scholarly journals Intracellular lipid droplet accumulation occurs early following viral infection and is required for an efficient interferon response

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
E. A. Monson ◽  
K. M. Crosse ◽  
M. Duan ◽  
W. Chen ◽  
R. D. O’Shea ◽  
...  
Keyword(s):  
Viral Replication ◽  
Viral Infection ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Growth Factor Receptor ◽  
Interferon Response ◽  
Type I ◽  
Antiviral Immune Response

AbstractLipid droplets (LDs) are increasingly recognized as critical organelles in signalling events, transient protein sequestration and inter-organelle interactions. However, the role LDs play in antiviral innate immune pathways remains unknown. Here we demonstrate that induction of LDs occurs as early as 2 h post-viral infection, is transient and returns to basal levels by 72 h. This phenomenon occurs following viral infections, both in vitro and in vivo. Virally driven in vitro LD induction is type-I interferon (IFN) independent, and dependent on Epidermal Growth Factor Receptor (EGFR) engagement, offering an alternate mechanism of LD induction in comparison to our traditional understanding of their biogenesis. Additionally, LD induction corresponds with enhanced cellular type-I and -III IFN production in infected cells, with enhanced LD accumulation decreasing viral replication of both Herpes Simplex virus 1 (HSV-1) and Zika virus (ZIKV). Here, we demonstrate, that LDs play vital roles in facilitating the magnitude of the early antiviral immune response specifically through the enhanced modulation of IFN following viral infection, and control of viral replication. By identifying LDs as a critical signalling organelle, this data represents a paradigm shift in our understanding of the molecular mechanisms which coordinate an effective antiviral response.

scholarly journals Intracellular Lipid Droplet Accumulation Occurs Early Following Viral Infection and Is Required for an Efficient Interferon Response

2020 ◽  
Author(s):  
EA Monson ◽  
KM Crosse ◽  
M Duan ◽  
W Chen ◽  
RD O’Shea ◽  
...  
Keyword(s):  
Viral Replication ◽  
Viral Infection ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Interferon Response ◽  
Type I ◽  
Antiviral Immune Response ◽  
Alternate Mechanism

SummaryLipid droplets (LDs) are increasingly recognized as critical organelles in signalling events, transient protein sequestration and inter-organelle interactions. However, the role LDs play in antiviral innate immune pathways remains unknown. Here we demonstrate that induction of LDs occurs as early as 2 hours post viral infection, is transient, and returns to basal levels by 72 hours. This phenomenon occurred following viral infections, both in vitro and in vivo. Virally driven LD induction was type-I interferon (IFN) independent, however, was dependent on EGFR engagement, offering an alternate mechanism of LD induction in comparison to our traditional understanding of their biogenesis. Additionally, LD induction corresponded with enhanced cellular type-I and -III IFN production in infected cells, with enhanced LD accumulation decreasing viral replication of both HSV-1 and Zika virus (ZIKV). Here, we demonstrate for the first time, that LDs play vital roles in facilitating the magnitude of the early antiviral immune response specifically through the enhanced modulation of IFN following viral infection, and control of viral replication. By identifying LDs as a critical signalling organelle, this data represents a paradigm shift in our understanding of the molecular mechanisms which coordinate an effective antiviral response.

scholarly journals Transcriptional role of p53 in interferon-mediated antiviral immunity

2008 ◽  
Vol 205 (8) ◽  
pp. 1929-1938 ◽  
Author(s):  
César Muñoz-Fontela ◽  
Salvador Macip ◽  
Luis Martínez-Sobrido ◽  
Lauren Brown ◽  
Joseph Ashour ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Viral Replication ◽  
Viral Infections ◽  
Suppressor Gene ◽  
Central Component ◽  
Type I ◽  
Infected Cells

