scholarly journals Astrocyte Control of Zika Infection Is Independent of Interferon Type I and Type III Expression

Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 143
Author(s):  
Mithun Das ◽  
Monique L. Smith ◽  
Tomomi Furihata ◽  
Subir Sarker ◽  
Ross O’Shea ◽  
...  

Zika virus (ZIKV) is a pathogenic neurotropic virus that infects the central nervous system (CNS) and results in various neurological complications. Astrocytes are the dominant CNS cell producer of the antiviral cytokine IFN-β, however little is known about the factors involved in their ability to mediate viral infection control. Recent studies have displayed differential responses in astrocytes to ZIKV infection, and this study sought to elucidate astrocyte cell-specific responses to ZIKV using a variety of cell models infected with either the African (MR766) or Asian (PRVABC59) ZIKV strains. Expression levels of pro-inflammatory (TNF-α and IL-1β) and inflammatory (IL-8) cytokines following viral infection were low and mostly comparable within the ZIKV-resistant and ZIKV-susceptible astrocyte models, with better control of proinflammatory cytokines displayed in resistant astrocyte cells, synchronising with the viral infection level at specific timepoints. Astrocyte cell lines displaying ZIKV-resistance also demonstrated early upregulation of multiple antiviral genes compared with susceptible astrocytes. Interestingly, pre-stimulation of ZIKV-susceptible astrocytes with either poly(I:C) or poly(dA:dT) showed efficient protection against ZIKV compared with pre-stimulation with either recombinant IFN-β or IFN-λ, perhaps indicating that a more diverse antiviral gene expression is necessary for astrocyte control of ZIKV, and this is driven in part through interferon-independent mechanisms.

2019 ◽  
Author(s):  
Paulino Barragan-Iglesias ◽  
Úrzula Franco-Enzástiga ◽  
Vivekanand Jeevakumar ◽  
Andi Wangzhou ◽  
Vinicio Granados-Soto ◽  
...  

ABSTRACTOne of the first signs of viral infection is body-wide aches and pain. While this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization are well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I interferons stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENTIt is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. While specific mechanisms have been discovered for diverse bacteria and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type 1 interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling) that is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity


2018 ◽  
Vol 24 (4) ◽  
pp. 240-251 ◽  
Author(s):  
Naveen Surendran ◽  
Andrea Simmons ◽  
Michael E Pichichero

Each year millions of neonates die due to vaccine preventable infectious diseases. Our study seeks to develop novel neonatal vaccines and improve immunogenicity of early childhood vaccines by incorporating TLR agonist-adjuvant combinations that overcome the inherent neonatal Th2 bias and stimulate Th1 polarizing response from neonatal APCs. We systematically stimulated cord blood mononuclear cells with single and multiple combinations of TLR agonists and measured levels of IL-12p70, IFN-γ, IFN-α, IL-10, IL-13, TNF-α, IL-6 and IL-1β from cell culture supernatants. APC-specific surface expression levels of costimulatory markers CD40, CD83 and PD-L1 were assessed by flow cytometry. Whole blood assays were included to account for the effect of plasma inhibitory factors and APC intracellular TNF-α and IL-12p40 secretions were measured. We found robust Th1 polarizing IL-12p70, IFN-γ and IFN-α responses when cord blood APCs were stimulated with TLR agonist combinations that contained Poly I:C, Monophosphoryl Lipid A (MPLA) or R848. Addition of class A CpG oligonucleotide (ODN) to Th1 polarizing TLR agonist combinations significantly reduced cord blood IL-12p70 and IFN-γ levels and addition of a TLR2 agonist induced significantly high Th2 polarizing IL-13. Multi-TLR agonist combinations that included R848 induced lower inhibitory PD-L1 expression on cord blood classical dendritic cells than CpG ODN-containing combinations. Incorporation of combination adjuvants containing TLR3, TLR4 and TLR7/8 agonists to neonatal vaccines may be an effective strategy to overcome neonatal Th2 bias.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3441-3441
Author(s):  
Koichi Tabeta ◽  
Xin Du ◽  
Georgel Philippe ◽  
Kasper Hoebe ◽  
Navjiwan Mann ◽  
...  

