scholarly journals Impact of Měnglà virus proteins on human and bat innate immune pathways

2019 ◽  
Author(s):  
Caroline G. Williams ◽  
Joyce Sweeney Gibbons ◽  
Timothy R. Keiffer ◽  
Priya Luthra ◽  
Megan R. Edwards ◽  
...  
Keyword(s):  
Gene Expression ◽  
Marburg Virus ◽  
Innate Immune ◽  
Host Protein ◽  
Binding Motif ◽  
Type I ◽  
Type I Ifn ◽  
Promoter Activation ◽  
The Family ◽  
Immune Pathways

AbstractMěnglà virus (MLAV), identified inRousettusbats, is a phylogenetically distinct member of the familyFiloviridae. Because filoviruses Ebola virus (EBOV) and Marburg virus (MARV) modulate host innate immune pathways, MLAV VP35, VP40 and VP24 proteins were compared with their EBOV and MARV homologs for innate immune pathway modulation. In human andRousettuscells, MLAV VP35 behaved like EBOV and MARV VP35s, inhibiting virus-induced activation of the interferon (IFN)-β promoter. MLAV VP35 inhibited IRF3 phosphorylation and interacted with PACT, a host protein engaged by EBOV VP35 to inhibit RIG-I signaling. MLAV VP35 also inhibited PKR activation. MLAV VP40 was demonstrated to inhibit type I IFN induced gene expression in human and bat cells. It blocked STAT1 tyrosine phosphorylation induced either by type I IFN or over-expressed Jak1, paralleling MARV VP40. MLAV VP40 also inhibited virus-induced IFNβ promoter activation, a property shared by MARV VP40 and EBOV VP24. The inhibition of IFN induction was preserved in the presence of a Jak kinase inhibitor, demonstrating that inhibition of Jak-STAT signaling is not sufficient to explain inhibition of IFNβ promoter activation. MLAV VP24 did not inhibit IFN-induced gene expression or bind karyopherin α5, properties of EBOV VP24. MLAV VP24 also differed from MARV VP24 in that it failed to interact with Keap1 or activate an antioxidant response element reporter gene, due to the absence of a Keap1-binding motif. These studies demonstrate similarities between MLAV and MARV in how they suppress IFN responses and differences in how MLAV VP24 interacts with host pathways.ImportanceEBOV and MARV, members of the familyFiloviridae, are highly pathogenic zoonotic viruses that cause severe disease in humans. Both viruses use several mechanisms to modulate the host innate immune response, and these likely contribute to severity of disease. Here, we demonstrate that MLAV, a filovirus newly discovered in a bat, suppresses antiviral type I interferon responses in both human and bat cells. Inhibitory activities are possessed by MLAV VP35 and VP40, which parallels how MARV blocks IFN responses. However, whereas MARV activates cellular antioxidant responses through an interaction between its VP24 protein and host protein Keap1, MLAV VP24 lacks a Keap1 binding motif and fails to activate this cytoprotective response. These data indicate that MLAV possesses immune suppressing functions that could facilitate human infection. They also demonstrate key differences in MLAV versus either EBOV or MARV engagement of host signaling pathways.

scholarly journals Impact of Měnglà Virus Proteins on Human and Bat Innate Immune Pathways

2020 ◽  
Vol 94 (13) ◽  
Author(s):  
Caroline G. Williams ◽  
Joyce Sweeney Gibbons ◽  
Timothy R. Keiffer ◽  
Priya Luthra ◽  
Megan R. Edwards ◽  
...  
Keyword(s):  
Gene Expression ◽  
Kinase Inhibitor ◽  
Marburg Virus ◽  
Innate Immune ◽  
Host Protein ◽  
Binding Motif ◽  
Type I ◽  
Type I Ifn ◽  
Promoter Activation ◽  
The Family