Tumor suppressor p53 is activated by several stimuli, including DNA damage and oncogenic stress. Previous studies (Takaoka, A., S. Hayakawa, H. Yanai, D. Stoiber, H. Negishi, H. Kikuchi, S. Sasaki, K. Imai, T. Shibue, K. Honda, and T. Taniguchi. 2003. Nature. 424:516–523) have shown that p53 is also induced in response to viral infections as a downstream transcriptional target of type I interferon (IFN) signaling. Moreover, many viruses, including SV40, human papillomavirus, Kaposi's sarcoma herpesvirus, adenoviruses, and even RNA viruses such as polioviruses, have evolved mechanisms designated to abrogate p53 responses. We describe a novel p53 function in the activation of the IFN pathway. We observed that infected mouse and human cells with functional p53 exhibited markedly decreased viral replication early after infection. This early inhibition of viral replication was mediated both in vitro and in vivo by a p53-dependent enhancement of IFN signaling, specifically the induction of genes containing IFN-stimulated response elements. Of note, p53 also contributed to an increase in IFN release from infected cells. We established that this p53-dependent enhancement of IFN signaling is dependent to a great extent on the ability of p53 to activate the transcription of IFN regulatory factor 9, a central component of the IFN-stimulated gene factor 3 complex. Our results demonstrate that p53 contributes to innate immunity by enhancing IFN-dependent antiviral activity independent of its functions as a proapoptotic and tumor suppressor gene.

scholarly journals TRIM35 mediates protection against influenza infection by activating TRAF3 and degrading viral PB2

2020 ◽  
Vol 11 (12) ◽  
pp. 894-914
Author(s):  
Nan Sun ◽  
Li Jiang ◽  
Miaomiao Ye ◽  
Yihan Wang ◽  
Guangwen Wang ◽  
...  
Keyword(s):  
Influenza A ◽  
Viral Infections ◽  
Influenza Infection ◽  
Type I ◽  
Subsequent Formation ◽  
Antiviral Immune Response ◽  
Signaling Complex ◽  
Deficient Mice

AbstractTripartite motif (TRIM) family proteins are important effectors of innate immunity against viral infections. Here we identified TRIM35 as a regulator of TRAF3 activation. Deficiency in or inhibition of TRIM35 suppressed the production of type I interferon (IFN) in response to viral infection. Trim35-deficient mice were more susceptible to influenza A virus (IAV) infection than were wild-type mice. TRIM35 promoted the RIG-I-mediated signaling by catalyzing Lys63-linked polyubiquitination of TRAF3 and the subsequent formation of a signaling complex with VISA and TBK1. IAV PB2 polymerase countered the innate antiviral immune response by impeding the Lys63-linked polyubiquitination and activation of TRAF3. TRIM35 mediated Lys48-linked polyubiquitination and proteasomal degradation of IAV PB2, thereby antagonizing its suppression of TRAF3 activation. Our in vitro and in vivo findings thus reveal novel roles of TRIM35, through catalyzing Lys63- or Lys48-linked polyubiquitination, in RIG-I antiviral immunity and mechanism of defense against IAV infection.

scholarly journals Modelling dynamics of the type I interferon response to in vitro viral infection

2006 ◽  
Vol 3 (10) ◽  
pp. 699-709 ◽  
Author(s):  
Tom J Howat ◽  
Cristina Barreca ◽  
Peter O'Hare ◽  
Julia R Gog ◽  
Bryan T Grenfell
Keyword(s):  
Viral Infection ◽  
Dose Dependence ◽  
Interferon Response ◽  
Type I ◽  
Analytic Approximation ◽  
Herpes Simplex Virus 1 ◽  
Cell Monolayers ◽  
Simplex Virus

Innate immunity is crucial in the early stages of resistance to novel viral infection. The family of cytokines known as the interferons (IFNs) forms an essential component of this system: they are responsible for signalling that an infection is underway and for promoting an antiviral response in susceptible cells. We construct a spatial stochastic model, parameterized by experimental data and informed by analytic approximation, to capture the dynamics of virus–IFN interaction during in vitro infection of Madin–Darby bovine kidney cell monolayers by Herpes simplex virus 1. The dose dependence of infection progression, subsequent monolayer destruction and IFN-β production are investigated. Implications for in vivo infections, in particular the priming of susceptible cells by IFN-β during infection, are considered.

