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

2016 ◽  
Vol 90 (7) ◽  
pp. 3584-3599 ◽  
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.

scholarly journals Crosstalk between Dendritic Cells and Immune Modulatory Agents against Sepsis

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 323 ◽  
Author(s):  
Guoying Wang ◽  
Xianghui Li ◽  
Lei Zhang ◽  
Abualgasim Elgaili Abdalla ◽  
Tieshan Teng ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Critical Role ◽  
Innate Immune ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Th2 Responses ◽  
Novel Strategy

Dendritic cells (DCs) play a critical role in the immune system which sense pathogens and present their antigens to prime the adaptive immune responses. As the progression of sepsis occurs, DCs are capable of orchestrating the aberrant innate immune response by sustaining the Th1/Th2 responses that are essential for host survival. Hence, an in-depth understanding of the characteristics of DCs would have a beneficial effect in overcoming the obstacle occurring in sepsis. This paper focuses on the role of DCs in the progression of sepsis and we also discuss the reverse sepsis-induced immunosuppression through manipulating the DC function. In addition, we highlight some potent immunotherapies that could be used as a novel strategy in the early treatment of sepsis.

scholarly journals Systems Immunology Analyses Following Porcine Respiratory and Reproductive Syndrome Virus Infection and Vaccination

2021 ◽  
Vol 12 ◽  
Author(s):  
Loïc Vivien Bocard ◽  
Andrew Robert Kick ◽  
Corinne Hug ◽  
Heidi Erika Lisa Lischer ◽  
Tobias Käser ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Innate Immune ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Cell Responses ◽  
Adaptive Immune

This study was initiated to better understand the nature of innate immune responses and the relatively weak and delayed immune response against porcine reproductive and respiratory syndrome virus (PRRSV). Following modified live virus (MLV) vaccination or infection with two PRRSV-2 strains, we analyzed the transcriptome of peripheral blood mononuclear cells collected before and at three and seven days after vaccination or infection. We used blood transcriptional modules (BTMs)-based gene set enrichment analyses. BTMs related to innate immune processes were upregulated by PRRSV-2 strains but downregulated by MLV. In contrast, BTMs related to adaptive immune responses, in particular T cells and cell cycle, were downregulated by PRRSV-2 but upregulated by MLV. In addition, we found differences between the PRRSV strains. Only the more virulent strain induced a strong platelet activation, dendritic cell activation, interferon type I and plasma cell responses. We also calculated the correlations of BTM with the neutralizing antibody and the T-cell responses. Early downregulation (day 0–3) of dendritic cell and B-cell BTM correlated to both CD4 and CD8 T-cell responses. Furthermore, a late (day 3–7) upregulation of interferon type I modules strongly correlated to helper and regulatory T-cell responses, while inflammatory BTM upregulation correlated more to CD8 T-cell responses. BTM related to T cells had positive correlations at three days but negative associations at seven days post-infection. Taken together, this work contributes to resolve the complexity of the innate and adaptive immune responses against PRRSV and indicates a fundamentally different immune response to the less immunogenic MLV compared to field strains which induced robust adaptive immune responses. The identified correlates of T-cell responses will facilitate a rational approach to improve the immunogenicity of MLV.

scholarly journals Targeted mutations in a highly conserved motif of the nsp1β protein impair the interferon antagonizing activity of porcine reproductive and respiratory syndrome virus

2013 ◽  
Vol 94 (9) ◽  
pp. 1972-1983 ◽  
Author(s):  
Yanhua Li ◽  
Longchao Zhu ◽  
Steven R. Lawson ◽  
Ying Fang
Keyword(s):  
Gene Expression ◽  
Reverse Genetics ◽  
Innate Immune ◽  
Respiratory Syndrome Virus ◽  
Structural Protein ◽  
Virus Growth ◽  
Conserved Motif ◽  
Immune Genes ◽  
Infected Cells

