scholarly journals NUDT21 links mitochondrial IPS-1 to RLR-containing stress granules and activates host antiviral defense

2020 ◽  
Author(s):  
Saeko Aoyama-Ishiwatari ◽  
Tomohiko Okazaki ◽  
Shun-ichiro Iemura ◽  
Tohru Natsume ◽  
Yasushi Okada ◽  
...  
Keyword(s):  
Viral Infection ◽  
Host Defense ◽  
Rna Binding ◽  
Adaptor Protein ◽  
Stress Granules ◽  
Host Cells ◽  
Poly I:C ◽  
Mammalian Host ◽  
Type I ◽  
Resting Cells

SummaryViral RNA in the cytoplasm of mammalian host cells is recognized by retinoic acid– inducible protein–I (RIG-I)–like receptors (RLRs), which localize to cytoplasmic stress granules (SGs). Activated RLRs associate with the mitochondrial adaptor protein IPS-1, which activates antiviral host defense mechanisms including type I interferon (IFN) induction. It has remained unclear, however, how RLRs in SGs and IPS-1 in the mitochondrial outer membrane associate physically and engage in information transfer. Here we show that NUDT21, an RNA binding protein that regulates alternative transcript polyadenylation, physically associates with IPS-1 and mediates its localization to SGs in response to transfection with poly(I:C), a mimic of viral double-stranded RNA. We found that, despite its well-established function in the nucleus, a fraction of NUDT21 localizes to mitochondria in resting cells and becomes localized to SGs in response to poly(I:C) transfection. NUDT21 was also found to be required for efficient type I IFN induction in response to viral infection. Our results together indicate that NUDT21 links RLRs in SGs to mitochondrial IPS-1 and thereby activates host defense responses to viral infection.

scholarly journals Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

2019 ◽  
Author(s):  
Paulino Barragan-Iglesias ◽  
Úrzula Franco-Enzástiga ◽  
Vivekanand Jeevakumar ◽  
Andi Wangzhou ◽  
Vinicio Granados-Soto ◽  
...  
Keyword(s):  
Viral Infection ◽  
Viral Infections ◽  
Mrna Translation ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Drg Neurons ◽  
Pain Hypersensitivity ◽  
Type I Ifns ◽  
Pain Sensitization

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

scholarly journals Safety and Transcriptome Analysis of Live Attenuated Brucella Vaccine Strain S2 on Non-pregnant Cynomolgus Monkeys Without Abortive Effect on Pregnant Cynomolgus Monkeys

2021 ◽  
Vol 8 ◽  
Author(s):  
Shijing Sun ◽  
Hui Jiang ◽  
Qiaoling Li ◽  
Yufu Liu ◽  
Qiang Gao ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Vaccine Strain ◽  
Transcriptome Analysis ◽  
Rna Binding ◽  
Actin Binding ◽  
Economic Losses ◽  
Mammalian Host ◽  
Type I ◽  
Oligoadenylate Synthetase ◽  
Cynomolgus Monkeys

Brucellosis, caused by Brucella spp., is an important zoonotic disease leading to enormous economic losses in livestock, posing a great threat to public health worldwide. The live attenuated Brucella suis (B. suis) strain S2, a safe and effective vaccine, is widely used in animals in China. However, S2 vaccination in animals may raise debates and concerns in terms of safety to primates, particularly humans. In this study, we used cynomolgus monkey as an animal model to evaluate the safety of the S2 vaccine strain on primates. In addition, we performed transcriptome analysis to determine gene expression profiling on cynomolgus monkeys immunized with the S2 vaccine. Our results suggested that the S2 vaccine was safe for cynomolgus monkeys. The transcriptome analysis identified 663 differentially expressed genes (DEGs), of which 348 were significantly upregulated and 315 were remarkably downregulated. The Gene Ontology (GO) classification and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that these DEGs were involved in various biological processes (BPs), including the chemokine signaling pathway, actin cytoskeleton regulation, the defense response, immune system processing, and the type-I interferon signaling pathway. The molecular functions of the DEGs were mainly comprised of 2'-5'-oligoadenylate synthetase activity, double-stranded RNA binding, and actin-binding. Moreover, the cellular components of these DEGs included integrin complex, myosin II complex, and blood microparticle. Our findings alleviate the concerns over the safety of the S2 vaccine on primates and provide a genetic basis for the response from a mammalian host following vaccination with the S2 vaccine.