ABSTRACT Měnglà virus (MLAV), identified in Rousettus bats, is a phylogenetically distinct member of the family Filoviridae. Because the filoviruses Ebola virus (EBOV) and Marburg virus (MARV) modulate host innate immunity, MLAV VP35, VP40, and VP24 proteins were compared with their EBOV and MARV homologs for innate immune pathway modulation. In human and Rousettus cells, MLAV VP35 behaved like EBOV and MARV VP35s, inhibiting virus-induced activation of the interferon beta (IFN-β) promoter and interferon regulatory factor 3 (IRF3) phosphorylation. MLAV VP35 also interacted with PACT, a host protein engaged by EBOV VP35 to inhibit RIG-I signaling. MLAV VP35 also inhibits PKR activation. MLAV VP40 was demonstrated to inhibit type I IFN-induced gene expression in human and bat cells. It blocked STAT1 tyrosine phosphorylation induced either by type I IFN or overexpressed Jak1, paralleling MARV VP40. MLAV VP40 also inhibited virus-induced IFN-β promoter activation, a property shared by MARV VP40 and EBOV VP24. A Jak kinase inhibitor did not recapitulate this inhibition in the absence of viral proteins. Therefore, inhibition of Jak-STAT signaling is insufficient to explain inhibition of IFN-β promoter activation. MLAV VP24 did not inhibit IFN-induced gene expression or bind karyopherin α proteins, properties of EBOV VP24. MLAV VP24 differed from MARV VP24 in that it failed to interact with Keap1 or activate an antioxidant response element reporter gene due to the absence of a Keap1-binding motif. These functional observations support a closer relationship of MLAV to MARV than to EBOV but also are consistent with MLAV belonging to a distinct genus. IMPORTANCE EBOV and MARV, members of the family Filoviridae, are highly pathogenic zoonotic viruses that cause severe disease in humans. Both viruses use several mechanisms to modulate the host innate immune response, and these likely contribute to the severity of disease. Here, we demonstrate that MLAV, a filovirus newly discovered in a bat, suppresses antiviral type I interferon responses in both human and bat cells. Inhibitory activities are possessed by MLAV VP35 and VP40, which parallels how MARV blocks IFN responses. However, whereas MARV activates cellular antioxidant responses through an interaction between its VP24 protein and host protein Keap1, MLAV VP24 lacks a Keap1-binding motif and fails to activate this cytoprotective response. These data indicate that MLAV possesses immune-suppressing functions that could facilitate human infection. They also support the placement of MLAV in a different genus than either EBOV or MARV.

scholarly journals HIV blocks Type I IFN signaling through disruption of STAT1 phosphorylation

2018 ◽  
Vol 24 (8) ◽  
pp. 490-500 ◽  
Author(s):  
Nam V Nguyen ◽  
James T Tran ◽  
David Jesse Sanchez
Keyword(s):  
Gene Expression ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Antiviral State ◽  
Receptor Signaling Pathway ◽  
Multiple Signaling ◽  
Inducible Gene ◽  
Stat Pathway

This study investigates the modulation of Type I IFN induction of an antiviral state by HIV. IFNs, including IFN-α, are key innate immune cytokines that activate the JAK/STAT pathway leading to the expression of IFN-stimulated genes. IFN-stimulated gene expression establishes the antiviral state, limiting viral infection in IFN-α-stimulated microenvironments. Our previous studies have shown that HIV proteins disrupt the induction of IFN-α by degradation of IFN-β promoter stimulator-1, an adaptor protein for the up-regulation and release of IFN-α into the local microenvironment via the retinoic acid-inducible gene 1-like receptor signaling pathway. However, IFN-α is still released from other sources such as plasmacytoid dendritic cells via TLR-dependent recognition of HIV. Here we report that the activation of the JAK/STAT pathway by IFN-α stimulation is disrupted by HIV proteins Vpu and Nef, which both reduce IFN-α induction of STAT1 phosphorylation. Thus, HIV would still be able to avoid antiviral protection induced by IFN-α in the local microenvironment. These findings show that HIV blocks multiple signaling points that would lead to the up-regulation of IFN-stimulated genes, allowing more effective replication in IFN-α-rich environments.

Type-I IFN promotes humoral immunity in viral vector vaccination

2021 ◽  
Author(s):  
Chaojie Zhong ◽  
Fengliang Liu ◽  
Renee J. Hajnik ◽  
Lei Yao ◽  
Kangjing Chen ◽  
...  
Keyword(s):  
Humoral Immunity ◽  
Viral Vectors ◽  
Vaccine Development ◽  
Viral Vector ◽  
T Cell Response ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Type I ◽  
Type I Ifn ◽  
Immune Pathways

