scholarly journals JNK pathway restricts DENV, ZIKV and CHIKV infection by activating complement and apoptosis in mosquito salivary glands

2020 ◽  
Author(s):  
Avisha Chowdhury ◽  
Cassandra M. Modahl ◽  
Siok Thing Tan ◽  
Benjamin Wong Wei Xiang ◽  
Dorothée Missé ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Salivary Glands ◽  
Antiviral Effect ◽  
Negative Regulator ◽  
Chikv Infection ◽  
Jnk Pathway ◽  
Antiviral Effects ◽  
Antiviral Function ◽  
Arbovirus Infection

AbstractArbovirus infection of Aedes aegypti salivary glands (SGs) determines transmission. However, there is a dearth of knowledge on SG immunity. Here, we characterized SG immune response to dengue, Zika and chikungunya viruses using high-throughput transcriptomics. The three viruses regulate components of Toll, IMD and JNK pathways. However, silencing of Toll and IMD components showed variable effects on SG infection by each virus. In contrast, regulation of JNK pathway produced consistent responses. Virus infection increased with depletion of component Kayak and decreased with depletion of negative regulator Puckered. Virus-induced JNK pathway regulates complement and apoptosis in SGs via TEP20 and Dronc, respectively. Individual and co-silencing of these genes demonstrate their antiviral effects and that both may function together. Co-silencing either TEP20 or Dronc with Puckered annihilates JNK pathway antiviral effect. We identified and characterized the broad antiviral function of JNK pathway in SGs, expanding the immune arsenal that blocks arbovirus transmission.

scholarly journals ISG15 Arg151 and the ISG15-Conjugating Enzyme UbE1L Are Important for Innate Immune Control of Sindbis Virus

2008 ◽  
Vol 83 (4) ◽  
pp. 1602-1610 ◽  
Author(s):  
Nadia V. Giannakopoulos ◽  
Elena Arutyunova ◽  
Caroline Lai ◽  
Deborah J. Lenschow ◽  
Arthur L. Haas ◽  
...  
Keyword(s):  
Virus Infection ◽  
Survival Benefit ◽  
Sindbis Virus ◽  
Innate Immune ◽  
Protein Conjugates ◽  
Antiviral Effects ◽  
Antiviral Function ◽  
Alpha Beta

ABSTRACT Interferon (IFN)-stimulated gene 15 (ISG15) is a ubiquitin-like molecule that conjugates to target proteins via a C-terminal LRLRGG motif and has antiviral function in vivo. We used structural modeling to predict human ISG15 (hISG15) residues important for interacting with its E1 enzyme, UbE1L. Kinetic analysis revealed that mutation of arginine 153 to alanine (R153A) ablated hISG15-hUbE1L binding and transthiolation of UbcH8. Mutation of other predicted UbE1L-interacting residues had minimal effects on the transfer of ISG15 from UbE1L to UbcH8. The capacity of hISG15 R153A to form protein conjugates in 293T cells was markedly diminished. Mutation of the homologous residue in mouse ISG15 (mISG15), arginine 151, to alanine (R151A) also attenuated protein ISGylation following transfection into 293T cells. We assessed the role of ISG15-UbE1L interactions in control of virus infection by constructing double subgenomic Sindbis viruses that expressed the mISG15 R151A mutant. While expression of mISG15 protected alpha/beta-IFN-receptor-deficient (IFN-αβR−/−) mice from lethality following Sindbis virus infection, expression of mISG15 R151A conferred no survival benefit. The R151A mutation also attenuated ISG15's ability to decrease Sindbis virus replication in IFN-αβR−/− mice or prolong survival of ISG15−/− mice. The importance of UbE1L was confirmed by demonstrating that mice lacking this ISG15 E1 enzyme were highly susceptible to Sindbis virus infection. Together, these data support a role for protein conjugation in the antiviral effects of ISG15.

scholarly journals Phosphatase Cdc25A Negatively Regulates the Antiviral Immune Response by Inhibiting TBK1 Activity

2018 ◽  
Vol 92 (19) ◽  
Author(s):  
Dandan Qi ◽  
Lei Hu ◽  
Tong Jiao ◽  
Tinghong Zhang ◽  
Xiaomei Tong ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Phosphatase Activity ◽  
Signaling Pathway ◽  
Sendai Virus ◽  
Rna Virus ◽  
Negative Regulator ◽  
Luciferase Assay ◽  
Dna Virus ◽  
Antiviral Immune Response

