Type I interferon-dependent CCL4 is induced by a cGAS/STING pathway that bypasses viral inhibition and protects infected tissue, independent of viral burden.

08:00 EDT 11th October 2019 | BioPortfolio

Summary of "Type I interferon-dependent CCL4 is induced by a cGAS/STING pathway that bypasses viral inhibition and protects infected tissue, independent of viral burden."

Type I interferons (T1-IFN) are critical in the innate immune response, acting upon infected and uninfected cells to initiate an antiviral state by expressing genes that inhibit multiple stages of the lifecycle of many viruses. T1-IFN triggers the production of Interferon-Stimulated Genes (ISGs), activating an antiviral program that reduces virus replication. The importance of the T1-IFN response is highlighted by the evolution of viral evasion strategies to inhibit the production or action of T1-IFN in virus-infected cells. T1-IFN is produced via activation of pathogen sensors within infected cells, a process that is targeted by virus-encoded immunomodulatory molecules. This is probably best exemplified by the prototypic poxvirus, Vaccinia virus (VACV), which uses at least 6 different mechanisms to completely block the production of T1-IFN within infected cells in vitro. Yet, mice lacking aspects of T1-IFN signaling are often more susceptible to infection with many viruses, including VACV, than wild-type mice. How can these opposing findings be rationalized? The cytosolic DNA sensor cGAS has been implicated in immunity to VACV, but has yet to be linked to the production of T1-IFN in response to VACV infection. Indeed, there are two VACV-encoded proteins that effectively prevent cGAS-mediated activation of T1-IFN. We find that the majority of VACV-infected cells in vivo do not produce T1-IFN, but that a small subset of VACV-infected cells in vivo utilize cGAS to sense VACV and produce T1-IFN to protect infected mice. The protective effect of T1-IFN is not mediated via ISG-mediated control of virus replication. Rather, T1-IFN drives increased expression of CCL4, which recruits inflammatory monocytes that constrain the VACV lesion in a virus replication-independent manner by limiting spread within the tissue. Our findings have broad implications in our understanding of pathogen detection and viral evasion in vivo, and highlight a novel immune strategy to protect infected tissue.


Journal Details

This article was published in the following journal.

Name: PLoS pathogens
ISSN: 1553-7374
Pages: e1007778


DeepDyve research library

PubMed Articles [25386 Associated PubMed Articles listed on BioPortfolio]

Sterile Lung Inflammation Induced by Silica Exacerbates Mycobacterium tuberculosis Infection via STING-Dependent Type 2 Immunity.

Lung inflammation induced by silica impairs host control of tuberculosis, yet the underlying mechanism remains unclear. Here, we show that silica-driven exacerbation of M. tuberculosis infection asso...

Avian oncogenic herpesvirus antagonizes the cGAS-STING DNA-sensing pathway to mediate immune evasion.

The cellular DNA sensor cGMP-AMP synthase (cGAS) detects cytosolic viral DNA via the stimulator of interferon genes (STING) to initiate innate antiviral response. Herpesviruses are known to target key...

The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death.

Pathogenic and other cytoplasmic DNAs activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to induce inflammation via transcriptional activation by IRF3 and nucl...

STING modulators: Predictive significance in drug discovery.

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) - stimulator of interferon genes (STING) signaling pathway plays the critical role in the immune response to DNA. Pharmacological...

Accumulation of cytosolic dsDNA contributes to fibroblast-like synoviocytes-mediated rheumatoid arthritis synovial inflammation.

The accumulation of cytosolic dsDNA plays important roles in the regulation of cellular processes. However, whether cytosolic dsDNA is involved in the pathogenesis of rheumatoid arthritis (RA) is not ...

Clinical Trials [10876 Associated Clinical Trials listed on BioPortfolio]

SAbR-induced Innate Immunity

The study is an exploratory prospective, single center study with correlative endpoints. The study will investigate the association of tumor cGAS STING signaling with SAbR. Tumor core biop...

Interferon-Alpha for Diabetes Mellitus Type 1

This study will see if interferon-alpha given early in the disease can stop or slow the immune attack on insulin-producing cells. In addition, the study will examine the safety and efficac...

Efficiency of a Jellyfish Sting Inhibitor Sun Lotion and Protocols for Jellyfish Sting Pain Relief

The purpose of the study is to investigate the effectiveness of a sun lotion containing a specific Jellyfish sting inhibitor versus regular sun lotions as controls. In addition, to investi...

Genetic and Biochemical Markers of Interferon-Induced Depression.

The purpose of this study is to identify predictors and associated biochemical markers of interferon-induced depression. It is hypothesized that genetic variation in genes related to the ...

In Hepatitis C Patients Treated With Interferon and Ribavirin, Does Hepcidin Contribute to Treatment Induced Anaemia

The standard treatment of chronic hepatitis C infection is pegylated interferon alpha combined with ribavirin. Anaemia is a common complication occurring in up to 30% of subjects. Unfortun...

Medical and Biotech [MESH] Definitions

Interferon secreted by leukocytes, fibroblasts, or lymphoblasts in response to viruses or interferon inducers other than mitogens, antigens, or allo-antigens. They include alpha- and beta-interferons (INTERFERON-ALPHA and INTERFERON-BETA).

An interferon regulatory factor that is induced by INTERFERONS as well as LMP-1 protein from EPSTEIN-BARR VIRUS. IRF-7 undergoes PHOSPHORYLATION prior to nuclear translocation and it activates GENETIC TRANSCRIPTION of multiple interferon GENES.

An interferon regulatory factor that binds upstream TRANSCRIPTIONAL REGULATORY ELEMENTS in the GENES for INTERFERON-ALPHA and INTERFERON-BETA. It functions as a transcriptional activator for the INTERFERON TYPE I genes.

A type II interferon produced by recombinant DNA technology. It is similar to the interferon secreted by lymphocytes and has antiviral and antineoplastic activity.

A DEAD box RNA helicase that contains two N-terminal CASPASE ACTIVATION AND RECRUITMENT DOMAINS. It functions as a sensor of viral NUCLEIC ACIDS such as DOUBLE-STRANDED RNA and activates the INNATE IMMUNE RESPONSE by inducing the expression of INTERFERON-ALPHA and INTERFERON-BETA. It may also regulate cell growth and APOPTOSIS.

Quick Search

DeepDyve research library

Relevant Topics

Antiretroviral Therapy Clostridium Difficile Ebola HIV & AIDS Infectious Diseases Influenza Malaria Measles Sepsis Swine Flu Tropical Medicine Tuberculosis Infectious diseases are caused by pathogenic...

Bioinformatics is the application of computer software and hardware to the management of biological data to create useful information. Computers are used to gather, store, analyze and integrate biological and genetic information which can then be applied...

Allergies Automimmune Disease Human Papillomavirus (HPV) Immunology Vaccine Immunology is the study of immunity and the defence mechanisms of the body. A greater understanding of immunology is needed to develop vaccines, understand ...

Searches Linking to this Article