scholarly journals Zika Virus Non-Structural Protein NS5 Inhibits the RIG-I Pathway and Interferon Lambda 1 Promoter Activation by Targeting IKK Epsilon

Viruses ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1024 ◽  
Author(s):  
Lundberg ◽  
Melén ◽  
Westenius ◽  
Jiang ◽  
Österlund ◽  
...  
Keyword(s):  
Immune Responses ◽  
Zika Virus ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Structural Protein ◽  
Regulatory Factor ◽  
Promoter Activation ◽  
Antiviral Responses ◽  
Pathogenic Viruses ◽  
Epithelial Barriers

The Zika virus (ZIKV) is a member of the Flaviviridae family and an important human pathogen. Most pathogenic viruses encode proteins that interfere with the activation of host innate immune responses. Like other flaviviruses, ZIKV interferes with the expression of interferon (IFN) genes and inhibits IFN-induced antiviral responses. ZIKV infects through epithelial barriers where IFN-λ1 is an important antiviral molecule. In this study, we analyzed the effects of ZIKV proteins on the activation of IFN-λ1 promoter. All ZIKV proteins were cloned and transiently expressed. ZIKV NS5, but no other ZIKV protein, was able to interfere with the RIG-I signaling pathway. This inhibition took place upstream of interferon regulatory factor 3 (IRF3) resulting in reduced phosphorylation of IRF3 and reduced activation of IFN-λ1 promoter. Furthermore, we showed that ZIKV NS5 interacts with the protein kinase IKKε, which is likely critical to the observed inhibition of phosphorylation of IRF3.

scholarly journals Pregnancy alters innate immune responses to Zika virus infection in the genital tract

2019 ◽  
Author(s):  
Kelsey E. Lesteberg ◽  
Dana S. Fader ◽  
J. David Beckham
Keyword(s):  
Virus Infection ◽  
Immune Responses ◽  
Zika Virus ◽  
Immune Cell ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Innate Immune Responses ◽  
Zikv Infection ◽  
Zika Virus Infection ◽  
Pregnant Mice

AbstractRecent outbreaks of Zika virus (ZIKV) have been associated with birth defects, including microcephaly and neurological impairment. However, the mechanisms which confer increased susceptibility to ZIKV during pregnancy remain unclear. We hypothesized that poor outcomes from ZIKV infection during pregnancy are due in part to pregnancy-induced alteration of innate immune cell frequencies and cytokine expression. To examine the impact of pregnancy on innate immune responses, we inoculated pregnant and non-pregnant female C57BL/6 mice with 5×105 FFU of ZIKV intravaginally. Innate immune cell frequencies and cytokine expression were measured by flow cytometry at day 3 post infection. Compared to non-pregnant mice, pregnant mice exhibited higher frequencies of uterine macrophages (CD68+) and tolerogenic dendritic cells (CD11c+ CD103+ and CD11c+ CD11b+). Additionally, ZIKV-infected pregnant mice had lower frequencies of CD45+ IL-12+ and CD11b+ IL-12+ cells in the uterus and spleen. These data show that pregnancy results in an altered innate immune response to ZIKV infection in the genital tract of mice and that pregnancy-associated immune modulation may play an important role in the severity of acute ZIKV infection.ImportancePregnant females longer duration that viremia following infection with Zika virus but the mechanism of this is not established. Innate immune cellular responses are important for controlling virus infection and are important for development and maintenance of pregnancy. Thus, the acute immune response to Zika virus during pregnancy may be altered so that the pregnancy can be maintained. To examine this interaction, we utilized a mouse model of Zika virus infection during pregnancy using intravaginal inoculation. We found that following Zika virus infection, pregnant mice exhibited increased expression of tolerant or non-inflammatory dendritic cells. Additionally, we found that pregnant mice have significantly depressed ability to secrete the cytokine IL-12 from innate immune cells in the uterus and the spleen while maintaining MHCII expression. These findings show that pregnancy-induced changes in the innate immune cells are biased towards tolerance and can result in decreased antigen-dependent stimulation of immune responses.

scholarly journals Unraveling the Underlying Interaction Mechanism Between Dabie bandavirus and Innate Immune Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Chuan-min Zhou ◽  
Xue-jie Yu
Keyword(s):  
Interaction Mechanism ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Responses ◽  
Structural Protein ◽  
Antiviral Responses ◽  
Host Virus Interactions ◽  
Virus Interactions ◽  
Severe Fever

