Modulation of Ubiquitin Signaling in Innate Immune Response by Herpesviruses

The ubiquitin proteasome system (UPS) is a protein degradation machinery that is crucial for cellular homeostasis in eukaryotes. Therefore, it is not surprising that the UPS coordinates almost all host cellular processes, including host–pathogen interactions. This protein degradation machinery acts predominantly by tagging substrate proteins designated for degradation with a ubiquitin molecule. These ubiquitin tags have been involved at various steps of the innate immune response. Hence, herpesviruses have evolved ways to antagonize the host defense mechanisms by targeting UPS components such as ubiquitin E3 ligases and deubiquitinases (DUBs) that establish a productive infection. This review delineates how herpesviruses usurp the critical roles of ubiquitin E3 ligases and DUBs in innate immune response to escape host-antiviral immune response, with particular focus on retinoic acid-inducible gene I (RIG-I)-like receptors (RLR), cyclic-GMP-AMP (cGAMP) synthase (cGAS), stimulator of interferon (IFN) genes (STING) pathways, and inflammasome signaling.

Download Full-text

PATTERN-RECOGNIZING RECEPTORS AND THE INNATE IMMUNE RESPONSE TO VIRAL INFECTION

The Journal of V. N. Karazin Kharkiv National University, Series "Medicine" ◽

10.26565/2313-6693-2018-36-13 ◽

2018 ◽

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Viral Infection ◽

Innate Immune Response ◽

English Literature ◽

Innate Immune ◽

Viral Pathogens ◽

Antiviral Immune Response ◽

Viral Antigens ◽

Wide Range

The innate immune response to viral pathogens is crucial in mobilizing defensive reactions of an organism during the development of an acute viral infection. Cells of the innate immunity system detect viral antigens due to genetically programmed pattern-recognition receptors (PRRs), which are located either on the cell surface or inside the certain intracellular components. These image-recognizing receptors include Toll-like receptors (TLRs), retinoic acid-inducible gene I-like receptors (RIG-I-like receptors), nucleotide oligomerization domain-like receptors (NOD-like receptors), also known as NACHT, LRR and PYD domains of the protein, and cytosolic DNA sensors. The trigger mechanisms for these receptors are viral proteins, and nucleic acids serve as activators. The presence of PRRs that are responsible for the determination of viral antigens in cellular components allows the cells of innate immunity to recognize a wide range of viral agents that replicate in various cellular structures, and develop an immune response to them. This article summarizes the disparate data presented in modern English literature on the role of PRRs and the associated signaling pathways. Understanding the recognition of viral pathogens required triggering a cascade of cytokine and interferon production provides insights into how viruses activate the signal paths of PRRs and the effect of the interaction of viral antigens and these receptors on the formation of the antiviral immune response.

Download Full-text

Lactobacillus delbrueckii CRL 581 Differentially Modulates TLR3-Triggered Antiviral Innate Immune Response in Intestinal Epithelial Cells and Macrophages

Microorganisms ◽

10.3390/microorganisms9122449 ◽

2021 ◽

Vol 9 (12) ◽

pp. 2449

Author(s):

Mariano Elean ◽

Leonardo Albarracin ◽

Kohtaro Fukuyama ◽

Binghui Zhou ◽

Mikado Tomokiyo ◽

...

Keyword(s):

Immune Response ◽

Epithelial Cells ◽

Innate Immune Response ◽

Intestinal Epithelial Cells ◽

Starter Culture ◽

Innate Immune ◽

Lactobacillus Delbrueckii ◽

Poly I:C ◽

Intestinal Epithelial ◽

Antiviral Immune Response

Lactobacillus delbrueckii subsp. lactis CRL 581 beneficially modulates the intestinal antiviral innate immune response triggered by the Toll-like receptor 3 (TLR3) agonist poly(I:C) in vivo. This study aimed to characterize further the immunomodulatory properties of the technologically relevant starter culture L. delbrueckii subsp. lactis CRL 581 by evaluating its interaction with intestinal epithelial cells and macrophages in the context of innate immune responses triggered by TLR3. Our results showed that the CRL 581 strain was able to adhere to porcine intestinal epithelial (PIE) cells and mucins. The CRL 581 strain also augmented the expression of antiviral factors (IFN-α, IFN-β, Mx1, OAS1, and OAS2) and reduced inflammatory cytokines in PIE cells triggered by TLR3 stimulation. In addition, the influence of L. delbrueckii subsp. lactis CRL 581 on the response of murine RAW macrophages to the activation of TLR3 was evaluated. The CRL 581 strain was capable of enhancing the expression of IFN-α, IFN-β, IFN-γ, Mx1, OAS1, TNF-α, and IL-1β. Of note, the CRL 581 strain also augmented the expression of IL-10 in macrophages. The results of this study show that the high proteolytic strain L. delbrueckii spp. lactis CRL 581 was able to beneficially modulate the intestinal innate antiviral immune response by regulating the response of both epithelial cells and macrophages relative to TLR3 activation.

