Interaction between innate immunity and porcine reproductive and respiratory syndrome virus

AbstractInnate immunity provides frontline antiviral protection and bridges adaptive immunity against virus infections. However, viruses can evade innate immune surveillance potentially causing chronic infections that may lead to pandemic diseases. Porcine reproductive and respiratory syndrome virus (PRRSV) is an example of an animal virus that has developed diverse mechanisms to evade porcine antiviral immune responses. Two decades after its discovery, PRRSV is still one of the most globally devastating viruses threatening the swine industry. In this review, we discuss the molecular and cellular composition of the mammalian innate antiviral immune system with emphasis on the porcine system. In particular, we focus on the interaction between PRRSV and porcine innate immunity at cellular and molecular levels. Strategies for targeting innate immune components and other host metabolic factors to induce ideal anti-PRRSV protection are also discussed.

Download Full-text

Evasion of Antiviral Innate Immunity by Porcine Reproductive and Respiratory Syndrome Virus

Frontiers in Microbiology ◽

10.3389/fmicb.2021.693799 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tong-Yun Wang ◽

Ming-Xia Sun ◽

Hong-Liang Zhang ◽

Gang Wang ◽

Guoqing Zhan ◽

...

Keyword(s):

Innate Immunity ◽

Immune Responses ◽

Viral Infections ◽

Respiratory Syndrome Virus ◽

Type I ◽

Swine Industry ◽

Interferon Stimulated Genes ◽

Β Receptor ◽

Underlying Mechanisms ◽

Antiviral Innate Immunity

Innate immunity is the front line for antiviral immune responses and bridges adaptive immunity against viral infections. However, various viruses have evolved many strategies to evade host innate immunity. A typical virus is the porcine reproductive and respiratory syndrome virus (PRRSV), one of the most globally devastating viruses threatening the swine industry worldwide. PRRSV engages several strategies to evade the porcine innate immune responses. This review focus on the underlying mechanisms employed by PRRSV to evade pattern recognition receptors signaling pathways, type I interferon (IFN-α/β) receptor (IFNAR)-JAK-STAT signaling pathway, and interferon-stimulated genes. Deciphering the antiviral immune evasion mechanisms by PRRSV will enhance our understanding of PRRSV’s pathogenesis and help us to develop more effective methods to control and eliminate PRRSV.

Download Full-text

The neuropeptide receptor NMUR-1 regulates the specificity of C. elegans innate immunity against pathogen infection

10.1101/2021.05.06.442992 ◽

2021 ◽

Author(s):

Phillip Wibisono ◽

Shawndra Wibisono ◽

Jan Watteyne ◽

Chia-Hui Chen ◽

Durai Sellegounder ◽

...

Keyword(s):

Innate Immunity ◽

Immune System ◽

Immune Responses ◽

Adaptive Immune System ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Genes ◽

C Elegans ◽

Adaptive Immune ◽

Functional Assays

A key question in current immunology is how the innate immune system generates high levels of specificity. Like most invertebrates, Caenorhabditis elegans does not have an adaptive immune system and relies solely on innate immunity to defend itself against pathogen attacks, yet it can still differentiate different pathogens and launch distinct innate immune responses. Here, we have found that functional loss of NMUR-1, a neuronal GPCR homologous to mammalian receptors for the neuropeptide neuromedin U, has diverse effects on C. elegans survival against various bacterial pathogens. Transcriptomic analyses and functional assays revealed that NMUR-1 modulates C. elegans transcription activity by regulating the expression of transcription factors, which, in turn, controls the expression of distinct immune genes in response to different pathogens. Our study has uncovered a molecular basis for the specificity of C. elegans innate immunity that could provide mechanistic insights into understanding the specificity of vertebrate innate immunity.