The genus Bandavirus consists of seven tick-borne bunyaviruses, among which four are known to infect humans. Dabie bandavirus, severe fever with thrombocytopenia syndrome virus (SFTSV), poses serious threats to public health worldwide. SFTSV is a tick-borne virus mainly reported in China, South Korea, and Japan with a mortality rate of up to 30%. To date, most immunology-related studies focused on the antagonistic role of SFTSV non-structural protein (NSs) in sequestering RIG-I-like-receptors (RLRs)-mediated type I interferon (IFN) induction and type I IFN mediated signaling pathway. It is still elusive whether the interaction of SFTSV and other conserved innate immune responses exists. As of now, no specific vaccines or therapeutics are approved for SFTSV prevention or treatments respectively, in part due to a lack of comprehensive understanding of the molecular interactions occurring between SFTSV and hosts. Hence, it is necessary to fully understand the host-virus interactions including antiviral responses and viral evasion mechanisms. In this review, we highlight the recent progress in understanding the pathogenesis of SFTS and speculate underlying novel mechanisms in response to SFTSV infection.

scholarly journals Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Bin Zhou ◽  
Fei Qi ◽  
Fangyi Wu ◽  
Hongbo Nie ◽  
Yifan Song ◽  
...  
Keyword(s):  
Immune Responses ◽  
Transcriptome Analysis ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Innate Immune ◽  
Endogenous Retroviruses ◽  
Innate Immune Responses ◽  
Antiviral Responses ◽  
Positive Regulator ◽  
Deficient Mice

ABSTRACT Endogenous retroviruses (ERVs) are transposable elements that cause host genome instability and usually play deleterious roles in disease such as tumorigenesis. Recent advances also suggest that this “enemy within” may encode a viral mimic to induce antiviral immune responses through viral sensors. Here, through whole-genome transcriptome analysis with RNA sequencing (RNA-Seq), we discovered that a full-length ERV-derived long noncoding RNA (lncRNA), designated lnc-EPAV (ERV-derived lncRNA positively regulates antiviral responses), was a positive regulator of NF-κB signaling. lnc-EPAV expression was rapidly upregulated by viral RNA mimics or RNA viruses to facilitate the expression of RELA, an NF-κB subunit that plays a crucial role in antiviral responses. Transcriptome analysis of lnc-EPAV-silenced macrophages showed that lnc-EPAV was critical for RELA target gene expression and innate immune responses. Consistently, lnc-EPAV-deficient mice exhibited reduced expression of type I interferons (IFNs) and, consequently, increased viral loads and mortality following lethal RNA virus infection. Mechanistically, lnc-EPAV promoted expression of RELA by competitively binding to and displacing SFPQ, a transcriptional repressor of Rela. Altogether, our work demonstrates an alternative mechanism by which ERVs regulate antiviral immune responses. IMPORTANCE Endogenous retroviruses are transposable genetic elements comprising 8% to 10% of the human and mouse genomes. Although most ERVs have been inactivated due to deleterious mutations, some are still transcribed. However, the biological functions of transcribed ERVs are largely unknown. Here, we identified a full-length ERV-derived lncRNA, designated lnc-EPAV, as a positive regulator of host innate immune responses. We found that silencing lnc-EPAV impaired virus-induced cytokine production, resulting in increased viral replication in cells. The lnc-EPAV-deficient mice exhibited enhanced susceptibility to viral challenge. We also found that lnc-EPAV regulated expression of RELA, an NF-κB subunit that plays a critical role in antiviral responses. ERV-derived lncRNA coordinated with a transcription repressor, SFPQ, to control Rela transcription. Our report provides new insights into the previously unrecognized immune gene regulatory mechanism of ERV-derived lncRNAs.

scholarly journals The Viral Macrodomain Counters Host Antiviral ADP-Ribosylation

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 384 ◽  
Author(s):  
Yousef M. O. Alhammad ◽  
Anthony R. Fehr
Keyword(s):  
Immune Responses ◽  
Protein Interactions ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Protein Protein Interactions ◽  
Granule Formation ◽  
Inflammatory Cytokine Production ◽  
Adp Ribosylation ◽  
Antiviral Responses ◽  
Host Defense Response

Macrodomains, enzymes that remove ADP-ribose from proteins, are encoded by several families of RNA viruses and have recently been shown to counter innate immune responses to virus infection. ADP-ribose is covalently attached to target proteins by poly-ADP-ribose polymerases (PARPs), using nicotinamide adenine dinucleotide (NAD+) as a substrate. This modification can have a wide variety of effects on proteins including alteration of enzyme activity, protein–protein interactions, and protein stability. Several PARPs are induced by interferon (IFN) and are known to have antiviral properties, implicating ADP-ribosylation in the host defense response and suggesting that viral macrodomains may counter this response. Recent studies have demonstrated that viral macrodomains do counter the innate immune response by interfering with PARP-mediated antiviral defenses, stress granule formation, and pro-inflammatory cytokine production. Here, we will describe the known functions of the viral macrodomains and review recent literature demonstrating their roles in countering PARP-mediated antiviral responses.

scholarly journals Reprogramming Interferon Regulatory Factor Signaling in Cardiometabolic Diseases

