scholarly journals Grass Carp Reovirus VP35 Degrades MAVS Through the Autophagy Pathway to Inhibit Fish Interferon Production

2021 ◽  
Vol 12 ◽  
Author(s):  
Long-Feng Lu ◽  
Can Zhang ◽  
Zhuo-Cong Li ◽  
Xiao-Yu Zhou ◽  
Jing-Yu Jiang ◽  
...  
Keyword(s):  
Grass Carp ◽  
Host Cells ◽  
Poly I:C ◽  
Dependent Manner ◽  
Grass Carp Reovirus ◽  
Polycytidylic Acid ◽  
Autophagy Pathway ◽  
Mitochondrial Antiviral Signaling ◽  
Dose Dependent ◽  
35 Kda Protein

Fish interferon (IFN) is a crucial cytokine for a host to resist external pathogens, conferring cells with antiviral capacity. Meanwhile, grass carp reovirus (GCRV) is a strong pathogen that causes high mortality in grass carp. Therefore, it is necessary to study the strategy used by GCRV to evade the cellular IFN response. In this study, we found that GCRV 35-kDa protein (VP35) inhibited the host IFN production by degrading mitochondrial antiviral signaling (MAVS) protein through the autophagy pathway. First, the overexpression of VP35 inhibited the IFN activation induced by polyinosinic-polycytidylic acid (poly I:C) and MAVS, and the expression of downstream IFN-stimulated genes (ISGs) was also decreased by using VP35 under the stimulation. Second, VP35 interacted with MAVS; the experiments of truncated mutants of MAVS demonstrated that the caspase recruitment domain (CARD) and proline-rich (PRO) domains of MAVS were not necessary for this binding. Then, MAVS was degraded by using VP35 in a dose-dependent manner, and 3-MA (the autophagy pathway inhibitor) significantly blocked the degradation, meaning that MAVS was degraded by using VP35 in the autophagy pathway. The result of MAVS degradation suggested that the antiviral capacity of MAVS was remarkably depressed when interrupted by VP35. Finally, in the host cells, VP35 reduced ifn transcription and made the cells vulnerable to virus infection. In conclusion, our results reveal that GCRV VP35 impairs the host IFN response by degrading MAVS through the autophagy pathway, supplying evidence of a fish virus immune evasion strategy.

scholarly journals Grass Carp Reovirus (GCRV) Giving Its All to Suppress IFN Production by Countering MAVS-TBK1 Activation

2019 ◽  
Author(s):  
Long-Feng Lu ◽  
Zhuo-Cong Li ◽  
Can Zhang ◽  
Xiao-Yu Zhou ◽  
Yu Zhou ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Grass Carp ◽  
Biological Effects ◽  
Viral Proteins ◽  
Host Cells ◽  
Signaling Transduction ◽  
Grass Carp Reovirus ◽  
Fish Virus ◽  
Fish Viruses ◽  
Mitochondrial Antiviral Signaling

AbstractAs a crucial signaling pathway for interferon (IFN) production, the RIG-I-like receptor (RLR) axis is usually the host target of viruses to enhance viral infection. To date, though immune evasion methods to contrapose IFN production have been characterized for a series of terrestrial viruses, the strategies employed by fish viruses remain unclear. Here, we report that all grass carp reovirus (GCRV) proteins encoded by segments S1 to S11 interact with fish RLR factors, specifically for mitochondrial antiviral signaling protein-TANK-binding kinase 1 (MAVS-TBK1) signaling transduction, leading to decreased IFN expression. First, the GCRV viral proteins blunted the MAVS-induced expression of IFN but had little effect on TBK1-induced IFN expression. Subsequently, interestingly, co-immunoprecipitation experiments demonstrated that all GCRV viral proteins interacted with several RLR cascades, especially with TBK1. To further illustrate the mechanisms of these interactions between GCRV viral proteins and host RLRs, two of the viral proteins, NS79 (S4) and VP3 (S3), were selected as representative proteins for the study. The obtained data demonstrated that NS79 did not affect the stability of the host RLR protein, but was phosphorylated by gcTBK1, leading to the reduction of host substrate gcIRF3/7 phosphorylation. On the other hand, VP3 degraded gcMAVS and the degradation was significantly reversed by 3-MA. The biological effects of both NS79 and VP3 were consistently found to be related to the suppression of IFN expression and the promotion of viral evasion. Our findings shed light on the special evasion mechanism utilized by fish virus through IFN regulation, which might differ between fish and mammals.Author summaryThe RLR signaling pathway is crucial for IFN induction when host cells are infected with virus and RLR factors are targeted by virus. To date, the evasion mechanisms of fish viruses remain mysterious. In this study, we reveal that all 11 GCRV proteins interact with fish RLR factors and suppress the activation of MAVS-TBK1 signaling transduction, leading to the reduction of IFN expression. Two viral proteins were employed as examples to investigate the different evasion mechanisms of GCRV. These findings reveal the novel countermeasures used by fish virus to avoid the host IFN response.

