Multi‐ancestral GWAS identifies shared and Asian‐specific loci for SLE and links type III interferon signaling and lysosomal function to the disease

2021 ◽  
Author(s):  
Yong‐Fei Wang ◽  
Wei Wei ◽  
Pattarin Tangtanatakul ◽  
Lichuan Zheng ◽  
Yao Lei ◽  
...  
Keyword(s):  
Interferon Signaling ◽  
Lysosomal Function ◽  
Type Iii ◽  
Type Iii Interferon

Regeneration After Radiation- and Immune-Mediated Tissue Injury Is Not Enhanced by Type III Interferon Signaling

2019 ◽  
Vol 103 (4) ◽  
pp. 970-976 ◽  
Author(s):  
Julius C. Fischer ◽  
Chia-Ching Lin ◽  
Simon Heidegger ◽  
Alexander Wintges ◽  
Martin Schlapschy ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Interferon Signaling ◽  
Type Iii ◽  
Immune Mediated ◽  
Type Iii Interferon

scholarly journals Symmetric Arginine Dimethylation Is Selectively Required for mRNA Splicing and the Initiation of Type I and Type III Interferon Signaling

Cell Reports ◽  
2020 ◽  
Vol 30 (6) ◽  
pp. 1935-1950.e8 ◽  
Author(s):  
Patrick J. Metz ◽  
Keith A. Ching ◽  
Tao Xie ◽  
Paulina Delgado Cuenca ◽  
Sherry Niessen ◽  
...  
Keyword(s):  
Mrna Splicing ◽  
Type I ◽  
Interferon Signaling ◽  
Type Iii ◽  
Type Iii Interferon

scholarly journals A genetic screen identifies a protective type III interferon response to Cryptosporidium that requires TLR3 dependent recognition

2021 ◽  
Author(s):  
Alexis R. Gibson ◽  
Adam Sateriale ◽  
Jennifer E. Dumaine ◽  
Julie B. Engiles ◽  
Jodi A. Gullicksrud ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Interferon Response ◽  
Interferon Signaling ◽  
Gpi Anchor ◽  
Type Iii ◽  
Genome Wide ◽  
A Genome ◽  
Immunocompromised Mice ◽  
Type Iii Interferon ◽  
Recognition Receptor

AbstractCryptosporidium is a leading cause of severe diarrhea and diarrheal-related death in children worldwide. As an obligate intracellular parasite, Cryptosporidium relies on intestinal epithelial cells to provide a niche for its growth and survival, but little is known about the contributions that the infected cell makes to this relationship. Here we conducted a genome wide CRISPR/Cas9 knockout screen to discover host genes required for Cryptosporidium parvum infection and/or host cell survival. Gene enrichment analysis indicated that the host interferon response, glycosaminoglycan (GAG) and glycosylphosphatidylinositol (GPI) anchor biosynthesis are important determinants of susceptibility to C. parvum infection. Several of these pathways are linked to parasite attachment and invasion and C-type lectins on the surface of the parasite. Evaluation of transcript and protein induction of innate interferons revealed a pronounced type III interferon response to Cryptosporidium in human cells as well as in mice. Treatment of mice with IFNλ reduced infection burden and protected immunocompromised mice from severe outcomes including death, with effects that required STAT1 signaling in the enterocyte. Initiation of this type III interferon response was dependent on sustained intracellular growth and mediated by the pattern recognition receptor TLR3. We conclude that host cell intrinsic recognition of Cryptosporidium results in IFNλ production critical to early protection against this infection.Author SummaryCryptosporidium infection is an important contributor to global childhood mortality. There are currently no vaccines available, and the only drug has limited efficacy in immunocompromised individuals and malnourished children who need it most. To discover which host proteins are essential for Cryptosporidium infection, we conducted a genome wide knockout screen in human host cells. Our results confirm the importance of glycosaminoglycans on the surface of epithelial cells for attachment and invasion of the parasite. We also found that host GPI anchor biosynthesis and interferon signaling pathways were enriched by our screen. Examining the role of interferon signaling further we found a type III interferon response, IFNλ, was generated in response to infection and shown to be initiated in the infected cell. Utilizing mouse models of infection, we found that the type III interferon response was important early during infection with its induction likely preceding IFNγ, a key cytokine for the control of this infection. We also determined that TLR3 was the pattern recognition receptor responsible for IFNλ production during Cryptosporidium infection. Our work shows that IFNλ acts directly on the enterocyte and its use in treating immunocompromised mice produced striking reductions in infection.

scholarly journals Chromosome 19 microRNAs exert antiviral activity independent from type III interferon signaling