Download Full-text

Induction of an Embryonic Mouse Innate Immune Response following Inoculation In Utero with Minute Virus of Mice

Journal of Virology ◽

10.1128/jvi.02908-14 ◽

2014 ◽

Vol 89 (4) ◽

pp. 2182-2191 ◽

Cited By ~ 4

Author(s):

Irina Rostovsky ◽

Claytus Davis

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

In Utero ◽

Innate Immune ◽

Productive Infection ◽

Interferon Response ◽

Minute Virus Of Mice ◽

Embryonic Mouse ◽

Minute Virus ◽

Ifn Γ

ABSTRACTWe used an embryonic-infection model system to show that MVMp, the prototypic minute virus of mice (MVM) serotype and a member of the genusProtoparvovirus, triggers a comprehensive innate immune response in the developing mouse embryo. Direct inoculation of the midtrimester embryoin uterowith MVMp results in a widespread, productive infection. During a 96-h infection course, embryonic beta interferon (IFN-β) and IFN-γ transcription were induced 90- and 60-fold, respectively. IFN-β levels correlated with the embryo viral burden, while IFN-γ levels first increased and then decreased. Production of proinflammatory cytokines, interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α), also increased, but by smaller amounts, approximately 7-fold each. We observed increased levels of downstream antiviral effector molecules, PKR and phosphorylated STAT2. Finally, we showed that there is an immune cell response to the virus infection. Infected tissues in the embryo exhibited an increased density of mature leukocytes compared to the same tissues in uninfected embryos. The responses we observed were almost completely restricted to the infected embryos. Uninfected littermates routinely exhibited small increases in innate immune components that rarely reached statistical significance compared to negative controls. Similarly, the placentae of infected embryos did not show any significant increase in transcription of innate immune cytokines. Since the placenta has both embryonic and maternal components, we suggest there is minimal involvement of the dam in the response to infection.IMPORTANCEInteraction between the small single-stranded vertebrate DNA viruses, the protoparvoviruses, and the host innate immune system has been unclear. The issue is important practically given the potential use of these viruses as oncotherapeutic agents. The data reported here stand in contrast to studies of innate immune response during protoparvovirus infection of adult hosts, which invariably reported no or minimal and sporadic induction of an interferon response during infection. We conclude that under conditions of robust and productive MVM infection, a normal murine host is able to mount a significant and broad innate immune response.

Download Full-text

Innate Immune Responses to Herpesvirus Infection

Cells ◽

10.3390/cells10082122 ◽

2021 ◽

Vol 10 (8) ◽

pp. 2122

Author(s):

Christine M. O’Connor ◽

Ganes C. Sen

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Defense Mechanisms ◽

Innate Immune ◽

Host Cells ◽

Innate Immune Responses ◽

Viral Pathogen ◽

Dna Viruses ◽

Host Innate Immune Response ◽

Human Herpesviruses

Infection of a host cell by an invading viral pathogen triggers a multifaceted antiviral response. One of the most potent defense mechanisms host cells possess is the interferon (IFN) system, which initiates a targeted, coordinated attack against various stages of viral infection. This immediate innate immune response provides the most proximal defense and includes the accumulation of antiviral proteins, such as IFN-stimulated genes (ISGs), as well as a variety of protective cytokines. However, viruses have co-evolved with their hosts, and as such, have devised distinct mechanisms to undermine host innate responses. As large, double-stranded DNA viruses, herpesviruses rely on a multitude of means by which to counter the antiviral attack. Herein, we review the various approaches the human herpesviruses employ as countermeasures to the host innate immune response.

Download Full-text

Fas-Associated Factor 1 Negatively Regulates the Antiviral Immune Response by Inhibiting Translocation of Interferon Regulatory Factor 3 to the Nucleus

Molecular and Cellular Biology ◽

10.1128/mcb.00744-15 ◽

2016 ◽

Vol 36 (7) ◽

pp. 1136-1151 ◽

Cited By ~ 12

Author(s):