Abstract The mammalian Toll-like receptors (TLRs) comprise a key interface between cells of the host and all classes of microbial pathogen. By sensing nucleic acids, the endosomal TLRs 3, 7, and 9 play a particularly important role in the detection of viral infection, and permit the host to mount an immediate and efficacious anti-viral response. In an effort to identify novel components of the TLR signaling apparatus, we have pursued a program of germline saturation mutagenesis with N-ethyl-N-nitrosourea (ENU) in mice. The germline mutants are produced on the C57BL/6 background, and peritoneal macrophages from individual animals are screened for their competence to respond to TLR-dependent microbial inducers. A strong phenodeviant called 3d was identified in the F3 generation as a non-responder to nucleoside-based molecules such as unmethylated CpG oligodeoxynucleotides, Resiquimod (a drug of the imidazoquinoline class) and Poly I:C. TNFa production induced by TLRs 3, 7, and 9 was completely prevented in 3d homozygotes. However, heterozygotes were unaffected, and the ability to produce TNFa in response to other bacterial compounds, sensed by TLRs 1, 2, 4, and 6, was intact. 3d homozygotes show extreme susceptibility to infection by mouse cytomegalovirus (MCMV) infection in vivo. After IP inoculation with MCMV (104 PFU), 3d mutants showed impaired production of type I and type II interferons, TNF, and IL-12 in serum (p<0.001). With larger inocula (5 x 105 PFU) a splenic viral titer approximately ten-thousand fold higher than that in controls (p<0.05) and rapid mortality (p<0.0001) were observed. This novel recessive phenotype is fully penetrant on the C57BL/6 and C3H/HeN x C57BL/6 hybrid backgrounds. The 3d mutation was mapped to mouse chromosome 19 using a panel of microsatellite markers and at present, has been confined to 0.4 a Mbp critical region on 3000 meioses. 3d appears to encode a protein essential for TLR-mediated detection of nucleic acids, which is indispensable for effective innate defense against viral infection.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5203-5203
Author(s):  
Zwi N. Berneman ◽  
Evelien L.J.M. Smits ◽  
Peter Ponsaerts ◽  
Nathalie Cools ◽  
Ann L.R. Van de Velde ◽  
...  

Abstract Leukemic cells exert immunosuppressive effects that interfere with dendritic cell function and hamper effective anti-leukemic immune responses. Recently, Toll-like receptor 3 (TLR3) was characterized in dendritic cells as an intracellular double-stranded (ds)RNA receptor which is triggered by viral infection or incubation with the synthetic dsRNA analogue polyriboinosinic polyribocytidylic acid [poly(I:C)], leading to maturation and activation of dendritic cells. Until now, little was known on the expression of TLR3 in leukemic cells and their responsiveness to dsRNA treatment. We assessed TLR3 expression in primary and transformed acute myeloid leukemia (AML) cells and hypothesized that the immunogenicity of AML cells could be improved by treatment with the synthetic TLR3 agonist poly(I:C), thereby mimicking viral infection of these leukemic cells. In view of this hypothesis, we electroporated or pulsed transformed and primary AML cells with poly(I:C) and analyzed the effect of poly(I:C) loading on TLR3 expression, costimulatory molecules, cytokine production and allogeneic T cell response. We also assessed the uptake of poly(I:C)-loaded leukemic cells by immature dendritic cells and the subsequent effect on dendritic cell activation and maturation status. We observed that primary and transformed AML cells respond to poly(I:C) electroporation by upregulation of TLR3 expression, apoptosis, elevated levels of costimulatory molecules CD80 and CD86 and by production of type I interferons (IFN). Furthermore, poly(I:C)-electroporated AML cells induced interferon-gamma production by allogeneic T cells. Upon phagocytosis of poly(I:C)-electroporated AML cells, dendritic cells showed an increased expression of maturation markers and marked production of proinflammatory cytokines. In contrast, this set of immune effects was absent or suboptimal when AML cells were passively pulsed with poly(I:C), indicating the superiority of transfection over pulsing with poly(I:C). These results demonstrate that poly(I:C) electroporation is a promising novel strategy to increase the immunogenicity of AML cells.


