scholarly journals The regulatory factor ELF1 triggers a critical wave of transcription in the antiviral response to type I interferon

2019 ◽  
Author(s):  
Leon Louis Seifert ◽  
Clara Si ◽  
Sarah Ballentine ◽  
Debjani Saha ◽  
Maren de Vries ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Type I Interferon ◽  
Regulatory Mechanisms ◽  
Interferon Response ◽  
Type I ◽  
Transcriptional Program ◽  
Ets Transcription Factor ◽  
Transcription Factor 1

ABSTRACTThe transcription of interferon-stimulated genes (ISGs) is classically triggered via activation of the JAK-STAT pathway, and together, ISGs raise a multifaceted antiviral barrier. An increasing body of evidence reports the existence of additional, non-canonical pathways and transcription factors that coordinate ISG expression. Detailed knowledge of how heterogenous mechanisms regulate ISG expression is crucial for the rational design of drugs targeting the type I interferon response. Here, we characterize the first ETS transcription factor family member as a regulator of non-canonical ISG expression: E74-like ETS transcription factor 1 (ELF1). Using high-content microscopy to quantify viral infection over time, we found that ELF1, itself an ISG, inhibits eight diverse RNA and DNA viruses uniquely at multi-cycle replication. ELF1 did not regulate expression of type I or II interferons, and ELF1’s antiviral effect was not abolished by the absence of STAT1 or by inhibition of JAK phosphorylation. Accordingly, comparative expression analyses by RNAseq revealed that the ELF1 transcriptional program is distinct from, and delayed with respect to, the immediate interferon response. Finally, knockdown experiments demonstrated that ELF1 is a critical component of the antiviral interferon response in vitro and in vivo. Our findings reveal a previously overlooked mechanism of non-canonical ISG regulation that both amplifies and prolongs the initial interferon response by expressing broadly antiviral restriction factors.AUTHOR SUMMARYOver 60 years after their discovery, we still struggle to understand exactly how interferons inhibit viruses. Our gap in knowledge stems, on one hand, from the sheer number of interferon-stimulated effector genes, of which only few have been characterized in mechanistic detail. On the other hand, our knowledge of interferon-regulated gene transcription is constantly evolving. We know that different regulatory mechanisms greatly influence the quality, magnitude, and timing of interferon-stimulated gene expression, all of which may contribute to the antiviral mechanism of interferons. Deciphering these regulatory mechanisms is indispensable for understanding this critical first line of host defense, and for harnessing the power of interferons in novel antiviral therapies. Here, we report a novel mechanism of interferon-induced gene regulation by an interferon-stimulated gene, which, paradoxically, inhibits viruses in the absence of additional interferon signaling: E74-like ETS transcription factor 1 (ELF1) raises an unusually delayed antiviral program that potently restricts propagation of all viruses tested in our study. Reduced levels of ELF1 significantly diminished interferon-mediated host defenses against influenza A virus in vitro and in vivo, suggesting a critical but previously overlooked role in the type I interferon response. The transcriptional program raised by ELF1 is vast and comprises over 400 potentially antiviral genes, which are almost entirely distinct from those known to be induced by interferon. Taken together, our data provide evidence for a critical secondary wave of antiviral protection that adds both “quality” and “time” to the type I interferon response.

scholarly journals Type I Interferon Response Limits Astrovirus Replication and Protects against Increased Barrier PermeabilityIn VitroandIn Vivo

2015 ◽  
Vol 90 (4) ◽  
pp. 1988-1996 ◽  
Author(s):  
Shauna A. Marvin ◽  
C. Theodore Huerta ◽  
Bridgett Sharp ◽  
Pamela Freiden ◽  
Troy D. Cline ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Barrier Permeability ◽  
Type I Ifns ◽  
Human Astroviruses ◽  
Human Astrovirus ◽  
New Evidence