ABSTRACT The phosphatase Cdc25A plays an important role in cell cycle regulation by dephosphorylating its substrates, such as cyclin-dependent kinases. In this study, we demonstrate that Cdc25A negatively regulates RIG-I-mediated antiviral signaling. We found that ectopic expression of Cdc25A in 293T cells inhibits the activation of beta interferon (IFN-β) induced by Sendai virus and poly(I·C), while knockdown of Cdc25A enhances the transcription of IFN-β stimulated by RNA virus infection. The inhibitory effect of Cdc25A on the antiviral immune response is mainly dependent on its phosphatase activity. Data from a luciferase assay indicated that Cdc25A can inhibit TBK1-mediated activation of IFN-β. Further analysis indicated that Cdc25A can interact with TBK1 and reduce the phosphorylation of TBK1 at S172, which in turn decreases the phosphorylation of its downstream substrate IRF3. Consistently, knockdown of Cdc25A upregulates the phosphorylation of both TBK1-S172 and IRF3 in Sendai virus-infected or TBK1-transfected 293T cells. In addition, we confirmed that Cdc25A can directly dephosphorylate TBK1-S172-p. These results demonstrate that Cdc25A inhibits the antiviral immune response by reducing the active form of TBK1. Using herpes simplex virus 1 (HSV-1) infection, an IFN-β reporter assay, and reverse transcription-quantitative PCR (RT-qPCR), we demonstrated that Cdc25A can also inhibit DNA virus-induced activation of IFN-β. Using a vesicular stomatitis virus (VSV) infection assay, we confirmed that Cdc25A can repress the RIG-I-like receptor (RLR)-mediated antiviral immune response and influence the antiviral status of cells. In conclusion, we demonstrate that Cdc25A negatively regulates the antiviral immune response by inhibiting TBK1 activity. IMPORTANCE The RLR-mediated antiviral immune response is critical for host defense against RNA virus infection. However, the detailed mechanism for balancing the RLR signaling pathway in host cells is not well understood. We found that the phosphatase Cdc25A negatively regulates the RNA virus-induced innate immune response. Our studies indicate that Cdc25A inhibits the RLR signaling pathway via its phosphatase activity. We demonstrated that Cdc25A reduces TBK1 activity and consequently restrains the activation of IFN-β transcription as well as the antiviral status of nearby cells. We showed that Cdc25A can also inhibit DNA virus-induced activation of IFN-β. Taken together, our findings uncover a novel function and mechanism for Cdc25A in regulating antiviral immune signaling. These findings reveal Cdc25A as an important negative regulator of antiviral immunity and demonstrate its role in maintaining host cell homeostasis following viral infection.

scholarly journals Novel Roles of the Picornaviral 3D Polymerase in Viral Pathogenesis

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Jason Kerkvliet ◽  
Ramakrishna Edukulla ◽  
Moses Rodriguez
Keyword(s):  
Immune Response ◽  
Antiviral Effect ◽  
Viral Pathogenesis ◽  
Structure And Function ◽  
Rna Dependent Rna Polymerase ◽  
Transgenic Expression ◽  
Antiviral Effects ◽  
Encephalomyelitis Virus ◽  
Picornavirus Infection ◽  
And Function

The RNA-dependent RNA-polymerase,3Dpol, is an essential component in the picornavirus genome for the replication of single stranded RNA. However, transgenic expression of3Dpolin mice has antiviral effects. Here, we discuss the structure and function of3Dpolduring picornavirus replication, we review the evidence and consequence of a host immune response to epitopes in3Dpolafter picornavirus infection, highlight data showing the antiviral effects of transgenic3Dpolfrom Theiler's murine encephalomyelitis virus (TMEV), and discuss potential mechanisms by which3Dpolis causing this antiviral effect in mice.

scholarly journals Tissue-autonomous immune response regulates stress signalling during hypertrophy

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Robert Krautz ◽  
Dilan Khalili ◽  
Ulrich Theopold
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Salivary Glands ◽  
Feedback Loop ◽  
Mapk Pathway ◽  
Therapeutic Approaches ◽  
Jnk Pathway ◽  
Immune Effector ◽  
Tissue Integrity ◽  
Stress Signalling