scholarly journals Further investigation of the characteristics and biological function of Eimeria tenella apical membrane antigen 1

Parasite ◽  
2020 ◽  
Vol 27 ◽  
pp. 70
Author(s):  
Qingjie Wang ◽  
Qiping Zhao ◽  
Shunhai Zhu ◽  
Bing Huang ◽  
Shuilan Yu ◽  
...  
Keyword(s):  
Rna Binding ◽  
Apical Membrane ◽  
Mapk Signaling ◽  
Eimeria Tenella ◽  
Host Cells ◽  
Differentially Expressed ◽  
Type I ◽  
Dependent Manner ◽  
Apical Membrane Antigen 1 ◽  
Apical Membrane Antigen

Apical membrane antigen 1 (AMA1) is a type I integral membrane protein that is highly conserved in apicomplexan parasites. Previous studies have shown that Eimeria tenella AMA1 (EtAMA1) is critical for sporozoite invasion of host cells. Here, we show that EtAMA1 is a microneme protein secreted by sporozoites, confirming previous results. Individual and combined treatment with antibodies of EtAMA1 and its interacting proteins, E. tenella rhoptry neck protein 2 (EtRON2) and Eimeria-specific protein (EtESP), elicited significant anti-invasion effects on the parasite in a concentration-dependent manner. The overexpression of EtAMA1 in DF-1 cells showed a significant increase of sporozoite invasion. Isobaric tags for relative and absolute quantitation (iTRAQ) coupled with LC-MS/MS were used to screen differentially expressed proteins (DEPs) in DF-1 cells transiently transfected with EtAMA1. In total, 3953 distinct nonredundant proteins were identified and 163 of these were found to be differentially expressed, including 91 upregulated proteins and 72 downregulated proteins. The DEPs were mainly localized within the cytoplasm and were involved in protein binding and poly(A)-RNA binding. KEEG analyses suggested that the key pathways that the DEPs belonged to included melanogenesis, spliceosomes, tight junctions, and the FoxO and MAPK signaling pathways. The data in this study not only provide a comprehensive dataset for the overall protein changes caused by EtAMA1 expression, but also shed light on EtAMA1’s potential molecular mechanisms during Eimeria infections.

scholarly journals Pseudomonas aeruginosa injects NDK into host cells through a type III secretion system

Microbiology ◽  
2014 ◽  
Vol 160 (7) ◽  
pp. 1417-1426 ◽  
Author(s):  
Dennis Neeld ◽  
Yongxin Jin ◽  
Candace Bichsel ◽  
Jinghua Jia ◽  
Jianhui Guo ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Type Iii Secretion ◽  
Type Iii Secretion System ◽  
Secretion System ◽  
Host Cells ◽  
Eukaryotic Cells ◽  
Mammalian Host ◽  
Type I ◽  
Dependent Manner ◽  
Type Iii

Pseudomonas aeruginosa is a Gram-negative opportunistic human pathogen possessing a type III secretion system (T3SS) which injects toxic effector proteins into mammalian host cells. In previous studies, P. aeruginosa strains lacking all of the known type III effectors were shown to cause cytotoxicity upon prolonged infection time. In this study, we report the identification of a new cytotoxin, nucleoside diphosphate kinase (NDK), which is injected into eukaryotic cells in a T3SS-dependent manner. Injection of NDK is inhibited by the presence of previously known effectors of the T3SS, with an effectorless strain injecting the highest amount, suggesting active competition with the known T3SS effectors. NDK is shown to cause a cytotoxic response when expressed in eukaryotic cells, and P. aeruginosa strains harbouring NDK also show a greater toxicity than strains lacking it. Interestingly, the cytotoxic effect of intracellular NDK is independent of its kinase activity. In previous studies, NDK was shown to be secreted into culture supernatants via a type I secretion system and cause cytotoxicity in a kinase-dependent manner. Therefore, the current study highlights an alternative route of NDK secretion as well as two different cytotoxic mechanisms of NDK, depending on the extra- or intra-cellular location of the protein.