Recombinant viral vectors are an important platform for vaccine delivery. Our recent study has demonstrated distinct innate immune profiles in responding to viral vectors of different families (e.g., adenovirus vs. poxvirus): while human Ad5 vector is minimally innate immune stimulatory, the poxviral vector ALVAC induces strong innate response and stimulates type-I IFN and inflammasome activation. However, impact of the innate immune signaling on vaccine-induced adaptive immunity in viral vector vaccination is less clear. Here, we showed that Modified Vaccinia Ankara (MVA), another poxviral vector, stimulated type-I IFN response in innate immune cells through cGAS-STING. Using MVA-HIV vaccine as a model, we found that type-I IFN signaling promoted the generation of humoral immunity in MVA-HIV vaccination in vivo . Following vaccination, type-I IFN receptor knockout (IFNAR1-/-) mice produced significantly lower levels of total and HIV gp120-specific antibodies compared to the wild-type (WT) mice. Consistent with the antibody response, type-I IFN signaling deficiency also led to reduced levels of plasma cells and memory-like B cells compared to those in WT mice. Furthermore, analysis of vaccine-induced CD4 T cells showed that type-I IFN signaling also promoted the generation of vaccine-specific CD4 T-cell response and T follicular helper (Tfh) response in mice. Together, our data indicate a role of type-I IFN signaling in promoting humoral immunity in poxviral vector vaccination. The study suggests that modulating type-I IFN and its associated innate immune pathways will likely affect vaccine efficacy. IMPORTANCE Viral vectors, including MVA, are an important antigen delivery platform and have been commonly used in vaccine development. Understanding the innate host-viral vector interactions and its impact on vaccine-induced immunity is critical but understudied. Using MVA-HIV vaccination of WT and IFNAR1-/- mice as a model, our study reports that type-I IFN signaling promotes humoral immunity in MVA vaccination, including vaccine-induced antibody, B-cell, and Tfh responses. Findings of the present study provide insights not only for basic understanding of host-viral vector interactions, but also for improving vaccine design by potentially modulating type-I IFN and its associated innate immune pathways in viral vector vaccination.

Upregulation of Interferon-Inducible and Damage Response Receptors in Chronic Graft-Versus-Host Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 922-922 ◽  
Author(s):  
Frances T. Hakim ◽  
Sarfraz Memon ◽  
Ping Jin ◽  
Matin M. Imanguli ◽  
Najibah Rehman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Innate Immune ◽  
Cellular Damage ◽  
Type I ◽  
Type I Ifn ◽  
Graft Versus Host ◽  
Damage Response ◽  
Time Courses ◽  
Inducible Genes ◽  
Normal Controls

Abstract Chronic Graft Versus Host Disease (CGVHD) remains the main source of non-relapse mortality and morbidity among recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although our lab and others have identified infiltrates of Th1/Tc1 and Th17 effectors in skin and oral mucosa, CGVHD targets multiple organs and no common factor or pathway has been demonstrated to reflect the broad range of CGVHD inflammatory and fibrotic manifestations. To identify the systemic cytokine pathways supporting the development and persistence of CGVHD, we chose to profile gene expression in circulating monocytes; monocytes up-regulate distinct patterns of gene expression in response to different cytokines, acting as in situ reporters. The NIH Natural History Study of CGVHD (NCT00092235) has primarily enrolled moderate to severely affected patients. Microarray analysis was performed on sorted monocytes from 10 normal controls (ND) and 26 patients selected from this cohort based on severe cutaneous involvement. Two interrelated pathways, each containing multiple genes, were consistently up-regulated across a cutaneous CGHVD spectrum ranging from lichenoid infiltrates to extensive sclerosis: (1) Interferon (IFN)-inducible genes including those involved in signaling, lymphocyte homeostasis and trafficking, apoptosis and antigen uptake and presentation (STAT1, CXCL10, TNFSF13B, TNFSF10, TAP1), and (2) innate immune receptors for pathogens and cellular damage that can trigger IFN production and inflammasome assembly (TLR2, TLR4, TLR7, AIM2, DDX58, CLEC4E). Using multiplex RNA gene expression assays (Nanostring) to verify these pathways, we found significant up-regulation of IFN-inducible and damage-response genes in 69 CGVHD patients with a broad range of organ involvement, as compared with 14 allo-HSCT patients never developing CGVHD, or with 19 normal controls (Figure 1A, B). These pathways were further substantiated in plasma ELISA assays showing elevated levels of IFN-induced chemokines (CXCL9, CXCL10) in both lichenoid and severe sclerotic patients. Immunohistochemistry substantiated expression of Type I IFN-induced factors (MxA) in inflammatory infiltrates in CGVHD-targeted organs: lichenoid and sclerotic skin, oral mucosa and salivary gland. Consistent with induction of Type I IFN by activation of TLR and RIG-I receptors, levels of expression of DDX58 and TLR7 correlated with up-regulation of Type I IFN inducible genes (OAS1, IFIT1, XAF1). Finally, multiplex RNA assessments on monocytes collected from 18 patients over serial time courses following NCI allo-HSCT protocols (NCT00520130 and NCT00074490) substantiated a pattern of parallel up-regulation of multiple IFN-inducible and damage responsive genes at CGVHD onset, and of decline upon therapy and resolution (Figure 1C). A key point is that comparable up-regulation of these pathways was found in patients with extensive lichenoid or sclerotic CGVHD, both in the established CGVHD patients in the initial microarray and in the serial time courses of CGVHD development. These results support a model that IFN and inflammasome activation induced by the innate immune systemÕs response to damage initiates an inflammatory process in CGVHD; IFN then can induce damage receptors, chemokines, cytokines and enhanced antigen presentation that sustain CGVHD. These interlocking analyses of gene expression patterns, plasma analytes and tissue are the first to support a unifying hypothesis of induction of IFN by innate response to cellular damage as a mechanism for initiation and persistence of CGVHD. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cellular nucleic acid–binding protein is essential for type I interferon–mediated immunity to RNA virus infection