Non-structural protein 1β (nsp1β) of porcine reproductive and respiratory syndrome virus (PRRSV) contains a papain-like cysteine protease (PLPβ) domain and has been identified as the main viral protein antagonizing the host innate immune response. In this study, nsp1β was determined to suppress the expression of reporter genes as well as to suppress ‘self-expression’ in transfected cells, and this activity appeared to be associated with its interferon (IFN) antagonist function. To knock down the effect of nsp1β on IFN activity, a panel of site-specific mutations in nsp1β was analysed. Double mutations K130A/R134A (type 1 PRRSV) or K124A/R128A (type 2 PRRSV) targeting a highly conserved motif of nsp1β, GKYLQRRLQ (in bold), impaired the ability of nsp1β to suppress IFN-β and reporter gene expression, as well as to suppress ‘self-expression’ in vitro. Subsequently, viable recombinant viruses vSD01-08-K130A/R134A and vSD95-21-K124A/R128A, containing double mutations in the GKYLQRRLQ motif were generated using reverse genetics. In comparison with WT viruses, these nsp1β mutants showed impaired growth ability in infected cells, but the PLPβ cleavage function was not directly affected. The expression of selected innate immune genes was determined in vSD95-21-K124A/R128A mutant-infected cells. The results consistently showed that gene expression levels of IFN-α, IFN-β and IFN-stimulated gene 15 were upregulated in cells that were infected with the vSD95-21-K124A/R128A compared with that of WT virus. These data suggest that PRRSV nsp1β may selectively suppress cellular gene expression, including expression of genes involved in the host innate immune function. Modifying the key residues in the highly conserved GKYLQRRLQ motif could attenuate virus growth and improve the cellular innate immune responses.

Chapter 4: Pathogenesis of TBE with a focus on molecular mechanisms

2020 ◽  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Reverse Genetics ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Adaptive Immune Responses ◽  
Knock Out ◽  
Adaptive Immune ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus

In this chapter we describe the pathogenesis of tick-borne encephalitis virus (TBEV). To cause infection, TBEV needs to cross three different barriers; the physical, the innate and adaptive and the blood-brain barrier. The trigger of innate immune and adaptive immune responses, by TBEV is necessary to clear the infection. TBEV employs strategies to evade the innate immune response. Tools to study TBEV pathogenicity such as mouse knock-out models and reverse genetics are also discussed.

New Therapies for Emerging Endotypes of Asthma

2020 ◽  
Vol 71 (1) ◽  
pp. 289-302 ◽  
Author(s):  
Geoffrey Lowell Chupp ◽  
Ravdeep Kaur ◽  
Anne Mainardi
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Allergic Inflammation ◽  
Innate Immune ◽  
Adaptive Immune Responses ◽  
Successful Development ◽  
Adaptive Immune ◽  
Immune Phenotypes ◽  
Personalized Approach

The presentation, pathobiology, and prognosis of asthma are highly heterogeneous and challenging for clinicians to diagnose and treat. In addition to the adaptive immune response that underlies allergic inflammation, innate immune mechanisms are increasingly recognized to be critical mediators of the eosinophilic airway inflammation present in most patients with asthma. Efforts to classify patients by severity and immune response have identified a number of different clinical and immune phenotypes, indicating that the innate and adaptive immune responses are differentially active among patients with the disease. Advances in the detection of these subgroups using clinical characteristics and biomarkers have led to the successful development of targeted biologics. This has moved us to a more personalized approach to managing asthma. Here we review the emerging endotypes of asthma and the biologics that have been developed to treat them.

scholarly journals The Presence of Alpha Interferon at the Time of Infection Alters the Innate and Adaptive Immune Responses to Porcine Reproductive and Respiratory Syndrome Virus

2012 ◽  
Vol 19 (4) ◽  
pp. 508-514 ◽  
Author(s):  
Susan L. Brockmeier ◽  
Crystal L. Loving ◽  
Eric A. Nelson ◽  
Laura C. Miller ◽  
Tracy L. Nicholson ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Alpha Interferon ◽  
Respiratory Syndrome Virus ◽  
Cell Mediated Immunity ◽  
Swine Industry ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Time Of Infection