scholarly journals miR-26a Inhibits Feline Herpesvirus 1 Replication by Targeting SOCS5 and Promoting Type I Interferon Signaling

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 2 ◽  
Author(s):  
Jikai Zhang ◽  
Zhijie Li ◽  
Jiapei Huang ◽  
Hang Yin ◽  
Jin Tian ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Infection ◽  
Innate Immune Response ◽  
Antiviral Response ◽  
Innate Immune ◽  
Host Cells ◽  
Type I ◽  
Type I Ifn ◽  
Feline Herpesvirus ◽  
Herpesvirus 1

In response to viral infection, host cells activate various antiviral responses to inhibit virus replication. While feline herpesvirus 1 (FHV-1) manipulates the host early innate immune response in many different ways, the host could activate the antiviral response to counteract it through some unknown mechanisms. MicroRNAs (miRNAs) which serve as a class of regulatory factors in the host, participate in the regulation of the host innate immune response against virus infection. In this study, we found that the expression levels of miR-26a were significantly upregulated upon FHV-1 infection. Furthermore, FHV-1 infection induced the expression of miR-26a via a cGAS-dependent pathway, and knockdown of cellular cGAS significantly blocked the expression of miR-26a induced by poly (dA:dT) or FHV-1 infection. Next, we investigated the biological function of miR-26a during viral infection. miR-26a was able to increase the phosphorylation of STAT1 and promote type I IFN signaling, thus inhibiting viral replication. The mechanism study showed that miR-26a directly targeted host SOCS5. Knockdown of SOCS5 increased the phosphorylation of STAT1 and enhanced the type I IFN-mediated antiviral response, and overexpression of suppressor of the cytokine signalling 5 (SOCS5) decreased the phosphorylation of STAT1 and inhibited the type I IFN-mediated antiviral response. Meanwhile, with the knockdown of SOCS5, the upregulated expression of phosphorylated STAT1 and the anti-virus effect induced by miR-26a were significantly inhibited. Taken together, our data demonstrated a new strategy of host miRNAs against FHV-1 infection by enhancing IFN antiviral signaling.

scholarly journals Insulin mRNA is stored in RNA granules in resting beta cells

2021 ◽  
Author(s):  
Jovana Vasiljević ◽  
Djordje Vasiljević ◽  
Katharina Ganß ◽  
Anke Sönmez ◽  
Carolin Wegbrod ◽  
...  
Keyword(s):  
Beta Cells ◽  
Secretory Granule ◽  
Rna Binding ◽  
Stress Granules ◽  
Resting Cells ◽  
Glucose Stimulation ◽  
Min6 Cells ◽  
Rna Granules ◽  
Insulin Mrna ◽  
Insulin Secretory Granule

