly expressed in lymphocytes and plays a prominent role in B and T cell responses. Another class IA PI3K catalytic isoform, p110?, is a promising drug target in cancer but little is known about its function in lymphocytes. Here we used highly selective inhibitors to probe the function of p110? in lymphocyte responses in vitro and in vivo. p110? inhibition partially reduced B cell receptor (BCR)-dependent AKT activation and proliferation, and diminished survival supported by the cytokines BAFF and IL-4. Selective p110? inhibition suppressed B cell responses much more strongly, yet maximal suppression was achieved by targeting multiple PI3K isoforms. In mouse and human T cells, inhibition of single class IA isoforms had little effect on proliferation, whereas pan-class I inhibition did suppress T cell expansion. In mice, selective p110? inhibition using the investigational agent MLN1117 (previously known as INK1117) did not disrupt the marginal zone B cell compartment and did not block T cell-dependent germinal center formation. In contrast, the selective p110? inhibitor IC87114 strongly suppressed germinal center formation and reduced marginal zone B cell numbers, similar to a pan-class I inhibitor. These findings show that although acute p110? inhibition partially diminishes AKT activation, selective p110? inhibitors are likely to be less immunosuppressive in vivo compared with p110? or pan-class I inhibitors.

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Antiviral activity of lambda interferon in chickens.

Project description:Interferons (IFNs) are essential components of the antiviral defense system of vertebrates. In mammals, functional receptors for type III IFN (lambda interferon [IFN-λ]) are found mainly on epithelial cells, and IFN-λ was demonstrated to play a crucial role in limiting viral infections of mucosal surfaces. To determine whether IFN-λ plays a similar role in birds, we produced recombinant chicken IFN-λ (chIFN-λ) and we used the replication-competent retroviral RCAS vector system to generate mosaic-transgenic chicken embryos that constitutively express chIFN-λ. We could demonstrate that chIFN-λ markedly inhibited replication of various virus strains, including highly pathogenic influenza A viruses, in ovo and in vivo, as well as in epithelium-rich tissue and cell culture systems. In contrast, chicken fibroblasts responded poorly to chIFN-λ. When applied in vivo to 3-week-old chickens, recombinant chIFN-λ strongly induced the IFN-responsive Mx gene in epithelium-rich organs, such as lungs, tracheas, and intestinal tracts. Correspondingly, these organs were found to express high transcript levels of the putative chIFN-λ receptor alpha chain (chIL28RA) gene. Transfection of chicken fibroblasts with a chIL28RA expression construct rendered these cells responsive to chIFN-λ treatment, indicating that receptor expression determines cell type specificity of IFN-λ action in chickens. Surprisingly, mosaic-transgenic chickens perished soon after hatching, demonstrating a detrimental effect of constitutive chIFN-λ expression. Our data highlight fundamental similarities between the IFN-λ systems of mammals and birds and suggest that type III IFN might play a role in defending mucosal surfaces against viral intruders in most if not all vertebrates.

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Interferon Lambda Alleles Predict Innate Antiviral Immune Responses and Hepatitis C Virus Permissiveness.

Project description:Hepatitis C virus (HCV) infection can result in viral chronicity or clearance. Although host genetics and particularly genetic variation in the interferon lambda (IFNL) locus are associated with spontaneous HCV clearance and treatment success, the mechanisms guiding these clinical outcomes remain unknown. Using a laser capture microdissection-driven unbiased systems virology approach, we isolated and transcriptionally profiled HCV-infected and adjacent primary human hepatocytes (PHH) approaching single cell resolution. An innate antiviral immune signature dominated the transcriptional response, but differed in magnitude and diversity between HCV-infected and adjacent cells. Molecular signatures associated with more effective antiviral control were determined by comparing donors with high and low infection frequencies. Cells from donors with clinically unfavorable IFNL genotypes were infected at a greater frequency and exhibited dampened antiviral and cell death responses. These data suggest that early virus-host interactions, particularly host genetics and induction of innate immunity, critically determine the outcome of HCV infection. Cell populations of primary human hepatocytes were collected via laser capture microdissection, their transcriptomes were amplified and analyzed via whole Illumina genome microarray. Three populations were collected: virus infected cells, cells adjacent to infected cells (“adjacent”) and mock infected cells. Cells from multiple donors were employed to address host genetic variability on our observed phenotypes. Nine different donors were assessed on 1-day post infection and three donors were assessed 3 days post infection and and four donors were assessed on 7 days post infection. For each cell population (virus infected, adjacent or mock), four biological replicate arrays were performed. In total, we analyzed 186 microarrays

2014-02-12 | E-GEOD-54648 | biostudies-arrayexpress

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