Download Full-text

Innate immunity and the pneumococcus

Microbiology ◽

10.1099/mic.0.28551-0 ◽

2006 ◽

Vol 152 (2) ◽

pp. 285-293 ◽

Cited By ~ 52

Author(s):

Gavin K. Paterson ◽

Tim J. Mitchell

Keyword(s):

Innate Immunity ◽

Immune System ◽

Streptococcus Pneumoniae ◽

Immune Responses ◽

Innate Immune System ◽

Innate Immune ◽

First Line ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Made In

The innate immune system provides a non-specific first line of defence against microbes and is crucial both in the development and effector stages of subsequent adaptive immune responses. Consistent with its importance, study of the innate immune system is a broad and fast-moving field. Here we provide an overview of the recent key advances made in this area with relation to the important pathogen Streptococcus pneumoniae (the pneumococcus).

Download Full-text

Introns encode dsRNAs undetected by RIG-I/MDA5/interferons and sensed via RNase L

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2102134118 ◽

2021 ◽

Vol 118 (46) ◽

pp. e2102134118

Author(s):

Alisha Chitrakar ◽

Kristina Solorio-Kirpichyan ◽

Eliza Prangley ◽

Sneha Rath ◽

Jin Du ◽

...

Keyword(s):

Innate Immunity ◽

Immune Responses ◽

Innate Immune ◽

Rna Decay ◽

Antiviral Defense ◽

Rnase L ◽

Innate Immune Responses ◽

Double Stranded Rna ◽

Turn On ◽

Nuclear Rna

Double-stranded RNA (dsRNA), a hallmark viral material that activates antiviral interferon (IFN) responses, can appear in human cells also in the absence of viruses. We identify phosphorothioate DNAs (PS DNAs) as triggers of such endogenous dsRNA (endo-dsRNA). PS DNAs inhibit decay of nuclear RNAs and induce endo-dsRNA via accumulation of high levels of intronic and intergenic inverted retroelements (IIIR). IIIRs activate endo-dsRNA responses distinct from antiviral defense programs. IIIRs do not turn on transcriptional RIG-I/MDA5/IFN signaling, but they trigger the dsRNA-sensing pathways of OAS3/RNase L and PKR. Thus, nuclear RNA decay and nuclear-cytosolic RNA sorting actively protect from these innate immune responses to self. Our data suggest that the OAS3/RNase L and PKR arms of innate immunity diverge from antiviral IFN responses and monitor nuclear RNA decay by sensing cytosolic escape of IIIRs. OAS3 provides a receptor for IIIRs, whereas RNase L cleaves IIIR-carrying introns and intergenic RNAs.

Download Full-text

Novel Functions of IFI44L as a Feedback Regulator of Host Antiviral Responses

Journal of Virology ◽

10.1128/jvi.01159-19 ◽

2019 ◽

Vol 93 (21) ◽

Cited By ~ 9

Author(s):

Marta L. DeDiego ◽

Luis Martinez-Sobrido ◽

David J. Topham

Keyword(s):