ABSTRACTLittle is known about intrinsic epithelial cell responses against astrovirus infection. Here we show that human astrovirus type 1 (HAstV-1) infection induces type I interferon (beta interferon [IFN-β]) production in differentiated Caco2 cells, which not only inhibits viral replication by blocking positive-strand viral RNA and capsid protein synthesis but also protects against HAstV-1-increased barrier permeability. Excitingly, we found similar resultsin vivousing a murine astrovirus (MuAstV) model, providing new evidence that virus-induced type I IFNs may protect against astrovirus replication and pathogenesisin vivo.IMPORTANCEHuman astroviruses are a major cause of pediatric diarrhea, yet little is known about the immune response. Here we show that type I interferon limits astrovirus infection and preserves barrier permeability bothin vitroandin vivo. Importantly, we characterized a new mouse model for studying astrovirus replication and pathogenesis.

scholarly journals The ETS transcription factor ELF1 regulates a broadly antiviral program distinct from the type I interferon response

2019 ◽  
Vol 15 (11) ◽  
pp. e1007634 ◽  
Author(s):  
Leon Louis Seifert ◽  
Clara Si ◽  
Debjani Saha ◽  
Mohammad Sadic ◽  
Maren de Vries ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Ets Transcription Factor

scholarly journals Early Control of H5N1 Influenza Virus Replication by the Type I Interferon Response in Mice

2009 ◽  
Vol 83 (11) ◽  
pp. 5825-5834 ◽  
Author(s):  
Kristy J. Szretter ◽  
Shivaprakash Gangappa ◽  
Jessica A. Belser ◽  
Hui Zeng ◽  
Hualan Chen ◽  
...  
Keyword(s):  
H5n1 Virus ◽  
Type I Interferon ◽  
Influenza Viruses ◽  
Interferon Response ◽  
Type I ◽  
Wild Type ◽  
H5n1 Influenza ◽  
Deficient Mice

ABSTRACT Widespread distribution of highly pathogenic avian H5N1 influenza viruses in domesticated and wild birds continues to pose a threat to public health, as interspecies transmission of virus has resulted in increasing numbers of human disease cases. Although the pathogenic mechanism(s) of H5N1 influenza viruses has not been fully elucidated, it has been suggested that the ability to evade host innate responses, such as the type I interferon response, may contribute to the virulence of these viruses in mammals. We investigated the role that type I interferons (alpha/beta interferon [IFN-α/β]) might play in H5N1 pathogenicity in vivo, by comparing the kinetics and outcomes of H5N1 virus infection in IFN-α/β receptor (IFN-α/βR)-deficient and SvEv129 wild-type mice using two avian influenza A viruses isolated from humans, A/Hong Kong/483/97 (HK/483) and A/Hong Kong/486/97 (HK/486), which exhibit high and low lethality in mice, respectively. IFN-α/βR-deficient mice experienced significantly more weight loss and more rapid time to death than did wild-type mice. HK/486 virus caused a systemic infection similar to that with HK/483 virus in IFN-α/βR-deficient mice, suggesting a role for IFN-α/β in controlling the systemic spread of this H5N1 virus. HK/483 virus replicated more efficiently than HK/486 virus both in vivo and in vitro. However, replication of both viruses was significantly reduced following pretreatment with IFN-α/β. These results suggest a role for the IFN-α/β response in the control of H5N1 virus replication both in vivo and in vitro, and as such it may provide some degree of protection to the host in the early stages of infection.

scholarly journals E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Peng Gao ◽  
Xianwei Ma ◽  
Ming Yuan ◽  
Yulan Yi ◽  
Guoke Liu ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Type I Interferon ◽  
Zinc Fingers ◽  
E3 Ligase ◽  
Type I ◽  
E3 Ligases ◽  
Protein Posttranslational Modifications ◽  
Antiviral Innate Immunity

