Correction: Type I IFNs facilitate innate immune control of the opportunistic bacteria Burkholderia cenocepacia in the macrophage cytosol

The mammalian immune system is constantly challenged by signals from both pathogenic and non-pathogenic microbes. Many of these non-pathogenic microbes have pathogenic potential if the immune system is compromised. The importance of type I interferons (IFNs) in orchestrating innate immune responses to pathogenic microbes has become clear in recent years. However, the control of opportunistic pathogens–and especially intracellular bacteria–by type I IFNs remains less appreciated. In this study, we use the opportunistic, Gram-negative bacterial pathogen Burkholderia cenocepacia (Bc) to show that type I IFNs are capable of limiting bacterial replication in macrophages, preventing illness in immunocompetent mice. Sustained type I IFN signaling through cytosolic receptors allows for increased expression of autophagy and linear ubiquitination mediators, which slows bacterial replication. Transcriptomic analyses and in vivo studies also show that LPS stimulation does not replicate the conditions of intracellular Gram-negative bacterial infection as it pertains to type I IFN stimulation or signaling. This study highlights the importance of type I IFNs in protection against opportunistic pathogens through innate immunity, without the need for damaging inflammatory responses.

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Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

Journal of Virology ◽

10.1128/jvi.02749-15 ◽

2015 ◽

Vol 90 (5) ◽

pp. 2403-2417 ◽

Cited By ~ 41

Author(s):

Chuan Xia ◽

Madhuvanthi Vijayan ◽

Curtis J. Pritzl ◽

Serge Y. Fuchs ◽

Adrian B. McDermott ◽

...

Keyword(s):

Signaling Pathway ◽

Influenza A Virus ◽

Influenza A ◽

Type I Interferon ◽

Innate Immune ◽

Host Cells ◽

Type I ◽

Type I Ifn ◽

Type I Ifns ◽

Ha Protein

ABSTRACTInfluenza A virus (IAV) employs diverse strategies to circumvent type I interferon (IFN) responses, particularly by inhibiting the synthesis of type I IFNs. However, it is poorly understood if and how IAV regulates the type I IFN receptor (IFNAR)-mediated signaling mode. In this study, we demonstrate that IAV induces the degradation of IFNAR subunit 1 (IFNAR1) to attenuate the type I IFN-induced antiviral signaling pathway. Following infection, the level of IFNAR1 protein, but not mRNA, decreased. Indeed, IFNAR1 was phosphorylated and ubiquitinated by IAV infection, which resulted in IFNAR1 elimination. The transiently overexpressed IFNAR1 displayed antiviral activity by inhibiting virus replication. Importantly, the hemagglutinin (HA) protein of IAV was proved to trigger the ubiquitination of IFNAR1, diminishing the levels of IFNAR1. Further, influenza A viral HA1 subunit, but not HA2 subunit, downregulated IFNAR1. However, viral HA-mediated degradation of IFNAR1 was not caused by the endoplasmic reticulum (ER) stress response. IAV HA robustly reduced cellular sensitivity to type I IFNs, suppressing the activation of STAT1/STAT2 and induction of IFN-stimulated antiviral proteins. Taken together, our findings suggest that IAV HA causes IFNAR1 degradation, which in turn helps the virus escape the powerful innate immune system. Thus, the research elucidated an influenza viral mechanism for eluding the IFNAR signaling pathway, which could provide new insights into the interplay between influenza virus and host innate immunity.IMPORTANCEInfluenza A virus (IAV) infection causes significant morbidity and mortality worldwide and remains a major health concern. When triggered by influenza viral infection, host cells produce type I interferon (IFN) to block viral replication. Although IAV was shown to have diverse strategies to evade this powerful, IFN-mediated antiviral response, it is not well-defined if IAV manipulates the IFN receptor-mediated signaling pathway. Here, we uncovered that influenza viral hemagglutinin (HA) protein causes the degradation of type I IFN receptor subunit 1 (IFNAR1). HA promoted phosphorylation and polyubiquitination of IFNAR1, which facilitated the degradation of this receptor. The HA-mediated elimination of IFNAR1 notably decreased the cells' sensitivities to type I IFNs, as demonstrated by the diminished expression of IFN-induced antiviral genes. This discovery could help us understand how IAV regulates the host innate immune response to create an environment optimized for viral survival in host cells.

