Interferons Reshape the 3D Conformation and Accessibility of Macrophage Chromatin

AbstractEngagement of macrophages in innate immune responses is directed and enhanced by type I and type II interferons. An essential component of IFN activity is the use of JAK-STAT signal transduction for the transcriptional control of interferon-stimulated genes (ISG). Here, we study the immediate early nuclear response to type I IFN and IFN-γ in murine macrophages. Despite their distinct immunological activities, both IFN types triggered highly overlapping epigenomic and transcriptional changes. These changes included a rapid rearrangement of the 3D chromatin organization and an increase of DNA accessibility at ISG loci. ISGF3, the major transcriptional regulator of ISG, controlled homeostatic as well as induced-state DNA accessibility at a subset of ISG. Increases in DNA accessibility correlated with the appearance of activating histone marks at surrounding nucleosomes. Collectively our data emphasize changes in the three-dimensional nuclear space and epigenome as an important facet of transcriptional control by the IFN-induced JAK-STAT pathway.

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Baculovirus-inducing fast-acting innate immunity kills Plasmodium liver stages

10.1101/320036 ◽

2018 ◽

Cited By ~ 1

Author(s):

Talha Bin Emran ◽

Mitsuhiro Iyori ◽

Yuki Ono ◽

Fitri Amelia ◽

Yenni Yusuf ◽

...

Keyword(s):

Mammalian Cells ◽

Type I ◽

Innate Immune Responses ◽

Independent Manner ◽

Liver Stage ◽

Interferon Stimulated Genes ◽

Rna Transcripts ◽

Double Stranded Dna ◽

Further Development

ABSTRACTBaculovirus (BV), an enveloped insect virus with a circular double-stranded DNA genome, possesses unique characteristics that induce strong innate immune responses in mammalian cells. Here, we show that BV administration not only sterilely protects BALB/c mice for at least 7 days from subsequent Plasmodium berghei sporozoite infection but also eliminates existing liver-stage parasites completely, effects superior to those of primaquine, and does so in a TLR9-independent manner. Six hours post-BV administration, IFN-α and IFN-γ were robustly produced in serum, and RNA transcripts of interferon-stimulated genes were drastically upregulated in the liver. The in vivo passive transfer of post-BV administration serum effectively eliminated liver-stage parasites, and IFN-α neutralization abolished this effect, indicating that the BV liver-stage parasite killing mechanism is downstream of the type I IFN signaling pathway. Our results demonstrate that BV is a potent IFN-inducing prophylactic and therapeutic agent with great potential for further development as a new malaria vaccine and/or anti-hypnozoite drug.

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Cell-based screen identifies human type I interferon-stimulated regulators of Toxoplasma gondii Infection

10.1101/2022.01.02.474728 ◽

2022 ◽

Author(s):

Anton Gossner ◽

Anna Raper ◽

Musa A Hassan

Keyword(s):

Host Cells ◽

Rapid Screening ◽

Human Macrophage ◽

Type I ◽

Loss Of Function ◽

Macrophage Response ◽

Interferon Stimulated Genes ◽

Type I Ifns ◽

Transcriptional Changes ◽

Toxoplasma Gondii Infection

Macrophages activated with interferons (IFNs) respond with transcriptional changes that enhance clearance of intracellular pathogens such as Toxoplasma, a ubiquitous apicomplexan parasite that infects more than a billion people worldwide. Although IFNs generally inhibit Toxoplasma, the parasite can also induce components of the host IFN signalling pathway to enhance survival in host cells. Compared to the type II IFN gamma (IFNγ), the role of type I IFNs in macrophage response to Toxoplasma is relatively not well characterized. Here, using fluorescent Toxoplasma and a CRISPR/Cas9 knockout library that only targets interferon-stimulated genes (ISGs), we adapted a loss-of-function flow cytometry-based approach to systematically identify type I ISGs that control Toxoplasma growth in THP-1 cells, a human macrophage cell line. The system enabled the rapid screening of more than 1900 ISGs for type I (IFNα)-induced inhibitors and enhancers of Toxoplasma growth in THP-1 cells. We identified 26 genes that are associated with Toxoplasma growth arrest out of which we confirmed MAX, SNX5, F2RL2, and SSB, as potent IFNα-induced inhibitors of Toxoplasma in THP1 cells. These findings provide a genetic and experimental roadmap to elucidate type I IFN-induced cell-autonomous responses to Toxoplasma.