AbstractUbiquitination is one of the most prevalent protein posttranslational modifications. Here, we show that E3 ligase Nedd4l positively regulates antiviral immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Deficiency of Nedd4l significantly impairs type I interferon and proinflammatory cytokine production induced by virus infection both in vitro and in vivo. Nedd4l deficiency inhibits virus-induced ubiquitination of TRAF3, the binding between TRAF3 and TBK1, and subsequent phosphorylation of TBK1 and IRF3. Nedd4l directly interacts with TRAF3 and catalyzes K29-linked ubiquitination of Cys56 and Cys124, two cysteines that constitute zinc fingers, resulting in enhanced association between TRAF3 and E3 ligases, cIAP1/2 and HECTD3, and also increased K48/K63-linked ubiquitination of TRAF3. Mutation of Cys56 and Cys124 diminishes Nedd4l-catalyzed K29-linked ubiquitination, but enhances association between TRAF3 and the E3 ligases, supporting Nedd4l promotes type I interferon production in response to virus by catalyzing ubiquitination of the cysteines in TRAF3.

scholarly journals Development of Small-Molecule STING Activators for Cancer Immunotherapy

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 33
Author(s):  
Hee Ra Jung ◽  
Seongman Jo ◽  
Min Jae Jeon ◽  
Hyelim Lee ◽  
Yeonjeong Chu ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Cyclic Gmp ◽  
Therapeutic Potential ◽  
Interferon Response ◽  
Type I ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Sting Pathway

In cancer immunotherapy, the cyclic GMP–AMP synthase–stimulator of interferon genes (STING) pathway is an attractive target for switching the tumor immunophenotype from ‘cold’ to ‘hot’ through the activation of the type I interferon response. To develop a new chemical entity for STING activator to improve cyclic GMP-AMP (cGAMP)-induced innate immune response, we identified KAS-08 via the structural modification of DW2282, which was previously reported as an anti-cancer agent with an unknown mechanism. Further investigation revealed that direct STING binding or the enhanced phosphorylation of STING and downstream effectors were responsible for DW2282-or KAS-08-mediated STING activity. Furthermore, KAS-08 was validated as an effective STING pathway activator in vitro and in vivo. The synergistic effect of cGAMP-mediated immunity and efficient anti-cancer effects successfully demonstrated the therapeutic potential of KAS-08 for combination therapy in cancer treatment.

scholarly journals Effect of GHRH and GHRP-2 treatment in vitro on GH secretion and levels of GH, pituitary transcription factor-1, GHRH-receptor, GH-secretagogue-receptor and somatostatin receptor mRNAs in ovine pituitary cells

2004 ◽  
pp. 235-242 ◽  
Author(s):  
M Yan ◽  
M Hernandez ◽  
R Xu ◽  
C Chen
Keyword(s):  
Transcription Factor ◽  
Somatostatin Receptor ◽  
Receptor Subtypes ◽  
Pituitary Cells ◽  
Dependent Manner ◽  
Gh Secretion ◽  
Somatostatin Receptor Subtypes ◽  
Transcription Factor 1

OBJECTIVE: Growth hormone (GH)-releasing hormone (GHRH) and GH-releasing peptides (GHRPs) stimulate the release of GH through their specific receptors on somatotropes. Combined GHRH and GHRP administration causes a synergistic GH release in vivo by an unknown mechanism. The current study focuses on the direct action of GHRH and GHRP on several molecular targets in somatotropes. DESIGN AND METHODS: To clarify the mechanism of action, ovine somatotropes were used to measure the expression of mRNAs encoding for GH, pituitary transcription factor-1 (Pit-1), GH-secretagogue receptor (GHS-R), GHRH-R, somatostatin receptor subtypes (sst-1 and sst-2) and GH release after GHRH and GHRP-2 treatment for 0.5, 1, 1.5 and 2 h. RESULTS: GHRH (10 nM), GHRP-2 (100 nM) and combined GHRH-GHRP-2 increased the levels of GH mRNA and GH release from 0.5 to 2 h in a time-dependent manner. The levels of Pit-1, GHRH-R and GHS-R mRNA were increased after 0.5 h treatment of cells with GHRH and GHRP-2. The levels of sst-1 but not sst-2 mRNA were significantly increased after 0.5 and 1 h of GHRH treatment. In contrast, both sst-1 and sst-2 mRNA expression was inhibited after 0.5-2 h of GHRP treatment. CONCLUSIONS: These data demonstrate a direct in vitro modification of ovine somatotropes by GHRH and GHRP-2 resulting in altered GHRH-R, GHS-R, Pit-1, sst-1, sst-2 and GH gene expression; this may underlie the regulatory action of GHRH and GHRP-2 on GH secretion.

