scholarly journals Interleukin-1 receptor antagonist mediates type I interferon-driven susceptibility to Mycobacterium tuberculosis

2018 ◽  
Author(s):  
Daisy X. Ji ◽  
Katherine J. Chen ◽  
Naofumi Mukaida ◽  
Igor Kramnik ◽  
K. Heran Darwin ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Receptor Antagonist ◽  
Bacterial Infections ◽  
Type I Interferon ◽  
Inbred Mouse ◽  
Interleukin 1 ◽  
Mouse Strains ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns

AbstractThe bacterium Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB) and is responsible for more human mortality than any other single pathogen1. Although ~1.7 billion people are infected with Mtb2, most infections are asymptomatic. Progression to active disease occurs in ~10% of infected individuals and is predicted by an elevated type I interferon (IFN) response3–8. Type I IFNs are vital for antiviral immunity, but whether or how they mediate susceptibility to Mtb has been difficult to study, in part because the standard C57BL/6 (B6) mouse model does not recapitulate the IFN-driven disease that appears to occur in humans3–5,8. Here we examined B6. Sst1S congenic mice that carry the C3H “sensitive” allele of the Sst1 locus that renders them highly susceptible to Mtb infections9,10. We found that B6.Sst1S mice exhibit markedly increased type I IFN signaling, and that type I IFNs were required for the enhanced susceptibility of B6. Sst1S mice to Mtb. Type I IFNs affect the expression of hundreds of genes, several of which have previously been implicated in susceptibility to bacterial infections11,12. Nevertheless, we found that heterozygous deficiency in just a single IFN target gene, IL-1 receptor antagonist (IL-1Ra), is sufficient to reverse IFN-driven susceptibility to Mtb. As even a partial reduction in IL-1Ra levels led to significant protection, we hypothesized that IL-1Ra may be a plausible target for host-directed anti-TB therapy. Indeed, antibody-mediated neutralization of IL-1Ra provided therapeutic benefit to Mtb-infected B6. Sst1S mice. Our results illustrate how the diversity of inbred mouse strains can be exploited to better model human TB, and demonstrate that IL-1Ra is an important mediator of type I IFN-driven susceptibility to Mtb infections in vivo.

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

2015 ◽  
Vol 90 (5) ◽  
pp. 2403-2417 ◽  
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.

scholarly journals Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Daisy X Ji ◽  
Kristen C Witt ◽  
Dmitri I Kotov ◽  
Shally R Margolis ◽  
Alexander Louie ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Negative Regulator ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Viral Immunity ◽  
Type I Ifns ◽  
Important Negative Regulator

Type I interferons (IFNs) are essential for anti-viral immunity, but often impair protective immune responses during bacterial infections. An important question is how type I IFNs are strongly induced during viral infections, and yet are appropriately restrained during bacterial infections. The Super susceptibility to tuberculosis 1 (Sst1) locus in mice confers resistance to diverse bacterial infections. Here we provide evidence that Sp140 is a gene encoded within the Sst1 locus that represses type I IFN transcription during bacterial infections. We generated Sp140-/- mice and find they are susceptible to infection by Legionella pneumophila and Mycobacterium tuberculosis. Susceptibility of Sp140-/- mice to bacterial infection was rescued by crosses to mice lacking the type I IFN receptor (Ifnar-/-). Our results implicate Sp140 as an important negative regulator of type I IFNs that is essential for resistance to bacterial infections.