2020 ◽  
Vol 12 (4) ◽  
pp. 251-262
Author(s):  
Ru Zang ◽  
Huan Lian ◽  
Xuan Zhong ◽  
Qing Yang ◽  
Hong-Bing Shu

Abstract Toll-like receptor 3 (TLR3)-mediated signaling is important for host defense against RNA virus. Upon viral RNA stimulation, toll and interleukin-1 receptor domain-containing adaptor inducing IFN-β (TRIF) is recruited to TLR3 and then undergoes oligomerization, which is required for the recruitment of downstream molecules to transmit signals. Here, we identified zinc finger CCHC-type containing 3 (ZCCHC3) as a positive regulator of TLR3-mediated signaling. Overexpression of ZCCHC3 promoted transcription of downstream antiviral genes stimulated by the synthetic TLR3 ligand poly(I:C). ZCCHC3-deficiency markedly inhibited TLR3- but not TLR4-mediated induction of type I interferons (IFNs) and proinflammatory cytokines. Zcchc3−/− mice were more resistant to poly(I:C)- but not lipopolysaccharide-induced inflammatory death. Mechanistically, ZCCHC3 promoted recruitment of TRIF to TLR3 after poly(I:C) stimulation. Our findings reveal that ZCCHC3 plays an important role in TLR3-mediated innate immune response by promoting the recruitment of TRIF to TLR3 after ligand stimulation.


2017 ◽  
Vol 92 (2) ◽  
Author(s):  
Tianjun Xu ◽  
Qing Chu ◽  
Junxia Cui ◽  
Dekun Bi

ABSTRACT Effectively recognizing invading viruses and subsequently inducing innate antiviral immunity are essential for host antiviral defense. Although these processes are closely regulated by the host to maintain immune balance, viruses have evolved the ability to downregulate or upregulate these processes for their survival. MicroRNAs (miRNAs) are a family of small noncoding RNAs that play vital roles in modulating host immune response. Accumulating evidence demonstrates that host miRNAs as mediators are involved in regulating viral replication and host antiviral immunity in mammals. However, the underlying regulatory mechanisms in fish species are still poorly understood. Here, we found that rhabdovirus infection significantly upregulated host miR-3570 expression in miiuy croaker macrophages. Induced miR-3570 negatively modulated RNA virus-triggered type I interferon (IFN) and antiviral gene production, thus facilitating viral replication. Furthermore, miR-3570 was found to target and posttranscriptionally downregulate mitochondrial antiviral signaling protein (MAVS), which functions as a platform for innate antiviral signal transduction. Moreover, we demonstrated that miR-3570 suppressed the expression of MAVS, thereby inhibiting MAVS-mediated NF-κB and IRF3 signaling. The collective results demonstrated a novel regulation mechanism of MAVS-mediated immunity during RNA viral infection by miRNA. IMPORTANCE RNA viral infection could upregulate host miR-3570 expression in miiuy croaker macrophages. Induced miR-3570 negatively modulates RNA virus-triggered type I IFN and antiviral gene production, thus facilitating viral replication. Remarkably, miR-3570 could target and inhibit MAVS expression, which thus modulates MAVS-mediated NF-κB and IRF3 signaling. The collective results of this study suggest a novel regulation mechanism of MAVS-mediated immunity during RNA viral infection by miR-3570. Thus, a novel mechanism for virus evasion in fish is proposed.


2006 ◽  
Vol 80 (20) ◽  
pp. 9943-9950 ◽  
Author(s):  
Navkiran Gill ◽  
Philip M. Deacon ◽  
Brian Lichty ◽  
Karen L. Mossman ◽  
Ali A. Ashkar

ABSTRACT Toll-like receptors (TLRs) constitute a family of innate receptors that recognize and respond to a wide spectrum of microorganisms, including fungi, bacteria, viruses, and protozoa. Previous studies have demonstrated that ligands for TLR3 and TLR9 induce potent innate antiviral responses against herpes simplex virus type 2 (HSV-2). However, the factor(s) involved in this innate protection is not well-defined. Here we report that production of beta interferon (IFN-β) but not production of IFN-α, IFN-γ, or tumor necrosis factor alpha (TNF-α) strongly correlates with innate protection against HSV-2. Local delivery of poly(I:C) and CpG oligodeoxynucleotides induced significant production of IFN-β in the genital tract and provided complete protection against intravaginal (IVAG) HSV-2 challenge. There was no detectable IFN-β in mice treated with ligands for TLR4 or TLR2, and these mice were not protected against subsequent IVAG HSV-2 challenge. There was no correlation between levels of TNF-α or IFN-γ in the genital tract and protection against IVAG HSV-2 challenge following TLR ligand delivery. Both TNF-α−/− and IFN-γ−/− mice were protected against IVAG HSV-2 challenge following local delivery of poly(I:C). To confirm that type I interferon, particularly IFN-β, mediates innate protection, mice unresponsive to type I interferons (IFN-α/βR−/− mice) and mice lacking IFN regulatory factor-3 (IRF-3−/− mice) were treated with poly(I:C) and then challenged with IVAG HSV-2. There was no protection against HSV-2 infection following poly(I:C) treatment of IFN-α/βR−/− or IRF-3−/− mice. Local delivery of murine recombinant IFN-β protected C57BL/6 and IRF-3−/− mice against IVAG HSV-2 challenge. Results from these in vivo studies clearly suggest a strong correlation between IFN-β production and innate antiviral immunity against HSV-2.