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Herpes Simplex Virus 1 UL36USP Antagonizes Type I Interferon-Mediated Antiviral Innate Immunity

Journal of Virology ◽

10.1128/jvi.01161-18 ◽

2018 ◽

Vol 92 (19) ◽

Cited By ~ 14

Author(s):

Hui Yuan ◽

Jia You ◽

Hongjuan You ◽

Chunfu Zheng

Keyword(s):

Innate Immune ◽

Type I ◽

Type I Ifn ◽

Herpes Simplex Virus 1 ◽

Type I Ifns ◽

Specific Protease ◽

Ubiquitin Specific Protease ◽

Simplex Virus ◽

Antiviral Innate Immunity ◽

Hsv 1

ABSTRACT Type I interferons (IFNs), as major components of the innate immune system, play a vital role in host resistance to a variety of pathogens. Canonical signaling mediated by type I IFNs activates the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway through binding to the IFN-α/β receptor (IFNAR), resulting in transcription of IFN-stimulated genes (ISGs). However, viruses have evolved multiple strategies to evade this process. Here, we report that herpes simplex virus 1 (HSV-1) ubiquitin-specific protease (UL36USP) abrogates the type I IFN-mediated signaling pathway independent of its deubiquitinase (DUB) activity. In this study, ectopically expressed UL36USP inhibited IFN-β-induced activation of ISRE promoter and transcription of ISGs, and overexpression of UL36USP lacking DUB activity did not influence this effect. Furthermore, UL36USP was demonstrated to antagonize IFN-β-induced activation of JAKs and STATs via specifically binding to the IFNAR2 subunit and blocking the interaction between JAK1 and IFNAR2. More importantly, knockdown of HSV-1 UL36USP restored the formation of JAK1-IFNAR2 complex. These findings underline the roles of UL36USP-IFNAR2 interaction in counteracting the type I IFN-mediated signaling pathway and reveal a novel evasion mechanism of antiviral innate immunity by HSV-1. IMPORTANCE Type I IFNs mediate transcription of numerous antiviral genes, creating a remarkable antiviral state in the host. Viruses have evolved various mechanisms to evade this response. Our results indicated that HSV-1 encodes a ubiquitin-specific protease (UL36USP) as an antagonist to subvert type I IFN-mediated signaling. UL36USP was identified to significantly inhibit IFN-β-induced signaling independent of its deubiquitinase (DUB) activity. The underlying mechanism of UL36USP antagonizing type I IFN-mediated signaling was to specifically bind with IFNAR2 and disassociate JAK1 from IFNAR2. For the first time, we identify UL36USP as a crucial suppressor for HSV-1 to evade type I IFN-mediated signaling. Our findings also provide new insights into the innate immune evasion by HSV-1 and will facilitate our understanding of host-virus interplay.

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Interleukin-1- and Type I Interferon-Dependent Enhanced Immunogenicity of an NYVAC-HIV-1 Env-Gag-Pol-Nef Vaccine Vector with Dual Deletions of Type I and Type II Interferon-Binding Proteins

Journal of Virology ◽

10.1128/jvi.03061-14 ◽

2015 ◽

Vol 89 (7) ◽

pp. 3819-3832 ◽

Cited By ~ 5

Author(s):

Julie Delaloye ◽

Abdelali Filali-Mouhim ◽

Mark J. Cameron ◽

Elias K. Haddad ◽

Alexandre Harari ◽

...

Keyword(s):