Immune Responses ◽

Nuclear Factor Kappa B ◽

Virus Production ◽

Innate Immune ◽

Type I ◽

Nuclear Factor ◽

Innate Immune Responses ◽

Virus Infections ◽

Nuclear Factor Kappa ◽

Ifn Treatment

ABSTRACT We describe a novel function for the interferon (IFN)-induced protein 44-like (IFI44L) gene in negatively modulating innate immune responses induced after virus infections. Furthermore, we show that decreasing IFI44L expression impairs virus production and that IFI44L expression negatively modulates the antiviral state induced by an analog of double-stranded RNA (dsRNA) or by IFN treatment. The mechanism likely involves the interaction of IFI44L with cellular FK506-binding protein 5 (FKBP5), which in turn interacts with kinases essential for type I and III IFN responses, such as inhibitor of nuclear factor kappa B (IκB) kinase alpha (IKKα), IKKβ, and IKKε. Consequently, binding of IFI44L to FKBP5 decreased interferon regulatory factor 3 (IRF-3)-mediated and nuclear factor kappa-B (NF-κB) inhibitor (IκBα)-mediated phosphorylation by IKKε and IKKβ, respectively. According to these results, IFI44L is a good target for treatment of diseases associated with excessive IFN levels and/or proinflammatory responses and for reduction of viral replication. IMPORTANCE Excessive innate immune responses can be deleterious for the host, and therefore, negative feedback is needed. Here, we describe a completely novel function for IFI44L in negatively modulating innate immune responses induced after virus infections. In addition, we show that decreasing IFI44L expression impairs virus production and that IFI44L expression negatively modulates the antiviral state induced by an analog of dsRNA or by IFN treatment. IFI44L binds to the cellular protein FKBP5, which in turn interacts with kinases essential for type I and III IFN induction and signaling, such as the kinases IKKα, IKKβ, and IKKε. IFI44L binding to FKBP5 decreased the phosphorylation of IRF-3 and IκBα mediated by IKKε and IKKβ, respectively, providing an explanation for the function of IFI44L in negatively modulating IFN responses. Therefore, IFI44L is a candidate target for reducing virus replication.

Download Full-text

Mutations in a Highly Conserved Motif of nsp1β Protein Attenuate the Innate Immune Suppression Function of Porcine Reproductive and Respiratory Syndrome Virus

Journal of Virology ◽

10.1128/jvi.03069-15 ◽

2016 ◽

Vol 90 (7) ◽

pp. 3584-3599 ◽

Cited By ~ 23

Author(s):

Yanhua Li ◽

Duan-Liang Shyu ◽

Pengcheng Shang ◽

Jianfa Bai ◽

Kang Ouyang ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune ◽

Respiratory Syndrome Virus ◽

Adaptive Immune Responses ◽

Virus Growth ◽

Conserved Motif ◽

Adaptive Immune ◽

Infected Cells ◽

Growth Ability

ABSTRACTPorcine reproductive and respiratory syndrome virus (PRRSV) nonstructural protein 1β (nsp1β) is a multifunctional viral protein, which is involved in suppressing the host innate immune response and activating a unique −2/−1 programmed ribosomal frameshifting (PRF) signal for the expression of frameshifting products. In this study, site-directed mutagenesis analysis showed that the R128A or R129A mutation introduced into a highly conserved motif (123GKYLQRRLQ131) reduced the ability of nsp1β to suppress interferon beta (IFN-β) activation and also impaired nsp1β's function as a PRF transactivator. Three recombinant viruses, vR128A, vR129A, and vRR129AA, carrying single or double mutations in the GKYLQRRLQ motif were characterized. In comparison to the wild-type (WT) virus, vR128A and vR129A showed slightly reduced growth abilities, while the vRR129AA mutant had a significantly reduced growth ability in infected cells. Consistent with the attenuated growth phenotypein vitro, pigs infected with nsp1β mutants had lower levels of viremia than did WT virus-infected pigs. Compared to the WT virus in infected cells, all three mutated viruses stimulated high levels of IFN-α expression and exhibited a reduced ability to suppress the mRNA expression of selected interferon-stimulated genes (ISGs). In pigs infected with nsp1β mutants, IFN-α production was increased in the lungs at early time points postinfection, which was correlated with increased innate NK cell function. Furthermore, the augmented innate response was consistent with the increased production of IFN-γ in pigs infected with mutated viruses. These data demonstrate that residues R128 and R129 are critical for nsp1β function and that modifying these key residues in the GKYLQRRLQ motif attenuates virus growth ability and improves the innate and adaptive immune responses in infected animals.IMPORTANCEPRRSV infection induces poor antiviral innate IFN and cytokine responses, which results in weak adaptive immunity. One of the strategies in next-generation vaccine construction is to manipulate viral proteins/genetic elements involved in antagonizing the host immune response. PRRSV nsp1β was identified to be a strong innate immune antagonist. In this study, two basic amino acids, R128 and R129, in a highly conserved GKYLQRRLQ motif were determined to be critical for nsp1β function. Mutations introduced into these two residues attenuated virus growth and improved the innate and adaptive immune responses of infected animals. Technologies developed in this study could be broadly applied to current commercial PRRSV modified live-virus (MLV) vaccines and other candidate vaccines.