Membrane Nanoparticles Derived from ACE2-rich Cells Block SARS-CoV-2 Infection

2020 ◽  
Author(s):  
Cheng Wang ◽  
Shaobo Wang ◽  
Yin Chen ◽  
Jianqi Zhao ◽  
Songling Han ◽  
...  
Keyword(s):  
Viral Entry ◽  
Inhibitory Concentration ◽  
Cell Metabolism ◽  
Host Cells ◽  
Dependent Manner ◽  
Human Embryonic Kidney ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Dose Dependent

ABSTRACTThe ongoing COVID-19 epidemic worldwide necessitates the development of novel effective agents against SARS-CoV-2. ACE2 is the main receptor of SARS-CoV-2 S1 protein and mediates viral entry into host cells. Herein, the membrane nanoparticles prepared from ACE2-rich cells are discovered with potent capacity to block SARS-CoV-2 infection. The membrane of human embryonic kidney-239T cell highly expressing ACE2 is screened to prepare nanoparticles. The nanomaterial termed HEK-293T-hACE2 NPs contains 265.1 ng mg−1 of ACE2 on the surface and acts as a bait to trap SARS-CoV-2 S1 in a dose-dependent manner, resulting in reduced recruitment of the viral ligand to host cells. Interestingly, SARS-CoV-2 S1 can translocate to the cytoplasm and affect the cell metabolism, which is also inhibited by HEK-293T-hACE2 NPs. Further studies reveal that HEK-293T-hACE2 NPs can efficiently suppress SARS-CoV-2 S pseudovirions entry into human proximal tubular cells and block viral infection with a low half maximal inhibitory concentration. Additionally, this biocompatible membrane nanomaterial is sufficient to block the adherence of SARS-CoV-2 D614G-S1 mutant to sensitive cells. Our study demonstrates a easy-to-acheive memrbane nano-antagonist for curbing SARS-CoV-2, which enriches the existing antiviral arsenal and provides new possibilities to treat COVID-19. Graphical Table of Contents

scholarly journals Quercetin Suppresses Apoptosis and Attenuates Intervertebral Disc Degeneration via the SIRT1-Autophagy Pathway

2020 ◽  
Vol 8 ◽  
Author(s):  
Dong Wang ◽  
Xin He ◽  
Di Wang ◽  
Pandi Peng ◽  
Xiaolong Xu ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Protective Effect ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Specific Effect ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Autophagy Pathway ◽  
Dose Dependent

Intervertebral disc degeneration (IDD) has been generally accepted as the major cause of low back pain (LBP), which causes an enormous socioeconomic burden. Previous studies demonstrated that the apoptosis of nucleus pulposus (NP) cells and the dyshomeostasis of extracellular matrix (ECM) contributed to the pathogenesis of IDD, and effective therapies were still lacking. Quercetin, a natural flavonoid possessing a specific effect of autophagy stimulation and SIRT1 activation, showed some protective effect on a series of degenerative diseases. Based on previous studies, we hypothesized that quercetin might have therapeutic effects on IDD by inhibiting the apoptosis of NP cells and dyshomeostasis of ECM via the SIRT1-autophagy pathway. In this study, we revealed that quercetin treatment inhibited the apoptosis of NP cells and ECM degeneration induced by oxidative stress. We also found that quercetin promoted the expression of SIRT1 and autophagy in NP cells in a dose-dependent manner. Autophagy inhibitor 3-methyladenine (3-MA) reversed the protective effect of quercetin on apoptosis and ECM degeneration. Moreover, SIRT1 enzymatic activity inhibitor EX-527, suppressed quercetin-induced autophagy and the protective effect on NP cells, indicating that quercetin protected NP cells against apoptosis and prevented ECM degeneration via SIRT1-autophagy pathway. In vivo, quercetin was also demonstrated to alleviate the progression of IDD in rats. Taken together, our results suggest that quercetin prevents IDD by promoting SIRT1-dependent autophagy, indicating one novel and effective therapeutic method for IDD.