Immune Evasion ◽

Hiv Vaccine ◽

Innate Immune ◽

Vaccine Vector ◽

Type I ◽

Type Ii ◽

Type I Ifns ◽

Attractive Candidate ◽

Immunogenic Properties ◽

Hiv 1

ABSTRACTNYVAC, a highly attenuated, replication-restricted poxvirus, is a safe and immunogenic vaccine vector. Deletion of immune evasion genes from the poxvirus genome is an attractive strategy for improving the immunogenic properties of poxviruses. Using systems biology approaches, we describe herein the enhanced immunological profile of NYVAC vectors expressing the HIV-1 clade Cenv,gag,pol, andnefgenes (NYVAC-C) with single or double deletions of genes encoding type I (ΔB19R) or type II (ΔB8R) interferon (IFN)-binding proteins. Transcriptomic analyses of human monocytes infected with NYVAC-C, NYVAC-C with theB19Rdeletion (NYVAC-C-ΔB19R), or NYVAC-C withB8RandB19Rdeletions (NYVAC-C-ΔB8RB19R) revealed a concerted upregulation of innate immune pathways (IFN-stimulated genes [ISGs]) of increasing magnitude with NYVAC-C-ΔB19R and NYVAC-C-ΔB8RB19R than with NYVAC-C. Deletion ofB8RandB19Rresulted in an enhanced activation of IRF3, IRF7, and STAT1 and the robust production of type I IFNs and of ISGs, whose expression was inhibited by anti-type I IFN antibodies. Interestingly, NYVAC-C-ΔB8RB19R induced the production of much higher levels of proinflammatory cytokines (tumor necrosis factor [TNF], interleukin-6 [IL-6], and IL-8) than NYVAC-C or NYVAC-C-ΔB19R as well as a strong inflammasome response (caspase-1 and IL-1β) in infected monocytes. Top network analyses showed that this broad response mediated by the deletion ofB8RandB19Rwas organized around two upregulated gene expression nodes (TNF and IRF7). Consistent with these findings, monocytes infected with NYVAC-C-ΔB8RB19R induced a stronger type I IFN-dependent and IL-1-dependent allogeneic CD4+T cell response than monocytes infected with NYVAC-C or NYVAC-C-ΔB19R. Dual deletion of type I and type II IFN immune evasion genes in NYVAC markedly enhanced its immunogenic properties via its induction of the increased expression of type I IFNs and IL-1β and make it an attractive candidate HIV vaccine vector.IMPORTANCENYVAC is a replication-deficient poxvirus developed as a vaccine vector against HIV. NYVAC expresses several genes known to impair the host immune defenses by interfering with innate immune receptors, cytokines, or interferons. Given the crucial role played by interferons against viruses, we postulated that targeting the type I and type II decoy receptors used by poxvirus to subvert the host innate immune response would be an attractive approach to improve the immunogenicity of NYVAC vectors. Using systems biology approaches, we report that deletion of type I and type II IFN immune evasion genes in NYVAC poxvirus resulted in the robust expression of type I IFNs and interferon-stimulated genes (ISGs), a strong activation of the inflammasome, and upregulated expression of IL-1β and proinflammatory cytokines. Dual deletion of type I and type II IFN immune evasion genes in NYVAC poxvirus improves its immunogenic profile and makes it an attractive candidate HIV vaccine vector.

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Innate immune sensing of cancer: clues from an identified role for type I IFNs

Cancer Immunology Immunotherapy ◽

10.1007/s00262-012-1305-6 ◽

2012 ◽

Vol 61 (8) ◽

pp. 1343-1347 ◽

Cited By ~ 33

Author(s):

Thomas F. Gajewski ◽

Mercedes B. Fuertes ◽

Seng-Ryong Woo

Keyword(s):

Innate Immune ◽

Type I ◽

Type I Ifns ◽

Immune Sensing ◽

Innate Immune Sensing

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Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral Immune Responses by Suppressing IRF3- and NF-κB-Mediated Transcription

Journal of Virology ◽

10.1128/jvi.00181-19 ◽

2019 ◽

Vol 93 (11) ◽

Cited By ~ 9

Author(s):

Yu-Zhi Fu ◽

Shan Su ◽

Hong-Mei Zou ◽

Yi Guo ◽

Su-Yun Wang ◽

...

Keyword(s):

Immune Responses ◽

Dna Polymerase ◽

Inflammatory Cytokines ◽

Immune Evasion ◽

Innate Immune ◽

Transcriptional Level ◽

Type I ◽

Innate Immune Responses ◽

Type I Ifns ◽

Antiviral Genes

ABSTRACT Innate immunity is the first line of host defense against viral invasion. The induction of type I interferons (IFNs) and inflammatory cytokines is essential to host antiviral immune responses, which are also key targets of viral immune evasion. Human cytomegalovirus (HCMV) can establish long-term latent infections, in which immune evasion is a pivotal step. In this study, we identified HCMV protein UL44, a DNA polymerase processivity factor, as an inhibitor of the interferon regulatory factor 3 (IRF3)- and NF-κB-dependent antiviral response. Ectopic expression of UL44 inhibited HCMV-triggered induction of downstream effector genes and enhanced viral replication. Conversely, knockdown of UL44 potentiated HCMV-triggered induction of downstream antiviral genes. UL44 interacted with IRF3 and p65, and it inhibited the binding of IRF3 and NF-κB to the promoters of their downstream antiviral genes. These findings reveal an important mechanism of immune evasion by HCMV at the transcriptional level. IMPORTANCE Induction of type I IFNs and inflammatory cytokines plays pivotal roles in host antiviral innate immune responses. Viruses have evolved various mechanisms to interfere with these processes. HCMV causes severe ailments in immunodeficient populations and is a major cause of birth defects. It has been shown that HCMV antagonizes host innate immune defenses, which is important for establishing immune evasion and latent infection. In this study, we identified the HCMV DNA polymerase subunit UL44 as a suppressor of antiviral innate immune responses. Overexpression of UL44 impaired HCMV-triggered induction of type I IFNs and other antiviral genes and thus potentiated viral replication, whereas UL44 deficiency showed opposite effects. Mechanistic studies indicated that UL44 acts by inhibiting the binding of IRF3 and NF-κB to the promoters of downstream antiviral genes. These findings defined an important mechanism of HCMV immune evasion at the transcriptional level, which may provide a therapeutic target for the treatment of HCMV infection.