scholarly journals Development of Small-Molecule STING Activators for Cancer Immunotherapy

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 33
Author(s):  
Hee Ra Jung ◽  
Seongman Jo ◽  
Min Jae Jeon ◽  
Hyelim Lee ◽  
Yeonjeong Chu ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Cyclic Gmp ◽  
Therapeutic Potential ◽  
Interferon Response ◽  
Type I ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Sting Pathway

In cancer immunotherapy, the cyclic GMP–AMP synthase–stimulator of interferon genes (STING) pathway is an attractive target for switching the tumor immunophenotype from ‘cold’ to ‘hot’ through the activation of the type I interferon response. To develop a new chemical entity for STING activator to improve cyclic GMP-AMP (cGAMP)-induced innate immune response, we identified KAS-08 via the structural modification of DW2282, which was previously reported as an anti-cancer agent with an unknown mechanism. Further investigation revealed that direct STING binding or the enhanced phosphorylation of STING and downstream effectors were responsible for DW2282-or KAS-08-mediated STING activity. Furthermore, KAS-08 was validated as an effective STING pathway activator in vitro and in vivo. The synergistic effect of cGAMP-mediated immunity and efficient anti-cancer effects successfully demonstrated the therapeutic potential of KAS-08 for combination therapy in cancer treatment.

scholarly journals Innate triggering and antiviral effector functions of activin A

2021 ◽  
Author(s):  
Kinda Al-Hourani ◽  
Narayan Ramamurthy ◽  
Emanuele Marchi ◽  
Ruth M Eichinger ◽  
Lian N Lee ◽  
...  
Keyword(s):  
Viral Infection ◽  
Influenza A ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Activin A ◽  
Type I ◽  
Type I Ifn ◽  
Effector Functions

First-line defence against viral infection is contingent upon rapid detection of conserved viral structural and genomic motifs by germline-encoded pattern recognition receptors, followed by activation of the type I IFN system and establishment of an intracellular antiviral state. Novel antiviral functions of bone morphogenetic protein and related activin cytokines, acting in conjunction with, and independently of, type I IFN, have recently been described. Activin A mediates multiple innate and adaptive immune functions, including antiviral effects. However, how such effects are mediated and how activin might be triggered by viral infection have not been defined. Here we addressed this in vivo and in vitro, in humans and mice. Transcriptomic analyses delineated strikingly congruent patterns of gene regulation in hepatocytes stimulated with recombinant activin A and IFNα in vitro. Activin A mRNA, encoded by INHBA, is induced upon activation of RIG-I, MDA5 and TLR7/8 viral nucleic acid sensors in vitro, across multiple cell lines and in human peripheral blood mononuclear cells. In vivo, infection of mice with influenza A also upregulated Inhba mRNA in the lung; this local upregulation of Inhba is retained in MAVS knockout mice, indicating a role for non-RIG-I-like receptors in its induction. Activin induction and signalling were also detectable in patients with chronic viral hepatitis. Together, these data suggest Activin A is triggered in parallel with type I IFN responses and can trigger related antiviral effector functions. This model has implications for the development of targeted antiviral therapies, in addition to revealing novel facets of activin biology.

scholarly journals STAT2-Dependent Immune Responses Ensure Host Survival despite the Presence of a Potent Viral Antagonist

2018 ◽  
Vol 92 (14) ◽  
Author(s):  
Vu Thuy Khanh Le-Trilling ◽  
Kerstin Wohlgemuth ◽  
Meike U. Rückborn ◽  
Andreja Jagnjic ◽  
Fabienne Maaßen ◽  
...  
Keyword(s):  
Immune Responses ◽  
Viral Replication ◽  
Mutual Influence ◽  
Type I ◽  
Mcmv Infection ◽  
General Importance ◽  
Interferon Antagonism ◽  
Deficient Mice