scholarly journals Adenoviruses Use Lactoferrin as a Bridge for CAR-Independent Binding to and Infection of Epithelial Cells

2006 ◽  
Vol 81 (2) ◽  
pp. 954-963 ◽  
Author(s):  
Cecilia Johansson ◽  
Mari Jonsson ◽  
Marko Marttila ◽  
David Persson ◽  
Xiao-Long Fan ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Innate Immune System ◽  
Innate Immune ◽  
Host Cells ◽  
Tear Fluid ◽  
Adenovirus Infection ◽  
Dependent Manner ◽  
Polarized Cells ◽  
Adenovirus Receptor ◽  
Dose Dependent

ABSTRACT Most adenoviruses bind to the coxsackie- and adenovirus receptor (CAR). Surprisingly, CAR is not expressed apically on polarized cells and is thus not easily available to viruses. Consequently, alternative mechanisms for entry of coxsackievirus and adenovirus into cells have been suggested. We have found that tear fluid promotes adenovirus infection, and we have identified human lactoferrin (HLf) as the tear fluid component responsible for this effect. HLf alone was found to promote binding of adenovirus to epithelial cells in a dose-dependent manner and also infection of epithelial cells by adenovirus. HLf was also found to promote gene delivery from an adenovirus-based vector. The mechanism takes place at the binding stage and functions independently of CAR. Thus, we have identified a novel binding mechanism whereby adenovirus hijacks HLf, a component of the innate immune system, and uses it as a bridge for attachment to host cells.

scholarly journals Circulating ACE2-expressing Exosomes Block SARS-CoV-2 Infection as an Innate Antiviral Mechanism

2020 ◽  
Author(s):  
Lamiaa El-Shennawy ◽  
Andrew D. Hoffmann ◽  
Nurmaa K. Dashzeveg ◽  
Paul J. Mehl ◽  
Zihao Yu ◽  
...  
Keyword(s):  
Viral Entry ◽  
Therapeutic Potential ◽  
Adaptive Immune Response ◽  
Host Cells ◽  
Dependent Manner ◽  
Angiotensin Converting Enzyme 2 ◽  
Healthy Donors ◽  
Dose Dependent ◽  
Entry Receptor ◽  
Antiviral Mechanism

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19) with innate and adaptive immune response triggered in such patients by viral antigens. Both convalescent plasma and engineered high affinity human monoclonal antibodies have shown therapeutic potential to treat COVID-19. Whether additional antiviral soluble factors exist in peripheral blood remain understudied. Herein, we detected circulating exosomes that express the SARS-CoV-2 viral entry receptor angiotensin-converting enzyme 2 (ACE2) in plasma of both healthy donors and convalescent COVID-19 patients. We demonstrated that exosomal ACE2 competes with cellular ACE2 for neutralization of SARS-CoV-2 infection. ACE2-expressing (ACE2+) exosomes blocked the binding of the viral spike (S) protein RBD to ACE2+ cells in a dose dependent manner, which was 400- to 700-fold more potent than that of vesicle-free recombinant human ACE2 extracellular domain protein (rhACE2). As a consequence, exosomal ACE2 prevented SARS-CoV-2 pseudotype virus tethering and infection of human host cells at a 50-150 fold higher efficacy than rhACE2. A similar antiviral activity of exosomal ACE2 was further demonstrated to block wild-type live SARS-CoV-2 infection. Of note, depletion of ACE2+ exosomes from COVID-19 patient plasma impaired the ability to block SARS-CoV-2 RBD binding to host cells. Our data demonstrate that ACE2+ exosomes can serve as a decoy therapeutic and a possible innate antiviral mechanism to block SARS-CoV-2 infection.

scholarly journals Hidden Talents: Poly (I:C)-induced maternal immune activation improves mouse visual discrimination performance and reversal learning in a sex-dependent manner.