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Type I and III IFNs produced by the nasal epithelia and dimmed inflammation are key features of alpacas resolving MERS-CoV infection

10.1101/2020.11.23.395301 ◽

2020 ◽

Author(s):

Nigeer Te ◽

Jordi Rodon ◽

Maria Ballester ◽

Mónica Pérez ◽

Lola Pailler-García ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Nasal Mucosa ◽

Inflammatory Cytokine ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Interferon Stimulated Genes ◽

Anti Inflammatory ◽

Anti Inflammatory Cytokine

ABSTRACTWhile MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, provoking the induction of interferon stimulated genes (ISGs) along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, is central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.IMPORTANCEMiddle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a respiratory disease causing high mortality in humans. In camelids, the main MERS-CoV reservoir host, viral infection leads to subclinical disease. Our study describes transcriptional regulations of innate immunological pathways underlying asymptomatic clinical manifestations of alpacas in response to MERS-CoV. Concomitant to the peak of infection, these animals elicited a strong transient interferon response and induction of the anti-inflammatory cytokine IL10 in the nasal mucosa. This was associated to a dimmed regulation of pro-inflammatory cytokines and induction of interferon stimulated genes along the whole respiratory mucosa, leading to the rapid clearance of the virus. Thus, innate immune responses occurring in the nasal mucosa appear to be the key in controlling MERS-CoV disease by avoiding a cytokine storm. Understanding on how asymptomatic host reservoirs counteract MERS-CoV infection will aid in the development of antiviral drugs and vaccines.

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Type I and III IFNs produced by the nasal epithelia and dimmed inflammation are key features of alpacas resolving MERS-CoV infection

10.1101/2020.12.22.423939 ◽

2020 ◽

Author(s):

Nigeer Te ◽

Jordi Rodon ◽

Maria Ballester ◽

Mónica Pérez ◽

Lola Pailler-García ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Nasal Mucosa ◽

Inflammatory Cytokine ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Interferon Stimulated Genes ◽

Anti Inflammatory ◽

Anti Inflammatory Cytokine

AbstractWhile MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, provoking the induction of interferon stimulated genes (ISGs) along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, is central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.Author summaryMiddle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a respiratory disease causing high mortality in humans. In camelids, the main MERS-CoV reservoir host, viral infection leads to subclinical disease. Our study describes transcriptional regulations of innate immunological pathways underlying asymptomatic clinical manifestations of alpacas in response to MERS-CoV. Concomitant to the peak of infection, these animals elicited a strong transient interferon response and induction of the anti-inflammatory cytokine IL10 in the nasal mucosa. This was associated to a dimmed regulation of pro-inflammatory cytokines and induction of interferon stimulated genes along the whole respiratory mucosa, leading to the rapid clearance of the virus. Thus, innate immune responses occurring in the nasal mucosa appear to be the key in controlling MERS-CoV disease by avoiding a cytokine storm. Understanding on how asymptomatic host reservoirs counteract MERS-CoV infection will aid in the development of antiviral drugs and vaccines.

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Immunization with Attenuated Equine Herpesvirus 1 Strain KyA Induces Innate Immune Responses That Protect Mice from Lethal Challenge

Journal of Virology ◽

10.1128/jvi.00986-16 ◽

2016 ◽

Vol 90 (18) ◽

pp. 8090-8104 ◽

Cited By ~ 3

Author(s):

Seong K. Kim ◽

Akhalesh K. Shakya ◽

Dennis J. O'Callaghan

Keyword(s):