The glucose-stimulated biosynthesis of insulin in pancreatic islet beta cells is post-transcriptionally regulated. Several RNA-binding proteins (RBPs) that regulate Insulin mRNA stability and translation also bind mRNAs coding for other insulin secretory granule (ISG) proteins. However, an overview of these interactions and their glucose-induced remodelling is still missing. Here we identify two distinct sets of RBPs which were preferentially pulled down with the 5'-UTRs of mouse Ins1, Ins2, spliced Ins2, Ica512/Ptprn and Pc2/Pcsk2 mRNAs from extracts of either resting or stimulated mouse insulinoma MIN6 cells compared to those recovered with the 5'-UTR of mouse Tubg1 encoding for γ-tubulin. Among RBPs binding in resting conditions to all tested transcripts for ISG components was hnRNP A2/B1. Hnrnpa2b1 KO MIN6 cells contained lower levels of Ins1 mRNA, proinsulin and insulin compared to control cells. In resting cells, both hnRNP A2/B1 and Insulin mRNAs localized to stress granules, which dissolved upon glucose stimulation. Insulin mRNA-positive RNA granules were also found in human pancreatic beta cells in situ. Our results suggest that resting beta cells store mRNAs for insulin secretory granule proteins in stress granules through specific RNA protein interactions. Glucose stimulation remodels these interactions, releasing the transcripts, and another set of RBPs coordinates their translation.

scholarly journals SARS-CoV-2 ORF9b Antagonizes Type I and III Interferons by Targeting Multiple Components of RIG-I/MDA-5-MAVS, TLR3-TRIF, and cGAS-STING Signaling Pathways

2020 ◽  
Author(s):  
Lulu Han ◽  
Meng-Wei Zhuang ◽  
Yi Zheng ◽  
Jing Zhang ◽  
Mei-Ling Nan ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Sendai Virus ◽  
Active Form ◽  
Adaptor Protein ◽  
Antiviral Immunity ◽  
Clinical Findings ◽  
Etiologic Agent ◽  
Poly I:C ◽  
Type I ◽  
Reading Frame

AbstractSevere acute respiratory syndrome corona-virus 2 (SARS-CoV-2), the etiologic agent of the coronavirus disease 2019 (COVID-19), has a catastrophic effect on human health and society. Clinical findings indicated that the suppression of innate antiviral immunity, especially the type I and III interferon (IFN) production, contributes to the pathogenesis of COVID-19. However, how SARS-CoV-2 evades antiviral immunity still needs further investigations. Here, we reported that the open reading frame 9b (ORF9b) protein encoded by the SARS-CoV-2 genome inhibits the activation of type I and III IFN response by targeting multiple molecules of innate antiviral signaling pathways. SARS-CoV-2 ORF9b impaired the induction of type I and III IFNs by Sendai virus or the dsRNA mimic poly (I:C). SARS-CoV-2 ORF9b inhibits the activation of type I and III IFNs induced by the components of cytosolic dsRNA-sensing pathways of RIG-I/MDA5-MAVS signaling, including RIG-I, MDA-5, MAVS, TBK1, and IKKε rather than IRF3-5D, the active form of IRF3. SARS-CoV-2 ORF9b also suppressed the induction of type I and III IFNs by TRIF and STING, the adaptor protein of endosome RNA-sensing pathway of TLR3-TRIF signaling and the adaptor protein of cytosolic DNA-sensing pathway of cGAS-STING signaling, respectively. Mechanistically, SARS-CoV-2 ORF9b protein interacts with RIG-I, MDA-5, MAVS, TRIF, STING, TBK1, and prevents TBK1 phosphorylation, thus impeding the phosphorylation and nuclear trans-localization of IRF3 activation. Overexpression of SARS-CoV-2 ORF9b facilitates the replication of the vesicular stomatitis virus. Therefore, SARS-CoV-2 ORF9b negatively regulates antiviral immunity, thus, facilitate virus replication. This study contributes to our understanding of the molecular mechanism of how SARS-CoV-2 impaired antiviral immunity and providing an essential clue to the pathogenesis of COVID-19.

scholarly journals Characterization of JC Polyomavirus Entry by Serotonin Receptors

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 73
Author(s):  
Melissa Maginnis ◽  
Colleen L. Mayberry ◽  
Kashif Mehmood ◽  
Matthew Parent ◽  
Samuel Hess
Keyword(s):  
Viral Infection ◽  
Glial Cells ◽  
Demyelinating Disease ◽  
Antiviral Treatment ◽  
Treatment Options ◽  
Adaptor Protein ◽  
Host Cells ◽  
Binding Motif ◽  
Intracellular Loop ◽  
Jc Polyomavirus