ABSTRACTA pathogen encounter induces interferons, which signal via Janus kinases and STAT transcription factors to establish an antiviral state. However, the host and pathogens are situated in a continuous arms race which shapes host evolution toward optimized immune responses and the pathogens toward enhanced immune-evasive properties. Mouse cytomegalovirus (MCMV) counteracts interferon responses by pM27-mediated degradation of STAT2, which directly affects the signaling of type I as well as type III interferons. Using MCMV mutants lackingM27and mice lacking STAT2, we studied the opposing relationship between antiviral activities and viral antagonism in a natural host-pathogen pairin vitroandin vivo. In contrast to wild-type (wt) MCMV, ΔM27 mutant MCMV was efficiently cleared from all organs within a few days in BALB/c, C57BL/6, and 129 mice, highlighting the general importance of STAT2 antagonism for MCMV replication. Despite this effective and relevant STAT2 antagonism, wt and STAT2-deficient mice exhibited fundamentally different susceptibilities to MCMV infections. MCMV replication was increased in all assessed organs (e.g., liver, spleen, lungs, and salivary glands) of STAT2-deficient mice, resulting in mortality during the first week after infection. Taken together, the results of our study reveal the importance of cytomegaloviral interferon antagonism for viral replication as well as a pivotal role of the remaining STAT2 activity for host survival. This mutual influence establishes a stable evolutionary standoff situation with fatal consequences when the equilibrium is disturbed.IMPORTANCEThe host limits viral replication by the use of interferons (IFNs), which signal via STAT proteins. Several viruses evolved antagonists targeting STATs to antagonize IFNs (e.g., cytomegaloviruses, Zika virus, dengue virus, and several paramyxoviruses). We analyzed infections caused by MCMV expressing or lacking the STAT2 antagonist pM27 in STAT2-deficient and control mice to evaluate its importance for the host and the virusin vitroandin vivo. The inability to counteract STAT2 directly translates into exaggerated IFN susceptibilityin vitroand pronounced attenuationin vivo. Thus, the antiviral activity mediated by IFNs via STAT2-dependent signaling drove the development of a potent MCMV-encoded STAT2 antagonist which became indispensable for efficient virus replication and spread to organs required for dissemination. Despite this clear impact of viral STAT2 antagonism, the host critically required the remaining STAT2 activity to prevent overt disease and mortality upon MCMV infection. Our findings highlight a remarkably delicate balance between host and virus.

scholarly journals Heavily Armed Ancestors: CRISPR Immunity and Applications in Archaea with a Comparative Analysis of CRISPR Types in Sulfolobales

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1523
Author(s):  
Isabelle Anna Zink ◽  
Erika Wimmer ◽  
Christa Schleper
Keyword(s):  
Comparative Analysis ◽  
Molecular Mechanisms ◽  
Model Organisms ◽  
Special Focus ◽  
Natural Environments ◽  
Type I ◽  
Accessory Proteins ◽  
Type Iii

Prokaryotes are constantly coping with attacks by viruses in their natural environments and therefore have evolved an impressive array of defense systems. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is an adaptive immune system found in the majority of archaea and about half of bacteria which stores pieces of infecting viral DNA as spacers in genomic CRISPR arrays to reuse them for specific virus destruction upon a second wave of infection. In detail, small CRISPR RNAs (crRNAs) are transcribed from CRISPR arrays and incorporated into type-specific CRISPR effector complexes which further degrade foreign nucleic acids complementary to the crRNA. This review gives an overview of CRISPR immunity to newcomers in the field and an update on CRISPR literature in archaea by comparing the functional mechanisms and abundances of the diverse CRISPR types. A bigger fraction is dedicated to the versatile and prevalent CRISPR type III systems, as tremendous progress has been made recently using archaeal models in discerning the controlled molecular mechanisms of their unique tripartite mode of action including RNA interference, DNA interference and the unique cyclic-oligoadenylate signaling that induces promiscuous RNA shredding by CARF-domain ribonucleases. The second half of the review spotlights CRISPR in archaea outlining seminal in vivo and in vitro studies in model organisms of the euryarchaeal and crenarchaeal phyla, including the application of CRISPR-Cas for genome editing and gene silencing. In the last section, a special focus is laid on members of the crenarchaeal hyperthermophilic order Sulfolobales by presenting a thorough comparative analysis about the distribution and abundance of CRISPR-Cas systems, including arrays and spacers as well as CRISPR-accessory proteins in all 53 genomes available to date. Interestingly, we find that CRISPR type III and the DNA-degrading CRISPR type I complexes co-exist in more than two thirds of these genomes. Furthermore, we identified ring nuclease candidates in all but two genomes and found that they generally co-exist with the above-mentioned CARF domain ribonucleases Csx1/Csm6. These observations, together with published literature allowed us to draft a working model of how CRISPR-Cas systems and accessory proteins cross talk to establish native CRISPR anti-virus immunity in a Sulfolobales cell.