2021 ◽  
Author(s):  
Xin Zhao ◽  
Hieu Tran ◽  
Holly DeRose ◽  
Ryland C Roderick ◽  
Amanda C Kentner
Keyword(s):  
Reversal Learning ◽  
Immune Activation ◽  
Visual Discrimination ◽  
Early Life ◽  
Discrimination Performance ◽  
Poly I:C ◽  
Dependent Manner ◽  
Negative Consequences ◽  
Maternal Immune Activation ◽  
Polycytidylic Acid

While there is a strong focus on the negative consequences of maternal immune activation (MIA) on the developing brain, very little attention is directed towards potential advantages of early life challenges. In this study we utilized a polyinosine-polycytidylic acid (poly(I:C)) MIA model to test visual discrimination (VD) and reversal learning (RL) in mice using touchscreen technology. Significant sex differences emerged in that MIA improved the latency for males to make a correct choice in the VD task while females reached criterion sooner, made fewer errors and utilized fewer correction trials in RL compared to saline-treated controls. These surprising improvements were accompanied by the sex-specific upregulation of several neural markers critical to cognitive functioning (e.g., Gabrg2, Grin1, Grin2b, Htr2a, Chrm1, Prkca, and Camk2a mRNA in prefrontal cortex (PFC)), indicative of compensatory plasticity in response to the MIA challenge. In contrast, when exposed to a "two-hit" stress model (MIA combined with loss of the social component of environmental enrichment (EE)), mice showed no evidence of anhedonia but required an increased number of PD and RL correction trials. These animals also had significant reductions of CamK2a mRNA in the PFC. Appropriate functioning of synaptic plasticity, via mediators such as this protein kinase and others, are critical for behavioral flexibility. Although EE has been implicated in delaying the appearance of symptoms associated with certain brain disorders, these findings are in line with evidence that it also makes individuals more vulnerable to its loss. Overall, with the right "dose", early life stress exposure can confer at least some functional advantages, which are lost when the number or magnitude of these exposures become too great.

Infection of grass carp reovirus induced the expressional suppression of pro-viral Fibulin-4 in host cells

2018 ◽  
Vol 77 ◽  
pp. 294-297 ◽  
Author(s):  
Jialu Sheng ◽  
Fei Yu ◽  
Dubo Chen ◽  
Hao Wang ◽  
Liqun Lu
Keyword(s):  
Grass Carp ◽  
Host Cells ◽  
Grass Carp Reovirus

scholarly journals Grass Carp Reovirus VP41 Targets Fish MITA To Abrogate the Interferon Response

2017 ◽  
Vol 91 (14) ◽  
Author(s):  
Long-Feng Lu ◽  
Shun Li ◽  
Zhao-Xi Wang ◽  
Si-Qi Du ◽  
Dan-Dan Chen ◽  
...  
Keyword(s):  
Grass Carp ◽  
Critical Role ◽  
Adaptor Protein ◽  
Interferon Response ◽  
Hemorrhagic Disease ◽  
Grass Carp Reovirus ◽  
Antiviral Responses ◽  
Mitochondrial Antiviral Signaling ◽  
First Time ◽  
Irf3 Activation

ABSTRACT Although fish possess an efficient interferon (IFN) system to defend against aquatic virus infection, grass carp reovirus (GCRV) still causes hemorrhagic disease in grass carp. To date, GCRV's strategy for evading the fish IFN response is still unknown. Here, we report that GCRV VP41 inhibits fish IFN production by suppressing the phosphorylation of mediator of IFN regulatory factor 3 (IRF3) activation (MITA). First, the activation of the IFN promoter (IFNpro) stimulated by mitochondrial antiviral signaling protein (MAVS) and MITA was decreased by the overexpression of VP41, whereas such activation induced by TANK-binding kinase 1 (TBK1) was not affected. Second, VP41 was colocalized in the cellular endoplasmic reticulum (ER) and associated with MITA. Furthermore, as a phosphorylation substrate of TBK1, VP41 significantly decreased the phosphorylation of MITA. Truncation assays indicated that the transmembrane (TM) region of VP41 was indispensable for the suppression of IFNpro activity. Finally, after infection with GCRV, VP41 blunted the transcription of host IFN and facilitated viral RNA synthesis. Taken together, our findings suggest that GCRV VP41 prevents the fish IFN response by attenuating the phosphorylation of MITA for viral evasion. IMPORTANCE MITA is thought to act as an adaptor protein to facilitate the phosphorylation of IRF3 by TBK1 upon viral infection, and it plays a critical role in innate antiviral responses. Here, we report that GCRV VP41 colocalizes with MITA at the ER and reduces MITA phosphorylation by acting as a decoy substrate of TBK1, thus inhibiting IFN production. These findings reveal GCRV's strategy for evading the host IFN response for the first time.