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Absence of Mal/TIRAP Results in Abrogated Imidazoquinolinones-Dependent Activation of IRF7 and Suppressed IFNβ and IFN-I Activated Gene Production

International Journal of Molecular Sciences ◽

10.3390/ijms21238925 ◽

2020 ◽

Vol 21 (23) ◽

pp. 8925

Author(s):

Ewa Leszczyńska ◽

Edyta Makuch ◽

Małgorzata Mitkiewicz ◽

Izabella Jasyk ◽

Miwako Narita ◽

...

Keyword(s):

Immune Response ◽

Transcription Factor ◽

Intracellular Signaling ◽

Innate Immune ◽

Signaling Cascades ◽

Signaling Cascade ◽

Type I ◽

Type I Ifns ◽

Activation Of Transcription ◽

Intracellular Signaling Molecules

Activation of TLR7 by small imidazoquinoline molecules such as R848 or R837 initiates signaling cascades leading to the activation of transcription factors, such as AP-1, NF-κB, and interferon regulatory factors (IRFs) and afterward to the induction of cytokines and anti-viral Type I IFNs. In general, TLRs mediate these effects by utilizing different intracellular signaling molecules, one of them is Mal. Mal is a protein closely related to the antibacterial response, and its role in the TLR7 pathways remains poorly understood. In this study, we show that Mal determines the expression and secretion of IFNβ following activation of TLR7, a receptor that recognizes ssRNA and imidazoquinolines. Moreover, we observed that R848 induces Mal-dependent IFNβ production via ERK1/2 activation as well as the transcription factor IRF7 activation. Although activation of TLR7 leads to NF-κB-dependent expression of IRF7, this process is independent of Mal. We also demonstrate that secretion of IFNβ regulated by TLR7 and Mal in macrophages and dendritic cells leads to the IP-10 chemokine expression. In conclusion, our data demonstrate that Mal is a critical regulator of the imidazoquinolinones-dependent IFNβ production via ERK1/2/IRF7 signaling cascade which brings us closer to understanding the molecular mechanism’s regulation of innate immune response.

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Innate Immune Response to Adenoviral Vectors Is Mediated by both Toll-Like Receptor-Dependent and -Independent Pathways

Journal of Virology ◽

10.1128/jvi.02192-06 ◽

2007 ◽

Vol 81 (7) ◽

pp. 3170-3180 ◽

Cited By ~ 225

Author(s):

Jiangao Zhu ◽

Xiaopei Huang ◽

Yiping Yang

Keyword(s):

Gene Therapy ◽

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Adenoviral Vectors ◽

Innate Immune ◽

Type I ◽

Type I Ifn ◽

Adaptive Immune ◽

Type I Ifns

ABSTRACT Recombinant adenoviral vectors have been widely used for gene therapy applications and as vaccine vehicles for treating infectious diseases such as human immunodeficiency virus disease. The innate immune response to adenoviruses represents the most significant hurdle in clinical application of adenoviral vectors for gene therapy, but it is an attractive feature for vaccine development. How adenovirus activates innate immunity remains largely unknown. Here we showed that adenovirus elicited innate immune response through the induction of high levels of type I interferons (IFNs) by both plasmacytoid dendritic cells (pDCs) and non-pDCs such as conventional DCs and macrophages. The innate immune recognition of adenovirus by pDCs was mediated by Toll-like receptor 9 (TLR9) and was dependent on MyD88, whereas that by non-pDCs was TLR independent through cytosolic sensing of adenoviral DNA. Furthermore, type I IFNs were pivotal in innate and adaptive immune responses to adenovirus in vivo, and type I IFN blockade diminished immune responses, resulting in more stable transgene expression and reduction of inflammation. These findings indicate that adenovirus activates innate immunity by its DNA through TLR-dependent and -independent pathways in a cell type-specific fashion, and they highlight a critical role for type I IFNs in innate and adaptive immune responses to adenoviral vectors. Our results that suggest strategies to interfere with type I IFN pathway may improve the outcome of adenovirus-mediated gene therapy, whereas approaches to activate the type I IFN pathway may enhance vaccine potency.