JC polyomavirus (JCPyV) causes a lifelong persistent infection in the kidney in the majority of the population. In severely immunocompromised individuals, JCPyV can become reactivated, spread in the central nervous system, and infect glial cells, astrocytes, and oligodendrocytes which are necessary for myelin production. The viral infection and cytolytic destruction of glial cells leads to the development of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML), for which there are currently no approved treatment options. In order to develop effective antiviral therapies, it is essential to define the virus–host cell interactions that drive infection and the virus–receptor interactions that are major regulators of tissue tropism and viral disease outcomes. Following attachment to sialic acid receptors, JCPyV requires the serotonin 5-hydroxytryptamine (5-HT2) receptors to mediate internalization. However, the mechanism by which JCPyV utilizes 5-HT2 receptors to invade host cells is poorly understood. Using super-resolution fluorescence photoactivation localization microscopy (FPALM), we have determined that JCPyV localizes with 5-HT2 receptors at timepoints consistent with viral entry. Furthermore, we have determined that the 5-HT2 receptor-associated scaffolding proteins beta-arrestin, adaptor protein complex 2 (AP2) and dynamin are required for viral internalization through a clathrin-mediated endocytosis pathway. Additionally, we have identified a beta-arrestin-binding motif in the intracellular loop of the 5-HT2A receptor that is critical for JCPyV entry and infection. These findings highlight the importance of viral receptors in regulating viral infection and illuminate potential targets for antiviral treatment.

scholarly journals The RNA binding protein La/SS-B promotes RIG-I-mediated type I and type III IFN responses following Sendai viral infection

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Rebecca Mahony ◽  
Lindsay Broadbent ◽  
Jacen S. Maier-Moore ◽  
Ultan F. Power ◽  
Caroline A. Jefferies
Keyword(s):  
Viral Infection ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Type I ◽  
Type Iii ◽  
Type Iii Ifn

Role of Poly(ADP-ribose) polymerase (PARP1) in viral infection and its implication in SARS-CoV-2 pathogenesis

2021 ◽  
Vol 22 ◽  
Author(s):  
Jyotika Rajawat ◽  
Abhishek Chandra
Keyword(s):  
Viral Infection ◽  
Inflammatory Cytokines ◽  
Influenza A ◽  
Inflammatory Diseases ◽  
Heart Function ◽  
Host Cells ◽  
Type I ◽  
Global Pandemic ◽  
The One

Poly (ADP-ribose) polymerase 1 (PARP1) is a post-translational modifying enzyme and is also known to act as transcription factor and co-activator. PARP1 has been shown to be involved with diseases resulting in increased inflammation and several viral diseases have also been associated with PARP1 activation. PARP1 facilitates influenza A virus entry in host cells by degrading interferon receptor type I. PARP1 regulates expression of NFkB and downstream cytokine production and its inhibition is known to attenuate the expression of inflammatory cytokines. Thus, PARP1 plays an important role in host-pathogen interactions and pathogenesis. Moreover, pre-clinical and in vitro studies have shown that PARP1 inhibition may affect viability of several viruses including affecting replication of the SARS-CoV virus, a distant relative of the SARS-CoV-2 virus, the one which caused the SARS epidemic of 2002. Covid-19 has been declared a global pandemic; with symptoms of the disease now not limited to respiratory distress alone. Severe inflammation is observed in the lungs leading to a surge of cytokine release systemically, affecting heart function, ischemia and stroke. Inflammatory cytokines which are associated with severe comorbidities and mortalities due to chronic diseases are being upregulated in an acute fashion. There is no immediate treatment, and only palliative care is being provided. The current review will discuss mechanisms of PARP1 activation during viral infection, inflammatory diseases, cytokine expression and possibility of PARP1 in regulating cytokine storm and hyper-inflammation seen with Covid-19.

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