Postmitotic tissues are incapable of replacing damaged cells through proliferation, but need to rely on buffering mechanisms to prevent tissue disintegration. By constitutively activating the Ras/MAPK-pathway via RasV12-overexpression in the postmitotic salivary glands of Drosophila larvae, we overrode the glands adaptability to growth signals and induced hypertrophy. The accompanied loss of tissue integrity, recognition by cellular immunity and cell death are all buffered by blocking stress signalling through a genuine tissue-autonomous immune response. This novel, spatio-temporally tightly regulated mechanism relies on the inhibition of a feedback-loop in the JNK-pathway by the immune effector and antimicrobial peptide Drosomycin. While this interaction might allow growing salivary glands to cope with temporary stress, continuous Drosomycin expression in RasV12-glands favors unrestricted hypertrophy. These findings indicate the necessity to refine therapeutic approaches that stimulate immune responses by acknowledging their possible, detrimental effects in damaged or stressed tissues.

scholarly journals Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response

2020 ◽  
Vol 11 (8) ◽  
pp. 584-599 ◽  
Author(s):  
Mi Li ◽  
Hong-Bing Shu
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Innate Immune Response ◽  
Substrate Binding ◽  
Binding Activity ◽  
Innate Immune ◽  
Negative Regulator ◽  
Autoimmune Response ◽  
Serine Residue ◽  
Dna Virus

Abstract The cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in host defense by sensing cytosolic DNA derived from microbial pathogens or mis-located cellular DNA. Upon DNA binding, cGAS utilizes GTP and ATP as substrates to synthesize cGAMP, leading to MITA-mediated innate immune response. In this study, we identified the phosphatase PPP6C as a negative regulator of cGAS-mediated innate immune response. PPP6C is constitutively associated with cGAS in un-stimulated cells. DNA virus infection causes rapid disassociation of PPP6C from cGAS, resulting in phosphorylation of human cGAS S435 or mouse cGAS S420 in its catalytic pocket. Mutation of this serine residue of cGAS impairs its ability to synthesize cGAMP upon DNA virus infection. In vitro experiments indicate that S420-phosphorylated mcGAS has higher affinity to GTP and enzymatic activity. PPP6C-deficiency promotes innate immune response to DNA virus in various cells. Our findings suggest that PPP6C-mediated dephosphorylation of a catalytic pocket serine residue of cGAS impairs its substrate binding activity and innate immune response, which provides a mechanism for keeping the DNA sensor cGAS inactive in the absence of infection to avoid autoimmune response.

scholarly journals JNK pathway restricts DENV2, ZIKV and CHIKV infection by activating complement and apoptosis in mosquito salivary glands

2020 ◽  
Vol 16 (8) ◽  
pp. e1008754 ◽  
Author(s):  
Avisha Chowdhury ◽  
Cassandra M. Modahl ◽  
Siok Thing Tan ◽  
Benjamin Wong Wei Xiang ◽  
Dorothée Missé ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Chikv Infection ◽  
Jnk Pathway

scholarly journals Peptides in the composition of Laennec that show antiviral effects in the therapy of atopic dermatitis and herpes infection

2018 ◽  
Vol 15 (1) ◽  
pp. 82-90 ◽  
Author(s):  
I Yu Torshin ◽  
O A Gromova ◽  
E A Dibrova ◽  
A N Gromov ◽  
O A Nazarenko
Keyword(s):  
Atopic Dermatitis ◽  
Virus Infection ◽  
De Novo ◽  
Antiviral Effect ◽  
Viral Envelope ◽  
Herpes Infection ◽  
Antiviral Effects ◽  
Viral Particles ◽  
Peptide Composition ◽  
Infection Inhibition

A characteristic feature of atopic dermatitis is herpes infection, which necessitates application of antiviral therapy. The analysis of the peptide composition of Laennec drug by de novo mass spectrometric sequencing allowed us to identify over 10 peptides, characterized by potential antiviral effect at all stages of the viral life cycle. Laennec’s peptides can inhibit viral activation (inhibition of protein HCFC1), fusion of the viral envelope with the plasma membrane in the step of the host cell virus infection (inhibition of protein CD4), virus replication (inhibition of protein CTBP1), maturing of virion (inhibition of proteins CRM1, VPS4B, TPR, proline isomerase), budding of the viral particles from the cell membrane (inhibition of the NEDD4 protein). Laennek therapy in complex treatment of patients with atopic dermatitis and herpes virus infection can be substantiated by its pharmacologic activities including antiviral effect.

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