ALL-associated JAK1 mutations confer hypersensitivity to the antiproliferative effect of type I interferon

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3287-3295 ◽  
Author(s):  
Tekla Hornakova ◽  
Sabina Chiaretti ◽  
Muriel M. Lemaire ◽  
Robin Foà ◽  
Raouf Ben Abdelali ◽  
...  
Keyword(s):  
Cell Lines ◽  
Type I Interferon ◽  
Type I ◽  
Type I Ifn ◽  
Transcriptional Signature ◽  
Activating Mutations ◽  
Type I Ifns ◽  
Antitumorigenic Effect

Abstract Activating mutations in JAK1 have been reported in acute lymphoblastic leukemias (ALLs). In this study, we found a type I interferon (IFN) transcriptional signature in JAK1 mutation-positive human ALL samples. This signature was recapitulated in vitro by the expression of JAK1 mutants in BW5147 and BaF3 hematopoietic cell lines. Binding of JAK1 to the IFN receptor was essential because mutations in the FERM domain abrogated this effect. Beside the constitutive activation of the type I IFN signaling cascade, JAK1 mutations also strongly potentiated the response to IFN in vitro. Typically, the proliferation of cell lines expressing JAK1A634D was abrogated by type I IFNs. Interestingly, we found that different JAK1 mutations differentially potentiate responses to type I IFNs or to interleukin-9, another cytokine using JAK1 to mediate its effects. This suggests that the type of mutation influences the specificity of the effect on distinct cytokine receptor signaling. Finally, we also showed in an in vivo leukemia model that cells expressing JAK1A634D are hypersensitive to the antiproliferative and antitumorigenic effect of type I IFN, suggesting that type I IFNs should be considered as a potential therapy for ALL with JAK1-activating mutations.

scholarly journals Type I interferon signaling mediates Mycobacterium tuberculosis–induced macrophage death

2020 ◽  
Vol 218 (2) ◽  
Author(s):  
Li Zhang ◽  
Xiuju Jiang ◽  
Daniel Pfau ◽  
Yan Ling ◽  
Carl F. Nathan
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Critical Role ◽  
Type I ◽  
Type I Ifn ◽  
Paracrine Signaling ◽  
Type I Ifns ◽  
Genome Wide ◽  
Mouse Macrophages ◽  
Definition Of

Macrophages help defend the host against Mycobacterium tuberculosis (Mtb), the major cause of tuberculosis (TB). Once phagocytized, Mtb resists killing by macrophages, replicates inside them, and leads to their death, releasing Mtb that can infect other cells. We found that the death of Mtb-infected mouse macrophages in vitro does not appear to proceed by a currently known pathway. Through genome-wide CRISPR-Cas9 screening, we identified a critical role for autocrine or paracrine signaling by macrophage-derived type I IFNs in the death of Mtb-infected macrophages in vitro, and blockade of type I IFN signaling augmented the effect of rifampin, a first-line TB drug, in Mtb-infected mice. Further definition of the pathway of type I IFN–mediated macrophage death may allow for host-directed therapy of TB that is more selective than systemic blockade of type I IFN signaling.

scholarly journals Antibodies against type-I Interferon: detection and association with severe clinical outcome in COVID-19 patients

2021 ◽  
Author(s):  
David Goncalves ◽  
Mehdi Mezidi ◽  
Paul Bastard ◽  
Magali Perret ◽  
Kahina Saker ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Type I Interferon ◽  
Clinical Course ◽  
University Hospital ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns ◽  
Recombinant Type ◽  
Circulating Autoantibodies

Objectives Impairment of type I interferon (IFN-I) immunity has been reported in critically ill COVID-19 patients. This defect can be explained by the presence of circulating autoantibodies against IFN-I. We set out to improve the detection and the quantification of such antibodies (Abs) in a cohort of severe Covid-19 patients, in an effort to better document the prevalence of these Abs as the pandemics evolves and how they correlate with the clinical course of the disease. Methods Anti-IFN-a Abs was investigated 84 critical COVID-19 patients who were admitted to ICU at the Lyon University Hospital, France with a commercially available kit (Thermo-Fisher). Results Twenty-one patients out of 84 (25%) had anti-IFNa2 Ab above cut-off (>34ng/mL) in sera. A neutralizing activity against IFN-a2 was evidenced in 15 of them, suggesting that 18% of patients were positive for neutralizing anti-IFN-a and -w auto-Abs. In addition, in most of patients with neutralizing IFN-I Abs, we noticed an impairment of the IFN-I response. However, we did not find any difference in terms of clinical characteristics or outcome between critical COVID-19 patients with or without neutralizing anti-IFN-a2 auto-Abs in these conditions. Finally, we detected anti-type I IFN auto-Abs in sera of COVID-19 patients were detected throughout the ICU stay. Conclusions We report that 18% of severe COVID-19 patients were positive for these Anti-Type-I IFN Abs, confirming the detrimental role of these Abs on the antiviral response. Our results further support the use of recombinant type I IFNs not targeted by the auto-Abs (e.g., IFN-b) in COVID-19 patients with an impaired IFN-I response.