Immune Responses ◽

Alveolar Macrophages ◽

Innate Immune ◽

Equine Herpesvirus ◽

Innate Immune Responses ◽

Lethal Challenge ◽

Equine Herpesvirus 1 ◽

Interferon Stimulated Genes ◽

Ifn Γ ◽

Herpesvirus 1

ABSTRACTEquine herpesvirus 1 (EHV-1) is a major pathogen affecting equines worldwide. The virus causes respiratory disease, abortion, and, in some cases, neurological disease. EHV-1 strain KyA is attenuated in the mouse and equine, whereas wild-type strain RacL11 induces severe inflammation of the lung, causing infected mice to succumb at 4 to 6 days postinfection. Our previous results showed that KyA immunization protected CBA mice from pathogenic RacL11 challenge at 2 and 4 weeks postimmunization and that KyA infection elicited protective humoral and cell-mediated immune responses. To investigate the protective mechanisms of innate immune responses to KyA, KyA-immunized mice were challenged with RacL11 at various times postvaccination. KyA immunization protected mice from RacL11 challenge at 1 to 7 days postimmunization. Immunized mice lost less than 10% of their body weight and rapidly regained weight. Virus titers in the lungs of KyA-immunized mice were 1,000-fold lower at 2 days post-RacL11 challenge than virus titers in the lungs of nonimmunized mice, indicating accelerated virus clearance. Affymetrix microarray analysis revealed that gamma interferon (IFN-γ) and 16 antiviral interferon-stimulated genes (ISGs) were upregulated 3.1- to 48.2-fold at 8 h postchallenge in the lungs of RacL11-challenged mice that had been immunized with KyA. Murine IFN-γ inhibited EHV-1 infection of murine alveolar macrophages and protected mice against lethal EHV-1 challenge, suggesting that IFN-γ expression is important in mediating the protection elicited by KyA immunization. These results suggest that EHV-1 KyA may be used as a live attenuated EHV-1 vaccine as well as a prophylactic agent in horses.IMPORTANCEViral infection of cells initiates a signal cascade of events that ultimately attempts to limit viral replication and prevent infection through the expression of host antiviral proteins. In this study, we show that EHV-1 KyA immunization effectively protected CBA mice from pathogenic RacL11 challenge at 1 to 7 days postvaccination and increased the expression of IFN-γ and 16 antiviral interferon-stimulated genes (ISGs). The administration of IFN-γ blocked EHV-1 replication in murine alveolar macrophages and mouse lungs and protected mice from lethal challenge. To our knowledge, this is the first report of an attenuated EHV-1 vaccine that protects the animal at 1 to 7 days postimmunization by innate immune responses. Our findings suggested that IFN-γ serves as a novel prophylactic agent and may offer new strategies for the development of anti-EHV-1 agents in the equine.

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Type-I interferon signatures in SARS-CoV-2 infected Huh7 cells

Cell Death Discovery ◽

10.1038/s41420-021-00487-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Xi Chen ◽

Elisa Saccon ◽

K. Sofia Appelberg ◽

Flora Mikaeloff ◽

Jimmy Esneider Rodriguez ◽

...

Keyword(s):

Immune Responses ◽

Type I Interferon ◽

Innate Immune ◽

Interferon Response ◽

Type I ◽

Response Type ◽

Innate Immune Responses ◽

Interferon Stimulated Genes ◽

Huh7 Cells ◽

Related Proteins

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19) has caused a global health emergency. A key feature of COVID-19 is dysregulated interferon-response. Type-I interferon (IFN-I) is one of the earliest antiviral innate immune responses following viral infection and plays a significant role in the pathogenesis of SARS-CoV-2. In this study, using a proteomics-based approach, we identified that SARS-CoV-2 infection induces delayed and dysregulated IFN-I signaling in Huh7 cells. We demonstrate that SARS-CoV-2 is able to inhibit RIG-I mediated IFN-β production. Our results also confirm the recent findings that IFN-I pretreatment is able to reduce the susceptibility of Huh7 cells to SARS-CoV-2, but not post-treatment. Moreover, senescent Huh7 cells, in spite of showing accentuated IFN-I response were more susceptible to SARS-CoV-2 infection, and the virus effectively inhibited IFIT1 in these cells. Finally, proteomic comparison between SARS-CoV-2, SARS-CoV, and MERS-CoV revealed a distinct differential regulatory signature of interferon-related proteins emphasizing that therapeutic strategies based on observations in SARS-CoV and MERS-CoV should be used with caution. Our findings provide a better understanding of SARS-CoV-2 regulation of cellular interferon response and a perspective on its use as a treatment. Investigation of different interferon-stimulated genes and their role in the inhibition of SARS-CoV-2 pathogenesis may direct novel antiviral strategies.