Soonhwa Song ◽

Jae-Jin Lee ◽

Hee-Jung Kim ◽

Jeong Yoon Lee ◽

Jun Chang ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Target Genes ◽

Nuclear Translocation ◽

Antiviral Response ◽

Innate Immune ◽

Type I Interferons ◽

Type I ◽

Antiviral Immune Response ◽

Associated Factor

This study is designed to examine the cellular functions of human Fas-associated factor 1 (FAF1) containing multiple ubiquitin-related domains. Microarray analyses revealed that interferon-stimulated genes related to the antiviral response are significantly increased in FAF1-knockdown HeLa cells. Silencing FAF1 enhanced the poly(I·C)- and respiratory syncytial virus (RSV)-induced production of type I interferons (IFNs), the target genes of interferon regulator factor 3 (IRF3). IRF3 is a key transcription factor in IFN-β signaling responsible for the host innate immune response. This study also found that FAF1 and IRF3 physically associate with IPO5/importin-β3 and that overexpression of FAF1 reduces the interaction between IRF3 and IPO5/importin-β3. These findings suggest that FAF1 negatively regulates IRF3-mediated IFN-β production and the antiviral innate immune response by regulating nuclear translocation of IRF3. We conclude that FAF1 plays a novel role in negatively regulating virus-induced IFN-β production and the antiviral response by inhibiting the translocation of active, phosphorylated IRF3 from the cytosol to the nucleus.

Download Full-text

Piscirickettsia salmonis Imbalances the Innate Immune Response to Succeed in a Productive Infection in a Salmonid Cell Line Model

PLoS ONE ◽

10.1371/journal.pone.0163943 ◽

2016 ◽

Vol 11 (10) ◽

pp. e0163943 ◽

Cited By ~ 19

Author(s):

Claudio A. Álvarez ◽

Fernando A. Gomez ◽

Luis Mercado ◽

Ramón Ramírez ◽

Sergio H. Marshall

Keyword(s):

Immune Response ◽

Cell Line ◽

Innate Immune Response ◽

Innate Immune ◽

Productive Infection ◽

Line Model ◽

Cell Line Model ◽

Piscirickettsia Salmonis

Download Full-text

Development of an in vitro immunobiotic evaluation system against rotavirus infection in bovine intestinal epitheliocytes

Beneficial Microbes ◽

10.3920/bm2016.0155 ◽

2017 ◽

Vol 8 (2) ◽

pp. 309-321 ◽

Cited By ~ 9

Author(s):

H. Kobayashi ◽

P. Kanmani ◽

T. Ishizuka ◽

A. Miyazaki ◽

J. Soma ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Evaluation System ◽

Innate Immune ◽

Poly I:C ◽

Epithelial Cell Line ◽

Intestinal Epithelial ◽

Antiviral Immune Response ◽

Comprehensive Information

The bovine intestinal epithelial cell line (BIE cells) expresses the Toll-like receptor (TLR)3 and is able to mount an antiviral immune response after the stimulation with poly(I:C). In the present study, we aimed to further characterise the antiviral defence mechanisms in BIE cells by evaluating the innate immune response triggered by rotavirus (RV) infection. In addition, we attempted to determine whether immunobiotic bifidobacteria are able to confer protection of BIE cells against RV infection by beneficially modulating the antiviral immune response. RV OSU (porcine) and UK (bovine) effectively infected BIE cells, while a significant lower capacity to infect BIE cells was observed for human (Wa) and murine (EW) RV. We observed that viral infection in BIE cells triggered TLR3/RIG-I-mediated immune responses with activation of IRF3 and TRAF3, induction of interferon beta (IFN-β) and up-regulation of inflammatory cytokines. Our results also demonstrated that preventive treatments with Bifidobacterium infantis MCC12 or Bifidobacterium breve MCC1274 significantly reduced RV titres in infected BIE cells and differentially modulated the innate immune response. Of note, both strains significantly improved the production of the antiviral factor IFN-β in RV-infected BIE cells. In conclusion, this work provides comprehensive information on the antiviral immune response of BIE cells against RV, that can be further studied for the development of strategies aimed to improve antiviral defences in bovine intestinal epithelial cells. Our results also demonstrate that BIE cells could be used as a newly immunobiotic evaluation system against RV infection for application in the bovine host.

Download Full-text

TRIMming Type I Interferon-Mediated Innate Immune Response in Antiviral and Antitumor Defense

Viruses ◽

10.3390/v13020279 ◽

2021 ◽

Vol 13 (2) ◽

pp. 279

Author(s):

Ling Wang ◽

Shunbin Ning

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Stress Responses ◽

Viral Infections ◽

Immune Escape ◽

E3 Ligase ◽

Innate Immune ◽

Type I ◽

Antiviral Immune Response ◽

Wide Range

The tripartite motif (TRIM) family comprises at least 80 members in humans, with most having ubiquitin or SUMO E3 ligase activity conferred by their N-terminal RING domain. TRIMs regulate a wide range of processes in ubiquitination- or sumoylation-dependent manners in most cases, and fewer as adaptors. Their roles in the regulation of viral infections, autophagy, cell cycle progression, DNA damage and other stress responses, and carcinogenesis are being increasingly appreciated, and their E3 ligase activities are attractive targets for developing specific immunotherapeutic strategies for immune diseases and cancers. Given their importance in antiviral immune response, viruses have evolved sophisticated immune escape strategies to subvert TRIM-mediated mechanisms. In this review, we focus on their regulation of IFN-I-mediated innate immune response, which plays key roles in antiviral and antitumor defense.