Placenta ◽  
2018 ◽  
Vol 61 ◽  
pp. 33-38 ◽  
Author(s):  
Avraham Bayer ◽  
Nicholas J. Lennemann ◽  
Yingshi Ouyang ◽  
Elena Sadovsky ◽  
Megan A. Sheridan ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Interferon Signaling ◽  
Chromosome 19 ◽  
Type Iii ◽  
Type Iii Interferon

Distinct Roles of Type I and Type III Interferons During a Native Murine β Coronavirus Lung Infection

2021 ◽  
Author(s):  
Lokesh Sharma ◽  
Xiaohua Peng ◽  
Hua Qing ◽  
Brandon K. Hilliard ◽  
Jooyoung Kim ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Lung Infection ◽  
Viral Clearance ◽  
Type I Interferons ◽  
Type I ◽  
Interferon Signaling ◽  
Type Iii ◽  
Coronavirus Infection ◽  
Type Iii Interferon

Coronaviruses are a major healthcare threat to humankind. Currently, the host factors that contribute to limit disease severity in healthy young patients are not well defined. Interferons are key antiviral molecules, especially type I and type III interferons. The role of these interferons during coronavirus disease is a subject of debate. Here using mice that are deficient in type I (IFNAR1 -/- ), type III (IFNLR1 -/- ) or both (IFNAR1/LR1 -/- ) interferon signaling pathways and murine adapted coronavirus (MHV-A59) administered through intranasal route, we define the role of interferons in coronavirus infection. We show that type I interferons play a major role in host survival in this model while a minimal role of type III interferons was manifested only in the absence of type I interferons or during a lethal dose of coronavirus. IFNAR1 -/- and IFNAR1/LR1 -/- mice had an uncontrolled viral burden in the airways and lung and increased viral dissemination to other organs. The absence of only type III interferon signaling had no measurable difference in the viral load. The increased viral load in IFNAR1 -/- and IFNAR1/LR1 -/- mice was associated with increased tissue injury, especially evident in the lung and liver. Type I but not type III interferon treatment was able to promote survival if treated during early disease. Further, we show that type I interferon signaling in macrophages contributes to the beneficial effects during coronavirus infection in mice. Importance: The antiviral and pathological potential of type I and type III interferons during coronavirus infection remains poorly defined and opposite findings have been reported. We report that both type I and type III interferons have anti-coronaviral activities, but their potency and organ specificity differ. Type I interferons deficiency rendered the mice susceptible to even a sublethal murine coronavirus infection, while the type III interferon deficiency impaired survival only during a lethal infection or during a sublethal infection in absence of type I interferon signaling. While treatment with both type I and III interferons promoted viral clearance in the airways and lung, only type I interferons promoted the viral clearance in the liver and improved host survival upon early treatment (12 hours post infection). This study demonstrates distinct roles and potency of type I and type III interferons and their therapeutic potential during coronavirus lung infection.

scholarly journals Differential Regulation of Type I and Type III Interferon Signaling

2019 ◽  
Vol 20 (6) ◽  
pp. 1445 ◽  
Author(s):  
Megan L. Stanifer ◽  
Kalliopi Pervolaraki ◽  
Steeve Boulant
Keyword(s):  
Immune Response ◽  
Differential Regulation ◽  
Type I ◽  
Type Ii ◽  
Interferon Signaling ◽  
Type Iii ◽  
Type I Ifns ◽  
Current State ◽  
Type Iii Ifn ◽  
Type Iii Interferon

Interferons (IFNs) are very powerful cytokines, which play a key role in combatting pathogen infections by controlling inflammation and immune response by directly inducing anti-pathogen molecular countermeasures. There are three classes of IFNs: type I, type II and type III. While type II IFN is specific for immune cells, type I and III IFNs are expressed by both immune and tissue specific cells. Unlike type I IFNs, type III IFNs have a unique tropism where their signaling and functions are mostly restricted to epithelial cells. As such, this class of IFN has recently emerged as a key player in mucosal immunity. Since the discovery of type III IFNs, the last 15 years of research in the IFN field has focused on understanding whether the induction, the signaling and the function of these powerful cytokines are regulated differently compared to type I IFN-mediated immune response. This review will cover the current state of the knowledge of the similarities and differences in the signaling pathways emanating from type I and type III IFN stimulation.

scholarly journals Interferon Lambda Regulates Cellular and Humoral Immunity in Pristane-Induced Lupus

2021 ◽  
Vol 22 (21) ◽  
pp. 11747
Author(s):  
Tom Aschman ◽  
Sandra Schaffer ◽  
Stylianos Iason Biniaris Georgallis ◽  
Antigoni Triantafyllopoulou ◽  
Peter Staeheli ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Survival Rates ◽  
Mononuclear Phagocytes ◽  
Type I Interferons ◽  
Type I ◽  
Interferon Signaling ◽  
Type Iii ◽  
Cellular And Humoral Immunity ◽  
Type Iii Interferon