scholarly journals Interferon Regulatory Factor IRF-7 Induces the Antiviral Alpha Interferon Response and Protects against Lethal West Nile Virus Infection

2008 ◽  
Vol 82 (17) ◽  
pp. 8465-8475 ◽  
Author(s):  
Stephane Daffis ◽  
Melanie A. Samuel ◽  
Mehul S. Suthar ◽  
Brian C. Keller ◽  
Michael Gale ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Cortical Neurons ◽  
Interferon Regulatory Factor ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Factor ◽  
West Nile

ABSTRACT Type I interferon (IFN-α/β) comprises a family of immunomodulatory cytokines that are critical for controlling viral infections. In cell culture, many RNA viruses trigger IFN responses through the binding of RNA recognition molecules (RIG-I, MDA5, and TLR-3) and induction of interferon regulatory factor IRF-3-dependent gene transcription. Recent studies with West Nile virus (WNV) have shown that type I IFN is essential for restricting infection and that a deficiency of IRF-3 results in enhanced lethality. However, IRF-3 was not required for optimal systemic IFN production in vivo or in vitro in macrophages. To begin to define the transcriptional factors that regulate type I IFN after WNV infection, we evaluated IFN induction and virus control in IRF-7−/− mice. Compared to congenic wild-type mice, IRF-7−/− mice showed increased lethality after WNV infection and developed early and elevated WNV burdens in both peripheral and central nervous system tissues. As a correlate, a deficiency of IRF-7 blunted the systemic type I IFN response in mice. Consistent with this, IFN-α gene expression and protein production were reduced and viral titers were increased in IRF-7−/− primary macrophages, fibroblasts, dendritic cells, and cortical neurons. In contrast, in these cells the IFN-β response remained largely intact. Our data suggest that the early protective IFN-α response against WNV occurs through an IRF-7-dependent transcriptional signal.

scholarly journals Early Production of Type I Interferon during West Nile Virus Infection: Role for Lymphoid Tissues in IRF3-Independent Interferon Production

2007 ◽  
Vol 81 (17) ◽  
pp. 9100-9108 ◽  
Author(s):  
Nigel Bourne ◽  
Frank Scholle ◽  
Maria Carlan Silva ◽  
Shannan L. Rossi ◽  
Nathan Dewsbury ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Type I Interferon ◽  
High Titer ◽  
West Nile Virus Infection ◽  
Lymphoid Tissues ◽  
Genome Replication ◽  
Type I ◽  
West Nile

ABSTRACT Infection of cells with flaviviruses in vitro is reduced by pretreatment with small amounts of type I interferon (IFN-α/β). Similarly, pretreatment of animals with IFN and experiments using mice defective in IFN signaling have indicated a role for IFN in controlling flavivirus disease in vivo. These data, along with findings that flavivirus-infected cells block IFN signaling, suggest that flavivirus infection can trigger an IFN response. To investigate IFN gene induction by the very first cells infected during in vivo infection with the flavivirus West Nile virus (WNV), we infected mice with high-titer preparations of WNV virus-like particles (VLPs), which initiate viral genome replication in cells but fail to spread. These studies demonstrated a brisk production of IFN in vivo, with peak levels of over 1,000 units/ml detected in sera between 8 and 24 h after inoculation by either the intraperitoneal or footpad route. The IFN response was dependent on genome replication, and WNV genomes and WNV antigen-positive cells were readily detected in the popliteal lymph nodes (pLN) of VLP-inoculated mice. High levels of IFN mRNA transcripts and functional IFN were also produced in VLP-inoculated IFN regulatory factor 3 null (IRF3−/−) mice, indicating that IFN production was independent of the IRF3 pathways to IFN gene transcription, consistent with the IFN type produced (predominantly α).

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