Download Full-text

Mathematical modeling and analysis of innate and humoral immune responses to dengue infections

International Journal of Biomathematics ◽

10.1142/s1793524519500773 ◽

2019 ◽

Vol 12 (07) ◽

pp. 1950077 ◽

Cited By ~ 3

Author(s):

Sulanie Perera ◽

S. S. N. Perera

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Steady State ◽

Immune Responses ◽

Dengue Virus ◽

Innate Immune ◽

Virus Dynamics ◽

Quasi Steady State ◽

Humoral Immune ◽

Humoral Immune Responses

Dengue is an acute arthropode-borne virus, belonging to the family Flaviviridae. Currently, there are no vaccines or treatments available against dengue. Thus it is important to understand the dynamics of dengue in order to control the infection. In this paper, we study the long-term dynamics of the model that is presented in [S. D. Perera and S. S. N. Perera, Simulation model for dynamics of dengue with innate and humoral immune responses, Comput. Math. Methods Med. 2018 (2018) 8798057, 18 pp. https://doi.org/10.1155/2018/8798057 ] which describes the interaction of virus with infected and uninfected cells in the presence of innate and humoral immune responses. It was found the model has three equilibria, namely: infection free equilibrium, no immune equilibrium and endemic equilibrium, then analyzed its stability analytically. The analytical findings of each model have been exemplified by numerical simulations. Given the fact that intensity of dengue virus replication at early times of infection could determine clinical outcomes, it is important to understand the impact of innate immunity, which is believed to be the first line of defense against an invading pathogen. For this we carry out a simulation case study to investigate the importance of innate immune response on dengue virus dynamics. A comparison was done assuming that innate immunity was active; innate immunity was in quasi-steady state and innate immunity was inactive during the virus replication process. By a further analysis of the qualitative behavior of the quasi-steady state, it was observed that innate immune response plays a pivotal role in dengue virus dynamics. It can change the dynamical behavior of the system and is essential for the virus clearance.

Download Full-text

Flagellin from Recombinant Attenuated Salmonella enterica Serovar Typhimurium Reveals a Fundamental Role in Chicken Innate Immunity

Clinical and Vaccine Immunology ◽

10.1128/cvi.05569-11 ◽

2012 ◽

Vol 19 (3) ◽

pp. 304-312 ◽

Cited By ~ 6

Author(s):

Zhiming Pan ◽

Qiuxia Cong ◽

Shizhong Geng ◽

Qiang Fang ◽

Xilong Kang ◽

...

Keyword(s):

Innate Immunity ◽

Immune Responses ◽

Salmonella Enterica ◽

Rational Design ◽

Bacterial Load ◽

Innate Immune ◽

Innate Immune Responses ◽

Content Type ◽

Serovar Typhimurium

ABSTRACTRecombinant attenuatedSalmonellavaccines have been extensively studied, with a focus on eliciting specific immune responses against foreign antigens. However, very little is known about the innate immune responses, particularly the role of flagellin, in the induction of innate immunity triggered by recombinant attenuatedSalmonellain chickens. In the present report, we describe twoSalmonella entericaserovar Typhimurium vaccine strains, wild-type (WT) or flagellin-deficient (flhD)Salmonella, both expressing the fusion protein (F) gene of Newcastle disease virus. We examined the bacterial load and spatiotemporal kinetics of expression of inflammatory cytokine, chemokine, and Toll-like receptor 5 (TLR5) genes in the cecum, spleen, liver, and heterophils following oral immunization of chickens with the twoSalmonellastrains. TheflhDmutant exhibited an enhanced ability to establish systemic infection compared to the WT. In contrast, the WT strain induced higher levels of interleukin-1β (IL-1β), CXCLi2, and TLR5 mRNAs in cecum, the spleen, and the heterophils than theflhDmutant at different times postinfection. Collectively, the present data reveal a fundamental role of flagellin in the innate immune responses induced by recombinant attenuatedSalmonellavaccines in chickens that should be considered for the rational design of novel vaccines for poultry.