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LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

eLife ◽

10.7554/elife.51071 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 6

Author(s):

Chi G Weindel ◽

Samantha L Bell ◽

Krystal J Vail ◽

Kelsi O West ◽

Kristin L Patrick ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Mycobacterial Infection ◽

Innate Immune ◽

Type I ◽

Immune Gene ◽

Innate Immune Responses ◽

Interferon Stimulated Genes ◽

Mitochondrial Homeostasis ◽

Mitochondrial Defects ◽

Interferon Responses

The Parkinson’s disease (PD)-associated gene leucine-rich repeat kinase 2 (LRRK2) has been studied extensively in the brain. However, several studies have established that mutations in LRRK2 confer susceptibility to mycobacterial infection, suggesting LRRK2 also controls immunity. We demonstrate that loss of LRRK2 in macrophages induces elevated basal levels of type I interferon (IFN) and interferon stimulated genes (ISGs) and causes blunted interferon responses to mycobacterial pathogens and cytosolic nucleic acid agonists. Altered innate immune gene expression in Lrrk2 knockout (KO) macrophages is driven by a combination of mitochondrial stresses, including oxidative stress from low levels of purine metabolites and DRP1-dependent mitochondrial fragmentation. Together, these defects promote mtDNA leakage into the cytosol and chronic cGAS engagement. While Lrrk2 KO mice can control Mycobacterium tuberculosis (Mtb) replication, they have exacerbated inflammation and lower ISG expression in the lungs. These results demonstrate previously unappreciated consequences of LRRK2-dependent mitochondrial defects in controlling innate immune outcomes.

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Type-I interferon signatures in SARS-CoV-2 infected Huh7 cells

10.1101/2021.02.04.429738 ◽

2021 ◽

Author(s):

Xi Chen ◽

Elisa Saccon ◽

K. Sofia Appelberg ◽

Flora Mikaeloff ◽

Jimmy Esneider Rodriguez ◽

...

Keyword(s):

Immune Responses ◽

Type I Interferon ◽

Innate Immune ◽

Interferon Response ◽

Type I ◽

Response Type ◽

Innate Immune Responses ◽

Interferon Stimulated Genes ◽

Huh7 Cells ◽

Related Proteins

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19) has caused a global health emergency. A key feature of COVID-19 is dysregulated interferon-response. Type-I interferon (IFN-I) is one of the earliest antiviral innate immune responses following viral infection and plays a significant role in the pathogenesis of SARS-CoV-2. In this study, using a proteomics-based approach, we identified that SARS-CoV-2 infection induces delayed and dysregulated IFN-I signaling in Huh7 cells. We demonstrate that SARS-CoV-2 is able to inhibit RIG-I mediated IFN-β production. Our results also confirm the recent findings that IFN-I pretreatment is able to reduce susceptibility of Huh7 cells to SARS-CoV-2, but not post-treatment. Moreover, senescent Huh7 cells, in spite of showing accentuated IFN-I response were more susceptible to SARS-CoV-2 infection, and the virus effectively inhibited IFIT1 in these cells. Finally, proteomic comparison between SARS-CoV-2, SARS-CoV and MERS-CoV revealed a distinct differential regulatory signature of interferon-related proteins emphasizing that therapeutic strategies based on observations in SARS-CoV and MERS-CoV should be used with caution. Our findings provide a better understanding of SARS-CoV-2 regulation of cellular interferon response and a perspective on its use as a treatment. Investigation of different interferon stimulated genes and their role in inhibition of SARS-CoV-2 pathogenesis may direct novel antiviral strategies.