A pivotal role of type I interferons in systemic lupus erythematosus (SLE) is widely accepted. Type III interferons (IFN-λ) however, the most recently discovered cytokines grouped within the interferon family, have not been extensively studied in lupus disease models yet. Growing evidence suggests a role for IFN-λ in regulating both innate and adaptive immune responses, and increased serum concentrations have been described in multiple autoimmune diseases including SLE. Using the pristane-induced lupus model, we found that mice with defective IFN-λ receptors (Ifnlr1−/−) showed increased survival rates, decreased lipogranuloma formation and reduced anti-dsDNA autoantibody titers in the early phase of autoimmunity development compared to pristane-treated wild-type mice. Moreover, Ifnlr1−/− mice treated with pristane had reduced numbers of inflammatory mononuclear phagocytes and cNK cells in their kidneys, resembling untreated control mice. Systemically, circulating B cells and monocytes (CD115+Ly6C+) were reduced in pristane-treated Ifnlr1−/− mice. The present study supports a significant role for type III interferons in the pathogenesis of pristane-induced murine autoimmunity as well as in systemic and renal inflammation. Although the absence of type III interferon receptors does not completely prevent the development of autoantibodies, type III interferon signaling accelerates the development of autoimmunity and promotes a pro-inflammatory environment in autoimmune-prone hosts.

scholarly journals Disruption of Type III Interferon (IFN) Genes Ifnl2 and Ifnl3 Recapitulates Loss of the Type III IFN Receptor in the Mucosal Antiviral Response

2019 ◽  
Vol 93 (22) ◽  
Author(s):  
Stefan T. Peterson ◽  
Elizabeth A. Kennedy ◽  
Pamela H. Brigleb ◽  
Gwen M. Taylor ◽  
Kelly Urbanek ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Viral Infections ◽  
Murine Norovirus ◽  
Viral Pathogens ◽  
Genetic Ablation ◽  
Type Iii ◽  
Mucosal Surfaces ◽  
Receptor Interactions ◽  
Type Iii Ifn ◽  
Type Iii Interferon

ABSTRACT Type III interferon (IFN), or IFN lambda (IFN-λ), is an essential component of the innate immune response to mucosal viral infections. In both the intestine and the lung, signaling via the IFN-λ receptor (IFNLR) controls clinically important viral pathogens, including influenza virus, norovirus, and rotavirus. While it is thought that IFN-λ cytokines are the exclusive ligands for signaling through IFNLR, it is not known whether genetic ablation of these cytokines phenotypically recapitulates disruption of the receptor. Here, we report the serendipitous establishment of Ifnl2−/− Ifnl3−/− mice, which lack all known functional murine IFN-λ cytokines. We demonstrate that, like Ifnlr1−/− mice lacking IFNLR signaling, these mice display defective control of murine norovirus, reovirus, and influenza virus and therefore genocopy Ifnlr1−/− mice. Thus, for regulation of viral infections at mucosal sites of both the intestine and lung, signaling via IFNLR can be fully explained by the activity of known cytokines IFN-λ2 and IFN-λ3. Our results confirm the current understanding of ligand-receptor interactions for type III IFN signaling and highlight the importance of this pathway in regulation of mucosal viral pathogens. IMPORTANCE Type III interferons are potent antiviral cytokines important for regulation of viruses that infect at mucosal surfaces. Studies using mice lacking the Ifnlr1 gene encoding the type III interferon receptor have demonstrated that signaling through this receptor is critical for protection against influenza virus, norovirus, and reovirus. Using a genetic approach to disrupt murine type III interferon cytokine genes Ifnl2 and Ifnl3, we found that mice lacking these cytokines fully recapitulate the impaired control of viruses observed in mice lacking Ifnlr1. Our results support the idea of an exclusive role for known type III interferon cytokines in signaling via IFNLR to mediate antiviral effects at mucosal surfaces. These findings emphasize the importance of type III interferons in regulation of a variety of viral pathogens and provide important genetic evidence to support our understanding of the ligand-receptor interactions in this pathway.

Regulation of human endogenous retroviruses of the W family by type III interferon λ2 and HIV in astrocytes

Cytokine ◽  
2009 ◽  
Vol 48 (1-2) ◽  
pp. 65
Author(s):  
Alessandra Mei ◽  
Giuseppe Mameli ◽  
Caterina Serra ◽  
Luciana Poddighe ◽  
Elena Uleriand ◽  
...  
Keyword(s):  
Endogenous Retroviruses ◽  
Human Endogenous Retroviruses ◽  
Type Iii ◽  
Type Iii Interferon
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