scholarly journals Integrity of the Antiviral STING-mediated DNA Sensing in Tumor Cells Is Required to Sustain the Immunotherapeutic Efficacy of Herpes Simplex Oncolytic Virus

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3407 ◽  
Author(s):  
Guendalina Froechlich ◽  
Carmen Caiazza ◽  
Chiara Gentile ◽  
Anna Morena D’Alise ◽  
Maria De Lucia ◽  
...  
Keyword(s):  
Immune Checkpoint Blockade ◽  
Oncolytic Viruses ◽  
Type I ◽  
Dna Sensing ◽  
Antiviral Immune Response ◽  
Viral Spread ◽  
Immunosuppressive Tumor Microenvironment ◽  
Tumor Immunogenicity

The dichotomic contribution of cancer cell lysis and tumor immunogenicity is considered essential for effective oncovirotherapy, suggesting that the innate antiviral immune response is a hurdle for efficacy of oncolytic viruses. However, emerging evidence is resizing this view. By sensing cytosolic DNA, the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) axis can both counteract viral spread and contribute to the elicitation of adaptive immunity via type I interferon responses. In this paper, we analyzed the tumor-resident function of Sting-mediated DNA sensing in a combined approach of oncovirotherapy and PD-1 immune checkpoint blockade, in an immunocompetent murine model. While supporting increased lytic potential by oncolytic HER2-retargeted HSV-1 in vitro and in vivo, Sting-knockout tumors showed molecular signatures of an immunosuppressive tumor microenvironment. These signatures were correspondingly associated with ineffectiveness of the combination therapy in a model of established tumors. Results suggest that the impairment in antiviral response of Sting-knockout tumors, while favoring viral replication, is not able to elicit an adequate immunotherapeutic effect, due to lack of immunogenic cell death and the inability of Sting-knockout cancer cells to promote anti-tumor adaptive immune responses. Accordingly, we propose that antiviral, tumor-resident Sting provides fundamental contributions to immunotherapeutic efficacy of oncolytic viruses.

scholarly journals Research Progress of the Antiviral Bioactivities of Natural Flavonoids

2020 ◽  
Vol 10 (5) ◽  
pp. 271-283
Author(s):  
Lin Wang ◽  
Junke Song ◽  
Ailin Liu ◽  
Bin Xiao ◽  
Sha Li ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Viral Infections ◽  
Research Progress ◽  
Future Perspectives ◽  
Therapeutic Applications ◽  
Pharmaceutical Applications ◽  
Antiviral Activities

Abstract Flavonoids are now considered as an indispensable component in a variety of nutraceutical and pharmaceutical applications. Most recent researches have focused on the health aspects of flavonoids for humans. Especially, different flavonoids have been investigated for their potential antiviral activities, and several natural flavonoids exhibited significant antiviral properties both in vitro and in vivo. This review provides a survey of the literature regarding the evidence for antiviral bioactivities of natural flavonoids, highlights the cellular and molecular mechanisms of natural flavonoids on viruses, and presents the details of most reported flavonoids. Meanwhile, future perspectives on therapeutic applications of flavonoids against viral infections were discussed.

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