Interferon

About: Interferon is a research topic. Over the lifetime, 28969 publications have been published within this topic receiving 1219645 citations. The topic is also known as: IFN & interferons.

The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response

Abstract: TANK-binding kinase 1 (TBK1) is of central importance for the induction of type-I interferon (IFN) in response to pathogens. We identified the DEAD-box helicase DDX3X as an interaction partner of TBK1. TBK1 and DDX3X acted synergistically in their ability to stimulate the IFN promoter, whereas RNAi-mediated reduction of DDX3X expression led to an impairment of IFN production. Chromatin immunoprecipitation indicated that DDX3X is recruited to the IFN promoter upon infection with Listeria monocytogenes, suggesting a transcriptional mechanism of action. DDX3X was found to be a TBK1 substrate in vitro and in vivo. Phosphorylation-deficient mutants of DDX3X failed to synergize with TBK1 in their ability to stimulate the IFN promoter. Overall, our data imply that DDX3X is a critical effector of TBK1 that is necessary for type I IFN induction.

Platelet-derived growth factor-alpha receptor activation is required for human cytomegalovirus infection.

Abstract: Human platelet derived growth factor-alpha (PDGFR-α) receptor has been found to be a requirement for the infection of human cells by human cytomegalovirus (HCMV), the herpesvirus that's the most common cause of congenital human infections, and causes life threatening disease in HIV-infected and transplant patients. If the receptor is inactivated, HCMV cannot enter the cell and viral genes are not expressed. Importantly, two currently available pharmaceutical agents — the anticancer drug imatinib (Gleevec) and PDGFR-α blocking antibody IMC-3G3 — are active against the virus in human cells suggesting that they might prove useful in the treatment of HCMV infection. Human cytomegalovirus (HCMV) is a ubiquitous human herpesvirus that can cause life-threatening disease in the fetus and the immunocompromised host1. Upon attachment to the cell, the virus induces robust inflammatory, interferon- and growth-factor-like signalling2,3,4,5,6,7,8,9. The mechanisms facilitating viral entry and gene expression are not clearly understood4. Here we show that platelet-derived growth factor-α receptor (PDGFR-α) is specifically phosphorylated by both laboratory and clinical isolates of HCMV in various human cell types, resulting in activation of the phosphoinositide-3-kinase (PI(3)K) signalling pathway. Upon stimulation by HCMV, tyrosine-phosphorylated PDGFR-α associated with the p85 regulatory subunit of PI(3)K and induced protein kinase B (also known as Akt) phosphorylation, similar to the genuine ligand, PDGF-AA. Cells in which PDGFR-α was genetically deleted10 or functionally blocked were non-permissive to HCMV entry, viral gene expression or infectious virus production. Re-introducing human PDGFRA gene into knockout cells restored susceptibility to viral entry and essential viral gene expression. Blockade of receptor function with a humanized PDGFR-α blocking antibody (IMC-3G3)11 or targeted inhibition of its kinase activity with a small molecule (Gleevec)12 completely inhibited HCMV viral internalization and gene expression in human epithelial, endothelial and fibroblast cells. Viral entry in cells harbouring endogenous PDGFR-α was competitively inhibited by pretreatment with PDGF-AA. We further demonstrate that HCMV glycoprotein B directly interacts with PDGFR-α, resulting in receptor tyrosine phosphorylation, and that glycoprotein B neutralizing antibodies13 inhibit HCMV-induced PDGFR-α phosphorylation. Taken together, these data indicate that PDGFR-α is a critical receptor required for HCMV infection, and thus a target for novel anti-viral therapies.

Regulation of hepatic innate immunity by hepatitis C virus

Abstract: Hepatitis C virus (HCV) is a global public health problem involving chronic infection of the liver, which can cause liver disease and is linked with liver cancer. Viral innate immune evasion strategies and human genetic determinants underlie the transition of acute HCV infection to viral persistence and the support of chronic infection. Host genetic factors, such as sequence polymorphisms in IFNL3, a gene in the host interferon system, can influence both the outcome of the infection and the response to antiviral therapy. Recent insights into how HCV regulates innate immune signaling within the liver reveal a complex interaction of patient genetic background with viral and host factors of innate immune triggering and control that imparts the outcome of HCV infection and immunity.

Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS

Abstract: T cell-mediated fulminant hepatitis is a life-threatening event for which the underlying mechanism is not fully understood. Injection of concanavalin A (Con A) into mice recapitulates the histological and pathological sequelae of T cell-mediated hepatitis. In this model, both signal transducer and activator of transcription factor 1 (STAT1) and STAT3 are activated in the liver. Disruption of the STAT1 gene by way of genetic knockout attenuates liver injury, suppresses CD4(+) and NK T cell activation, and downregulates expression of proapoptotic interferon regulatory factor-1 protein and suppressor of cytokine signaling-1 (SOCS1), but enhances STAT3 activation and STAT3-controlled antiapoptotic signals. Studies from IFN-gamma-deficient mice indicate that IFN-gamma not only is the major cytokine responsible for STAT1 activation but also partially accounts for STAT3 activation. Moreover, downregulation of STAT3 activation in IL-6-deficient mice is associated with decreased STAT3-controlled antiapoptotic signals and expression of SOCS3, but upregulation of STAT1 activation and STAT1-induced proapoptotic signals and exacerbation of liver injury. Taken together, these findings suggest that STAT1 plays a harmful role in Con A-mediated hepatitis by activation of CD4(+) and NK T cells and directly inducing hepatocyte death, whereas STAT3 protects against liver injury by suppression of IFN-gamma signaling and induction of antiapoptotic protein Bcl-X(L). STAT1 and STAT3 in hepatocytes also negatively regulate one another through the induction of SOCS.