Physiology ◽  
2017 ◽  
Vol 32 (3) ◽  
pp. 210-223 ◽  
Author(s):  
Yaxing Zhang ◽  
Hongliang Li
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Immune Cells ◽  
Interferon Regulatory Factor ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Regulatory Factor ◽  
Cardiometabolic Diseases ◽  
Evolutionarily Conserved

Interferon regulatory factors (IRFs) are evolutionarily conserved proteins expressed not only in immune cells but also in other tissues and organs outside the immune system. In this review, we discuss mechanisms responsible for IRF-mediated innate immune responses and the function and mechanism of IRFs in cardiometabolic diseases. We focus on the role of IRFs in innate immunity and cardiometabolic homeostasis, and highlight reprogrammed IRF signaling.

scholarly journals Zika virus alters centrosome organization to suppress the innate immune response

2020 ◽  
Author(s):  
Andrew Kodani ◽  
Kristeene A. Knopp ◽  
Elizabeth Di Lullo ◽  
Hanna Retallack ◽  
Arnold R. Kriegstein ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Zika Virus ◽  
Nonstructural Protein ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Zikv Infection ◽  
Centrosomal Proteins ◽  
Nonstructural Protein Ns3

AbstractZika virus (ZIKV) is a flavivirus transmitted via mosquitoes and sex to cause congenital neurodevelopmental defects, including microcephaly. Inherited forms of microcephaly (MCPH) are associated with disrupted centrosome organization. Similarly, we found that ZIKV infection disrupted centrosome organization. ZIKV infection disrupted the organization of centrosomal proteins including CEP63, a MCPH-associated protein. The ZIKV nonstructural protein NS3 bound CEP63, and expression of NS3 was sufficient to alter centrosome architecture and CEP63 localization. Loss of CEP63 suppressed ZIKV-induced centrosome disorganization, indicating that ZIKV requires CEP63 to disrupt centrosome organization. ZIKV infection or loss of CEP63 decreased the centrosomal localization and stability of TANK-binding kinase 1 (TBK1), a regulator of the innate immune response. ZIKV infection or loss of CEP63 also increased the centrosomal accumulation of the CEP63 interactors, Mindbomb1 (MIB1) and DTX4, ubiquitin ligases that respectively activate and degrade TBK1. Therefore, we propose that ZIKV NS3 binds CEP63 to increase centrosomal DTX4 localization and destabilization of TBK1, thereby tempering the innate immune response. In addition to identifying a mechanism by which CEP63 controls the innate immune responses in ZIKV infection, we propose that the altered centrosomal organization caused by altered CEP63 function may contribute to ZIKV-associated microcephaly.

scholarly journals Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yajuan Rui ◽  
Jiaming Su ◽  
Si Shen ◽  
Ying Hu ◽  
Dingbo Huang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Nuclear Factor Κb ◽  
Innate Immune ◽  
Nuclear Accumulation ◽  
Innate Immune Responses ◽  
Structural Protein ◽  
Viral Protease ◽  
Downstream Signaling ◽  
Efficient Replication

AbstractThe emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways. In particular, the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways. Viral accessory protein ORF3a had the unique ability to inhibit STING, but not the RLR response. On the other hand, structural protein N was a unique RLR inhibitor. ORF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-κB signaling. 3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling. Diverse vertebrate STINGs, including those from humans, mice, and chickens, could be inhibited by ORF3a and 3CL of SARS-CoV-2. The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo. Since evasion of host innate immune responses is essential for the survival of all viruses, our study provides insights into the design of therapeutic agents against SARS-CoV-2.

scholarly journals Inhibition of innate immune response ameliorates Zika virus-induced neurogenesis deficit in human neural stem cells

2021 ◽  
Vol 15 (3) ◽  
pp. e0009183
Author(s):  
Pei Xu ◽  
Junling Gao ◽  
Chao Shan ◽  
Tiffany J. Dunn ◽  
Xuping Xie ◽  
...  
Keyword(s):  
Immune Responses ◽  
Asian American ◽  
Zika Virus ◽  
Innate Immune ◽  
Dependent Manner ◽  
Innate Immune Responses ◽  
Cell Stage ◽  
Human Neural Stem Cells ◽  
Promising Therapeutic Approach ◽  
Neural Stem Progenitor Cells

Global Zika virus (ZIKV) outbreaks and their strong link to microcephaly have raised major public health concerns. ZIKV has been reported to affect the innate immune responses in neural stem/progenitor cells (NS/PCs). However, it is unclear how these immune factors affect neurogenesis. In this study, we used Asian-American lineage ZIKV strain PRVABC59 to infect primary human NS/PCs originally derived from fetal brains. We found that ZIKV overactivated key molecules in the innate immune pathways to impair neurogenesis in a cell stage-dependent manner. Inhibiting the overactivated innate immune responses ameliorated ZIKV-induced neurogenesis reduction. This study thus suggests that orchestrating the host innate immune responses in NS/PCs after ZIKV infection could be promising therapeutic approach to attenuate ZIKV-associated neuropathology.

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