2021 ◽  
Vol 118 (26) ◽  
pp. e2100383118
Author(s):  
Yongzhi Chen ◽  
Xuqiu Lei ◽  
Zhaozhao Jiang ◽  
Katherine A. Fitzgerald
Keyword(s):  
Gene Expression ◽  
Nucleic Acid ◽  
Virus Infection ◽  
Rna Virus ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Nucleic Acid Binding ◽  
Nucleic Acid Binding Protein ◽  
Acid Binding Protein

Type I interferons (IFNs) are innate immune cytokines required to establish cellular host defense. Precise control of IFN gene expression is crucial to maintaining immune homeostasis. Here, we demonstrated that cellular nucleic acid–binding protein (CNBP) was required for the production of type I IFNs in response to RNA virus infection. CNBP deficiency markedly impaired IFN production in macrophages and dendritic cells that were infected with a panel of RNA viruses or stimulated with synthetic double-stranded RNA. Furthermore, CNBP-deficient mice were more susceptible to influenza virus infection than were wild-type mice. Mechanistically, CNBP was phosphorylated and translocated to the nucleus, where it directly binds to the promoter of IFNb in response to RNA virus infection. Furthermore, CNBP controlled the recruitment of IFN regulatory factor (IRF) 3 and IRF7 to IFN promoters for the maximal induction of IFNb gene expression. These studies reveal a previously unrecognized role for CNBP as a transcriptional regulator of type I IFN genes engaged downstream of RNA virus–mediated innate immune signaling, which provides an additional layer of control for IRF3- and IRF7-dependent type I IFN gene expression and the antiviral innate immune response.

scholarly journals Role of the Innate Immunity Signaling Pathway in the Pathogenesis of Sjögren’s Syndrome

2021 ◽  
Vol 22 (6) ◽  
pp. 3090
Author(s):  
Toshimasa Shimizu ◽  
Hideki Nakamura ◽  
Atsushi Kawakami
Keyword(s):  
Immune Responses ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Adaptive Immune ◽  
Sjögren‘S Syndrome

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of the salivary and lacrimal glands and extra-glandular lesions. Adaptive immune response including T- and B-cell activation contributes to the development of SS. However, its pathogenesis has not yet been elucidated. In addition, several patients with SS present with the type I interferon (IFN) signature, which is the upregulation of the IFN-stimulated genes induced by type I IFN. Thus, innate immune responses including type I IFN activity are associated with SS pathogenesis. Recent studies have revealed the presence of activation pattern recognition receptors (PRRs) including Toll-like receptors, RNA sensor retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, and inflammasomes in infiltrating and epithelial cells of the salivary glands among patients with SS. In addition, the activation of PRRs via the downstream pathway such as the type I IFN signature and nuclear factor kappa B can directly cause organ inflammation, and it is correlated with the activation of adaptive immune responses. Therefore, this study assessed the role of the innate immune signal pathway in the development of inflammation and immune abnormalities in SS.

Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING

2017 ◽  
Vol 31 (7) ◽  
pp. 3107-3115 ◽  
Author(s):  
Christine Rueckert ◽  
Ulfert Rand ◽  
Urmi Roy ◽  
Bahram Kasmapour ◽  
Till Strowig ◽  
...  
Keyword(s):  
Immune Cells ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Cells ◽  
Type I Ifn ◽  
Cyclic Dinucleotides

scholarly journals Arterivirus nsp4 Antagonizes Interferon Beta Production by Proteolytically Cleaving NEMO at Multiple Sites

2019 ◽  
Vol 93 (12) ◽  
Author(s):  
Jiyao Chen ◽  
Dang Wang ◽  
Zheng Sun ◽  
Li Gao ◽  
Xinyu Zhu ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Interferon Beta ◽  
Substrate Recognition ◽  
Innate Immune ◽  
Equine Arteritis Virus ◽  
Single Site ◽  
Respiratory Syndrome Virus ◽  
Type I ◽  
Type I Ifn ◽  
Recognition Mechanism

ABSTRACTEquine arteritis virus (EAV) and porcine reproductive and respiratory syndrome virus (PRRSV) represent two members of the familyArteriviridaeand pose major threats for the horse- and swine-breeding industries worldwide. A previous study suggested that PRRSV nsp4, a 3C-like protease, antagonizes interferon beta (IFN-β) production by cleaving the NF-κB essential modulator (NEMO) at a single site, glutamate 349 (E349). Here, we demonstrated that EAV nsp4 also inhibited virus-induced IFN-β production by targeting NEMO for proteolytic cleavage and that the scission occurred at four sites: E166, E171, glutamine 205 (Q205), and E349. Additionally, we found that, besides the previously reported cleavage site E349 in NEMO, scission by PRRSV nsp4 took place at two additional sites, E166 and E171. These results imply that while cleaving NEMO is a common strategy utilized by EAV and PRRSV nsp4 to antagonize IFN induction, EAV nsp4 adopts a more complex substrate recognition mechanism to target NEMO. By analyzing the abilities of the eight different NEMO fragments resulting from EAV or PRRSV nsp4 scission to induce IFN-β production, we serendipitously found that a NEMO fragment (residues 1 to 349) could activate IFN-β transcription more robustly than full-length NEMO, whereas all other NEMO cleavage products were abrogated for the IFN-β-inducing capacity. Thus, NEMO cleavage at E349 alone may not be sufficient to completely inactivate the IFN response via this signaling adaptor. Altogether, our findings suggest that EAV and PRRSV nsp4 cleave NEMO at multiple sites and that this strategy is critical for disarming the innate immune response for viral survival.IMPORTANCEThe arterivirus nsp4-encoded 3C-like protease (3CLpro) plays an important role in virus replication and immune evasion, making it an attractive target for antiviral therapeutics. Previous work suggested that PRRSV nsp4 suppresses type I IFN production by cleaving NEMO at a single site. In contrast, the present study demonstrates that both EAV and PRRSV nsp4 cleave NEMO at multiple sites and that this strategy is essential for disruption of type I IFN production. Moreover, we reveal that EAV nsp4 also cleaves NEMO at glutamine 205 (Q205), which is not targeted by PRRSV nsp4. Notably, targeting a glutamine in NEMO for cleavage has been observed only with picornavirus 3C proteases (3Cpro) and coronavirus 3CLpro. In aggregate, our work expands knowledge of the innate immune evasion mechanisms associated with NEMO cleavage by arterivirus nsp4 and describes a novel substrate recognition characteristic of EAV nsp4.

scholarly journals Differential Immune Responses to Hemorrhagic Fever-Causing Arenaviruses

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 138 ◽  
Author(s):  
Mantlo ◽  
Paessler ◽  
Huang
Keyword(s):  
Clinical Importance ◽  
Hemorrhagic Fever ◽  
Lassa Fever ◽  
Innate Immune ◽  
Host Immune System ◽  
Lassa Virus ◽  
Type I ◽  
Highly Pathogenic ◽  
The Family ◽  
Pro Inflammatory Cytokines

The family Arenaviridae contains several pathogens of major clinical importance. The Old World (OW) arenavirus Lassa virus is endemic in West Africa and is estimated to cause up to 300,000 infections each year. The New World (NW) arenaviruses Junín and Machupo periodically cause hemorrhagic fever outbreaks in South America. While these arenaviruses are highly pathogenic in humans, recent evidence indicates that pathogenic OW and NW arenaviruses interact with the host immune system differently, which may have differential impacts on viral pathogenesis. Severe Lassa fever cases are characterized by profound immunosuppression. In contrast, pathogenic NW arenavirus infections are accompanied by elevated levels of Type I interferon and pro-inflammatory cytokines. This review aims to summarize recent findings about interactions of these pathogenic arenaviruses with the innate immune machinery and the subsequent effects on adaptive immunity, which may inform the development of vaccines and therapeutics against arenavirus infections.

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