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Burkholderia cenocepacia Lipopolysaccharide Modification and Flagellin Glycosylation Affect Virulence but Not Innate Immune Recognition in Plants

mBio ◽

10.1128/mbio.00679-15 ◽

2015 ◽

Vol 6 (3) ◽

Cited By ~ 12

Author(s):

Maryam Khodai-Kalaki ◽

Angel Andrade ◽

Yasmine Fathy Mohamed ◽

Miguel A. Valvano

Keyword(s):

Nitric Oxide ◽

Arabidopsis Thaliana ◽

Galleria Mellonella ◽

Opportunistic Infections ◽

Innate Immune ◽

Burkholderia Cenocepacia ◽

Immune Recognition ◽

Content Type ◽

Opportunistic Bacteria ◽

Flagellin Glycosylation

ABSTRACTBurkholderia cenocepaciacauses opportunistic infections in plants, insects, animals, and humans, suggesting that “virulence” depends on the host and its innate susceptibility to infection. We hypothesized that modifications in key bacterial molecules recognized by the innate immune system modulate host responses toB. cenocepacia. Indeed, modification of lipopolysaccharide (LPS) with 4-amino-4-deoxy-l-arabinose and flagellin glycosylation attenuatesB. cenocepaciainfection inArabidopsis thalianaandGalleria mellonellainsect larvae. However,B. cenocepaciaLPS and flagellin triggered rapid bursts of nitric oxide and reactive oxygen species inA. thalianaleading to activation of thePR-1defense gene. These responses were drastically reduced in plants withfls2(flagellin FLS2 host receptor kinase),Atnoa1(nitric oxide-associated protein 1), anddnd1-1(reduced production of nitric oxide) null mutations. Together, our results indicate that LPS modification and flagellin glycosylation do not affect recognition by plant receptors but are required for bacteria to establish overt infection.IMPORTANCEVirulence and pathogenicity are properties ascribed to microbes, which actually require careful consideration of the host. Using the term “pathogen” to define a microbe without considering its host has recently been debated, since the microbe's capacity to establish a niche in a given host is a critical feature associated with infection. Opportunistic bacteria are a perfect example of microbes whose ability to cause disease is intimately related to the host's ability to recognize and respond to the infection. Here, we use the opportunistic bacteriumBurkholderia cenocepaciaand the host plantArabidopsis thalianato investigate the role of bacterial surface molecules, namely, lipopolysaccharide and flagellin, in contributing to infection and also in eliciting a host response. We reveal that both molecules can be modified by glycosylation, and although the modifications are critical for the bacteria to establish an infection, they do not impact the host's ability to recognize the pathogen.

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Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1603269113 ◽

2016 ◽

Vol 113 (24) ◽

pp. E3403-E3412 ◽

Cited By ~ 40

Author(s):

Baoyu Zhao ◽

Chang Shu ◽

Xinsheng Gao ◽

Banumathi Sankaran ◽

Fenglei Du ◽

...

Keyword(s):

Nonstructural Protein ◽

Binding Protein ◽

Adaptor Proteins ◽

Camp Response Element Binding ◽

Innate Immune ◽

Structural Basis ◽

Type I ◽

Creb Binding Protein ◽

Type I Ifns ◽

Nonstructural Protein 1

Type I IFNs are key cytokines mediating innate antiviral immunity. cGMP-AMP synthase, ritinoic acid-inducible protein 1 (RIG-I)–like receptors, and Toll-like receptors recognize microbial double-stranded (ds)DNA, dsRNA, and LPS to induce the expression of type I IFNs. These signaling pathways converge at the recruitment and activation of the transcription factor IRF-3 (IFN regulatory factor 3). The adaptor proteins STING (stimulator of IFN genes), MAVS (mitochondrial antiviral signaling), and TRIF (TIR domain-containing adaptor inducing IFN-β) mediate the recruitment of IRF-3 through a conserved pLxIS motif. Here we show that the pLxIS motif of phosphorylated STING, MAVS, and TRIF binds to IRF-3 in a similar manner, whereas residues upstream of the motif confer specificity. The structure of the IRF-3 phosphomimetic mutant S386/396E bound to the cAMP response element binding protein (CREB)-binding protein reveals that the pLxIS motif also mediates IRF-3 dimerization and activation. Moreover, rotavirus NSP1 (nonstructural protein 1) employs a pLxIS motif to target IRF-3 for degradation, but phosphorylation of NSP1 is not required for its activity. These results suggest a concerted mechanism for the recruitment and activation of IRF-3 that can be subverted by viral proteins to evade innate immune responses.

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