ABSTRACTPorcine reproductive and respiratory syndrome (PRRS) is one of the most devastating and costly diseases to the swine industry worldwide. Overall, the adaptive immune response to PRRS virus (PRRSV) is weak, which results in delayed elimination of virus from the host and inferior vaccine protection. PRRSV has been shown to induce a meager alpha interferon (IFN-α) response, and we hypothesized that elevated IFN-α levels early in infection would shorten the induction time and increase elements of the adaptive immune response. To test this, we measured both antibody and cell-mediated immunity in pigs after the administration of a nonreplicating human adenovirus type 5 vector expressing porcine IFN-α (Ad5–pIFN-α) at the time of PRRSV infection and compared the results to those for pigs infected with PRRSV alone. Viremia was delayed, and there was a decrease in viral load in the sera of pigs administered the Ad5–pIFN-α. Although seroconversion was slightly delayed in pigs receiving Ad5–pIFN-α, probably due to the early reduction in viral replication, little difference in the overall or neutralizing antibody response was seen. However, there was an increase in the number of virus-specific IFN-γ-secreting cells detected in the pigs receiving Ad5–pIFN-α, as well as an altered cytokine profile in the lung at 14 days postinfection, indicating that the presence of IFN-α at the time of infection can alter innate and adaptive immune responses to PRRSV.

Chapter 4: Pathogenesis of TBE with a focus on molecular mechanisms

2019 ◽  
Author(s):  
Andrea Kröger ◽  
Anna K. Överby
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Reverse Genetics ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Adaptive Immune Responses ◽  
Knock Out ◽  
Adaptive Immune ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus

• In this chapter we describe the pathogenesis of tick-borne encephalitis virus (TBEV). • To cause infection, TBEV needs to cross three different barriers; the physical, the innate and adaptive, and the blood-brain barrier. • The trigger of innate immune and adaptive immune responses, by TBEV is necessary to clear the infection. • TBEV employs strategies to evade the innate immune response. • Tools to study TBEV pathogenicity such as mouse knock-out models and reverse genetics are also discussed.

Chapter 4: Pathogenesis of TBE with a focus on molecular mechanisms

2021 ◽  
Author(s):  
Andrea Kröger ◽  
Anna K Överby
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Reverse Genetics ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Adaptive Immune Responses ◽  
Knock Out ◽  
Adaptive Immune ◽  
Tick Borne Encephalitis ◽  
Tick Borne Encephalitis Virus

In this chapter we describe the pathogenesis of tick-borne encephalitis virus (TBEV). To cause infection, TBEV needs to cross three different barriers; the physical, the innate and adaptive and the blood-brain barrier. The trigger of innate immune and adaptive immune responses, by TBEV is necessary to clear the infection. TBEV employs strategies to evade the innate immune response. Tools to study TBEV pathogenicity such as mouse knock-out models and reverse genetics are also discussed.

scholarly journals RIG-I and MDA5 Protect Mice From Pichinde Virus Infection by Controlling Viral Replication and Regulating Immune Responses to the Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Morgan Brisse ◽  
Qinfeng Huang ◽  
Mizanur Rahman ◽  
Da Di ◽  
Yuying Liang ◽  
...  
Keyword(s):  
Virus Infection ◽  
Immune Responses ◽  
Innate Immune ◽  
Double Knockout ◽  
Adaptive Immune Responses ◽  
Pichinde Virus ◽  
Adaptive Immune ◽  
Control Virus ◽  
In The Wild ◽  
Sensor Proteins

RIG-I and MDA5 are major cytoplasmic innate-immune sensor proteins that recognize aberrant double-stranded RNAs generated during virus infection to activate type 1 interferon (IFN-I) and IFN-stimulated gene (ISG) expressions to control virus infection. The roles of RIG-I and MDA5 in controlling replication of Pichinde virus (PICV), a mammarenavirus, in mice have not been examined. Here, we showed that MDA5 single knockout (SKO) and RIG-I/MDA5 double knockout (DKO) mice are highly susceptible to PICV infection as evidenced by their significant reduction in body weights during the course of the infection, validating the important roles of these innate-immune sensor proteins in controlling PICV infection. Compared to the wildtype mice, SKO and DKO mice infected with PICV had significantly higher virus titers and lower IFN-I expressions early in the infection but appeared to exhibit a late and heightened level of adaptive immune responses to clear the infection. When a recombinant rPICV mutant virus (rPICV-NPmut) that lacks the ability to suppress IFN-I was used to infect mice, as expected, there were heightened levels of IFN-I and ISG expressions in the wild-type mice, whereas infected SKO and DKO mice showed delayed mouse growth kinetics and relatively low, delayed, and transient levels of innate and adaptive immune responses to this viral infection. Taken together, our data suggest that PICV infection triggers activation of immune sensors that include but might not be necessarily limited to RIG-I and MDA5 to stimulate effective innate and adaptive immune responses to control virus infection in mice.

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