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Toxoplasma gondii Type-I ROP18 Targeting Human E3 Ligase TRIM21 for Immune Escape

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.685913 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lijie Yao ◽

Liqing Xu ◽

Lijuan Zhou ◽

Shuizhen Wu ◽

Weihao Zou ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Immune Responses ◽

Immune Escape ◽

Parasitophorous Vacuole ◽

E3 Ligase ◽

Innate Immune ◽

Intracellular Pathogen ◽

Type I ◽

Innate Immune Responses ◽

Ifn Γ

Toxoplasma gondii is an intracellular pathogen that exerts its virulence through inhibiting host’s innate immune responses, which is mainly related to the type II interferon (IFN-γ) response. IFN-γ inducible tripartite motif 21 (TRIM21), an E3 ligase, plays an important role in anti-infection responses against the intracellular pathogens including bacteria, virus, and parasite. We found that T. gondii virulence factor ROP18 of the type I RH strain (TgROP18I) interacted with human TRIM21, and promoted the latter’s phosphorylation, which subsequently accelerated TRIM21 degradation through lysosomal pathway. Furthermore, TRIM21 protein level was found to be upregulated during RH and CEP strains of T. gondii infection. TRIM21 knocking down reduced the ubiquitin labeling on the parasitophorous vacuole membrane (PVM) [which led to parasitophorous vacuole (PV) acidification and death of CEP tachyzoites], and relieved the inhibition of CEP proliferation induced by IFN-γ in human foreskin fibroblast (HFF) cells which was consistent with the result of TRIM21 overexpression. On the other hand, TRIM21 overexpression enhanced the inhibition of CEP proliferation, and inhibited the binding of IκB-α with p65 to activate the IFN-γ-inducible NF-κB pathway, which might be resulted by TRIM21-IκB-α interaction. In brief, our research identified that in human cells, IFN-γ-inducible TRIM21 functioned in the innate immune responses against type III T. gondii infection; however, TgROP18I promoted TRIM21 phosphorylation, leading to TRIM21 degradation for immune escape in type I strain infection.

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Yin Yang 1 Dynamically Regulates Antiviral Innate Immune Responses During Viral Infection

Cellular Physiology and Biochemistry ◽

10.1159/000485116 ◽

2017 ◽

Vol 44 (2) ◽

pp. 607-617 ◽

Cited By ~ 10

Author(s):

Jie Zan ◽

Hao Zhang ◽

Ai-Ping Gu ◽

Kai-Lun Zhong ◽

Min-Yi Lu ◽

...

Keyword(s):

Immune Responses ◽

Viral Infection ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Expression Levels ◽

Interferon Stimulated Genes ◽

Yin Yang 1 ◽

Yin Yang ◽

Interfering Rna

Background/Aims: Type I interferon (IFN-1) production and IFN-1 signaling play critical roles in the host antiviral innate immune responses. Although transcription factor Yin Yang 1 (YY1) has been reported to have a dual activator/repressor role during the regulation of interferon beta (IFN-β) promoter activity, the roles of YY1 in the regulation of upstream signaling pathways leading to IFN-1 induction and IFN-1 signaling during viral infection remain to be elucidated. Methods: The roles of YY1 in IFN-1 production and IFN-1 signaling were investigated using immunoblotting, real-time PCR, small interfering RNA (siRNA)-mediated YY1 knockdown, YY1 overexpression by transient transfection, and co-immunoprecipitation, using mouse cells. Results: YY1 was shown to interact with STAT1 in the absence of viral infection. Following viral infection, YY1 protein expression levels were decreased. YY1 knockdown led to a considerable downregulation of phosphorylated (p) TBK1 and pIRF3 expressions, while YY1 overexpression significantly upregulated pTBK1 and pIRF3 expression levels and promoted virus-induced IFN-β production. Additionally, YY1 knockdown led to a significant upregulation of pSTAT1, pSTAT2 and antiviral interferon-stimulated genes, and inhibited viral replication. Conclusion: We demonstrated here that YY1 interacts with STAT1 and dynamically regulates the induction of IFN-1 production and activation of IFN-1 signaling in different stages during viral infection.

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