2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Ye Hu ◽  
Xin Wang ◽  
Jiaying Song ◽  
Jiacheng Wu ◽  
Jia Xu ◽  
...  

AbstractTranscription factor IRF3 is critical for the induction of antiviral type I interferon (IFN-I). The epigenetic regulation of IFN-I production in antiviral innate immunity needs to be further identified. Here, we reported that epigenetic remodeler ARID1A, a critical component of the mSWI/SNF complex, could bind IRF3 and then was recruited to the Ifn-I promoter by IRF3, thus selectively promoting IFN-I but not TNF-α, IL-6 production in macrophages upon viral infection. Myeloid cell-specific deficiency of Arid1a rendered mice more susceptible to viral infection, accompanied with less IFN-I production. Mechanistically, ARID1A facilitates chromatin accessibility of IRF3 at the Ifn-I promoters by interacting with histone methyltransferase NSD2, which methylates H3K4 and H3K36 of the promoter regions. Our findings demonstrated the new roles of ARID1A and NSD2 in innate immunity, providing insight into the crosstalks of chromatin remodeling, histone modification, and transcription factors in the epigenetic regulation of antiviral innate immunity.


Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 465
Author(s):  
Michèle Bengue ◽  
Pauline Ferraris ◽  
Jonathan Barthelemy ◽  
Cheikh Tidiane Diagne ◽  
Rodolphe Hamel ◽  
...  

Mayaro virus (MAYV) and chikungunya virus (CHIKV) are known for their arthrotropism, but accumulating evidence shows that CHIKV infections are occasionally associated with serious neurological complications. However, little is known about the capacity of MAYV to invade the central nervous system (CNS). We show that human neural progenitors (hNPCs), pericytes and astrocytes are susceptible to MAYV infection, resulting in the production of infectious viral particles. In primary astrocytes, MAYV, and to a lesser extent CHIKV, elicited a strong antiviral response, as demonstrated by an increased expression of several interferon-stimulated genes, including ISG15, MX1 and OAS2. Infection with either virus led to an enhanced expression of inflammatory chemokines, such as CCL5, CXCL10 and CXCL11, whereas MAYV induced higher levels of IL-6, IL-12 and IL-15 in these cells. Moreover, MAYV was more susceptible than CHIKV to the antiviral effects of both type I and type II interferons. Taken together, this study shows that although MAYV and CHIKV are phylogenetically related, they induce different types of antiviral responses in astrocytes. This work is the first to evaluate the potential neurotropism of MAYV and shows that brain cells and particularly astrocytes and hNPCs are permissive to MAYV, which, consequently, could lead to MAYV-induced neuropathology.


2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jhao-Yin Lin ◽  
Rei-Lin Kuo ◽  
Hsing-I Huang

Abstract Background Neural stem cells (NSCs) residing in the central nervous system play an important role in neurogenesis. Several viruses can infect these neural progenitors and cause severe neurological diseases. The innate immune responses against the neurotropic viruses in these tissue-specific stem cells remain unclear. Methods Human NSCs were transfected with viral RNA mimics or infected with neurotropic virus for detecting the expression of antiviral interferons (IFNs) and downstream IFN-stimulated antiviral genes. Results NSCs are able to produce interferon-β (IFN-β) (type I) and λ1 (type III) after transfection with poly(I:C) and that downstream IFN-stimulated antiviral genes, such as ISG56 and MxA, and the viral RNA sensors RIG-I, MDA5, and TLR3, can be expressed in NSCs under poly(I:C) or IFN-β stimulation. In addition, our results show that the pattern recognition receptors RIG-I and MDA5, as well as the endosomal pathogen recognition receptor TLR3, but not TLR7 and TLR8, are involved in the activation of IFN-β transcription in NSCs. Furthermore, NSCs infected with the neurotropic viruses, Zika and Japanese encephalitis viruses, are able to induce RIG-I-mediated IFN-β expression. Conclusion Human NSCs have the ability to activate IFN signals against neurotropic viral pathogens.


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