Download Full-text

An Integrated View of Deubiquitinating Enzymes Involved in Type I Interferon Signaling, Host Defense and Antiviral Activities

Frontiers in Immunology ◽

10.3389/fimmu.2021.742542 ◽

2021 ◽

Vol 12 ◽

Author(s):

Guanghui Qian ◽

Liyan Zhu ◽

Gen Li ◽

Ying Liu ◽

Zimu Zhang ◽

...

Keyword(s):

Immune Responses ◽

Host Defense ◽

Critical Role ◽

Innate Immune ◽

Type I Interferons ◽

Future Perspective ◽

Type I ◽

Virus Infections ◽

Deubiquitinating Enzymes ◽

Antiviral Activities

Viral infectious diseases pose a great challenge to human health around the world. Type I interferons (IFN-Is) function as the first line of host defense and thus play critical roles during virus infection by mediating the transcriptional induction of hundreds of genes. Nevertheless, overactive cytokine immune responses also cause autoimmune diseases, and thus, tight regulation of the innate immune response is needed to achieve viral clearance without causing excessive immune responses. Emerging studies have recently uncovered that the ubiquitin system, particularly deubiquitinating enzymes (DUBs), plays a critical role in regulating innate immune responses. In this review, we highlight recent advances on the diverse mechanisms of human DUBs implicated in IFN-I signaling. These DUBs function dynamically to calibrate host defenses against various virus infections by targeting hub proteins in the IFN-I signaling transduction pathway. We also present a future perspective on the roles of DUB-substrate interaction networks in innate antiviral activities, discuss the promises and challenges of DUB-based drug development, and identify the open questions that remain to be clarified. Our review provides a comprehensive description of DUBs, particularly their differential mechanisms that have evolved in the host to regulate IFN-I-signaling-mediated antiviral responses.

Download Full-text

Integrated role of microRNA-30e-5p through targeting negative regulators of innate immune pathways during HBV infection and SLE

10.1101/2020.02.29.969014 ◽

2020 ◽

Author(s):

Richa Mishra ◽

Sanjana Bhattacharya ◽

Bhupendra S Rawat ◽

Ashish Kumar ◽

Akhilesh Kumar ◽

...

Keyword(s):

Innate Immunity ◽

Mouse Model ◽

Immune Responses ◽

Therapeutic Potential ◽

Innate Immune ◽

Locked Nucleic Acid ◽

Type I ◽

Innate Immune Responses ◽

Negative Regulators

AbstractPrecise regulation of innate immunity is crucial for the development of appropriate host immunity against microbial infections and the maintenance of immune homeostasis. The microRNAs are small non-coding RNA, post-transcriptional regulator of multiple genes and act as a rheostat for protein expression. Here, we identified microRNA(miR)-30e-5p (miR-30e) induced by the hepatitis B virus (HBV) and other viruses that act as a master regulator for innate immune responses. Moreover, pegylated type I interferons treatment to HBV patients for viral reduction also reduces the miRNA. Additionally, we have also shown the immuno-pathological effects of miR-30e in systemic lupus erythematous (SLE) patients and SLE mouse model. Mechanistically, the miR-30e targets multiple negative regulators namely TRIM38, TANK, ATG5, ATG12, BECN1, SOCS1, SOCS3 of innate immune signaling pathways and enhances innate immune responses. Furthermore, sequestering of endogenous miR-30e in PBMCs of SLE patients and SLE mouse model respectively by the introduction of antagomir and locked nucleic acid based inhibitor significantly reduces type I interferon and pro-inflammatory cytokines. Collectively, our study demonstrates the novel role of miR-30e in innate immunity and its prognostic and therapeutic potential in infectious and autoimmune diseases.

Download Full-text