scholarly journals The Lignan-containing Extract of Schisandra chinensis Berries Inhibits the Growth of Chlamydia pneumoniae

2015 ◽  
Vol 10 (6) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Elina Hakala ◽  
Leena L. Hanski ◽  
Teijo Yrjönen ◽  
Heikki J. Vuorela ◽  
Pia M. Vuorela
Keyword(s):  
Chlamydia Pneumoniae ◽  
Bacterial Species ◽  
Host Cells ◽  
Schisandrin B ◽  
Respiratory Pathogens ◽  
Dependent Manner ◽  
Schisandra Chinensis ◽  
Pure Compound ◽  
Different Strains ◽  
Dose Dependent

The purpose of this study was to investigate the effect and selectivity of an extract of Schisandra chinensis berries against Chlamydia pneumoniae and C. trachomatis. Among the ethnopharmacological uses of the extract from Schisandrae fructus are cough and pneumonia. Therefore we focused on respiratory pathogens. The extract completely inhibited the growth of C. pneumoniae strain CV6 at 250 μg/mL concentration. The inhibition of C. pneumoniae and C. trachomatis growth was dose dependent and established with three different strains. The extract inhibited C. pneumoniae production of infectious progeny in a dose dependent manner. Chlamydia selectivity was elucidated with growth inhibition measurements of three other respiratory bacterial species. A pure compound found in Schisandra chinensis berries, schisandrin B at 20.0 μg/mL concentration inhibited the growth of both C. pneumoniae and C. trachomatis. The extract was found to be non-toxic to the human host cells. These findings highlight the potential of the extract from Schisandra chinensis berries as a source for antichlamydial compounds.

scholarly journals Feline Infectious Peritonitis Virus Nsp5 Inhibits Type I Interferon Production by Cleaving NEMO at Multiple Sites

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 43 ◽  
Author(s):  
Si Chen ◽  
Jin Tian ◽  
Zhijie Li ◽  
Hongtao Kang ◽  
Jikai Zhang ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Sendai Virus ◽  
Nuclear Factor Κb ◽  
Poly I:C ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Feline Infectious Peritonitis Virus ◽  
Feline Infectious Peritonitis ◽  
Polycytidylic Acid

Feline infectious peritonitis (FIP), caused by virulent feline coronavirus, is the leading infectious cause of death in cats. The type I interferon (type I IFN)-mediated immune responses provide host protection from infectious diseases. Several coronaviruses have been reported to evolve diverse strategies to evade host IFN response. However, whether feline infectious peritonitis virus (FIPV) antagonizes the type I IFN signaling remains unclear. In this study, we demonstrated that FIPV strain DF2 infection not only failed to induce interferon-β (IFN-β) and interferon-stimulated gene (ISG) production, but also inhibited Sendai virus (SEV) or polyinosinic-polycytidylic acid (poly(I:C))-induced IFN-β production. Subsequently, we found that one of the non-structural proteins encoded by the FIPV genome, nsp5, interrupted type I IFN signaling in a protease-dependent manner by cleaving the nuclear factor κB (NF-κB) essential modulator (NEMO) at three sites—glutamine132 (Q132), Q205, and Q231. Further investigation revealed that the cleavage products of NEMO lost the ability to activate the IFN-β promoter. Mechanistically, the nsp5-mediated NEMO cleavage disrupted the recruitment of the TRAF family member-associated NF-κB activator (TANK) to NEMO, which reduced the phosphorylation of interferon regulatory factor 3 (IRF3), leading to the inhibition of type I IFN production. Our research provides new insights into the mechanism for FIPV to counteract host innate immune response.

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