Download Full-text

Vpu Mediates Depletion of Interferon Regulatory Factor 3 during HIV Infection by a Lysosome-Dependent Mechanism

Journal of Virology ◽

10.1128/jvi.00423-12 ◽

2012 ◽

Vol 86 (16) ◽

pp. 8367-8374 ◽

Cited By ~ 45

Author(s):

Brian P. Doehle ◽

Kristina Chang ◽

Arjun Rustagi ◽

John McNevin ◽

M. Juliana McElrath ◽

...

Keyword(s):

Immune Response ◽

Hiv Infection ◽

Interferon Regulatory Factor ◽

Innate Immune ◽

Productive Infection ◽

Type I ◽

Regulatory Factor ◽

Interferon Regulatory Factor 3 ◽

Antiviral Immune Response ◽

Immune Defenses

HIV has evolved sophisticated mechanisms to avoid restriction by intracellular innate immune defenses that otherwise serve to control acute viral infection and virus dissemination. Innate defenses are triggered when pattern recognition receptor (PRR) proteins of the host cell engage pathogen-associated molecule patterns (PAMPs) present in viral products. Interferon regulatory factor 3 (IRF3) plays a central role in PRR signaling of innate immunity to drive the expression of type I interferon (IFN) and interferon-stimulated genes (ISGs), including a variety of HIV restriction factors, that serve to limit viral replication directly and/or program adaptive immunity. Productive infection of T cells by HIV is dependent upon the targeted proteolysis of IRF3 that occurs through a virus-directed mechanism that results in suppression of innate immune defenses. However, the mechanisms by which HIV controls innate immune signaling and IRF3 function are not defined. Here, we examined the innate immune response induced by HIV strains identified through their differential control of PRR signaling. We identified viruses that, unlike typical circulating HIV strains, lack the ability to degrade IRF3. Our studies show that IRF3 regulation maps specifically to the HIV accessory protein Vpu. We define a molecular interaction between Vpu and IRF3 that redirects IRF3 to the endolysosome for proteolytic degradation, thus allowing HIV to avoid the innate antiviral immune response. Our studies reveal that Vpu is an important IRF3 regulator that supports acute HIV infection through innate immune suppression. These observations define the Vpu-IRF3 interface as a novel target for therapeutic strategies aimed at enhancing the immune response to HIV.

Download Full-text

West Nile Virus Nonstructural Protein 1 Inhibits TLR3 Signal Transduction

Journal of Virology ◽

10.1128/jvi.00226-08 ◽

2008 ◽

Vol 82 (17) ◽

pp. 8262-8271 ◽

Cited By ~ 114

Author(s):

Jason R. Wilson ◽

Paola Florez de Sessions ◽

Megan A. Leon ◽

Frank Scholle

Keyword(s):

Signal Transduction ◽

Immune Response ◽

West Nile Virus ◽

Innate Immune Response ◽

Mammalian Cells ◽

Innate Immune ◽

Productive Infection ◽

West Nile ◽

Antiviral State ◽

Nonstructural Protein 1

ABSTRACT The innate immune response is the first line of defense against foreign pathogens. The recognition of virus-associated molecular patterns, including double- and single-stranded RNA, by pattern recognition receptors initiates a cascade of signaling reactions. These result in the transcriptional upregulation and secretion of proinflammatory cytokines that induce an antiviral state. Many viruses have evolved mechanisms to antagonize these responses in order to help them establish a productive infection. We have previously shown that West Nile virus (WNV) is able to inhibit Toll-like receptor 3 (TLR3)-mediated activation of interferon (IFN) regulatory factor 3 (IRF3) (F. Scholle and P. W. Mason, Virology 342:77-87, 2005). In the present study, the WNV nonstructural (NS) proteins were analyzed individually for their ability to antagonize signal transduction mediated by TLR3. We report that expression of WNV NS1 inhibits TLR3-induced transcriptional activation of the IFN-β promoter and of an NF-κB-responsive promoter. This inhibition was due to a failure of the TLR3 ligand poly(I:C) to induce nuclear translocation of IRF3 and NF-κB. Furthermore, NS1 expression also inhibited TLR3-dependent production of interleukin-6 and the establishment of an antiviral state. The function of NS1 in flavivirus infection is not well understood. NS1 is required for viral RNA replication and is also secreted from mammalian cells but not from insect cells. Here, we identify a previously unrecognized role for NS1 in the modulation of signaling pathways of the innate immune response to WNV infection.

Download Full-text