ALL-Associated JAK1 Mutations Confer Hypersensitivity to the Anti-Proliferative Effect of Type I Interferon.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3066-3066
Author(s):  
Tekla Hornakova ◽  
Sabina Chiaretti ◽  
Muriel Lemaire ◽  
Robin Foà ◽  
Marco Tartaglia ◽  
...  
Keyword(s):  
Cell Lines ◽  
Type I Interferon ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Type I ◽  
Type I Ifn ◽  
Activating Mutations ◽  
Type I Ifns

Abstract Abstract 3066 Poster Board III-3 Recently, we and others reported activating mutations in JAK1 in acute lymphoblastic leukemia (ALL). These mutations are relatively common in adult patients with T cell ALL. JAK1 is a tyrosine kinase that associates to different cytokine receptors to mediate signal transduction. The associations of the mutant JAK1 with receptors like IL-2R or IL-9R are necessary to promote tumorigenicity by inducing constitutive signaling via the activation of the receptor complex. Because JAK1 mutations confer poor prognosis to the patients, there is a need for new therapies that could specifically target the leukemic blast. Starting from patient samples, we show here that JAK1-mutant ALL blasts are characterized by a type-I interferon (IFN) transcriptional signature. This signature was recapitulated in vitro by the expression of JAK1 mutants in BW5147 and BaF3 hematopoietic cell lines. Binding of JAK1 to the IFN receptor was essential since mutations in the FERM domain abrogated this effect. Beside the constitutive activation of the type I IFN signaling cascade, JAK1 mutations also strongly potentiated the response to IFN in vitro. Typically, the proliferation of cell lines expressing JAK1A634D was abrogated by type I IFNs. Interestingly, we found that different JAK1 mutations differentially potentiate responses to type I IFNs or to IL-9, another cytokine using JAK1 to mediate its effects. This suggests that the type of mutation influences the specificity of the effect on distinct cytokine receptor signaling. Finally, we also showed in an in vivo leukemia model that cells expressing JAK1A634D are hypersensitive to the anti-proliferative and anti-tumorigenic effect of type I IFN, suggesting that type I IFNs should be considered as a potential therapy for ALL with JAK1 activating mutations. Disclosures No relevant conflicts of interest to declare.

scholarly journals Type I Interferon Dependent hsa-miR-145-5p Downregulation Modulates MUC1 and TLR4 Overexpression in Salivary Glands From Sjögren’s Syndrome Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Daniela Jara ◽  
Patricia Carvajal ◽  
Isabel Castro ◽  
María-José Barrera ◽  
Sergio Aguilera ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Type I Interferon ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Type I ◽  
Mrna Levels ◽  
Type I Ifn ◽  
Type I Ifns ◽  
Tlr4 Mrna ◽  
Sjögren‘S Syndrome

Sjögren’s syndrome (SS) is an autoimmune disease that mainly affects salivary glands (SG) and is characterized by overactivation of the type I interferon (IFN) pathway. Type I IFNs can decrease the levels of hsa-miR-145-5p, a miRNA with anti-inflammatory roles that is downregulated in SG from SS-patients. Two relevant targets of hsa-miR-145-5p, mucin 1 (MUC1) and toll-like receptor 4 (TLR4) are overexpressed in SS-patients and contribute to SG inflammation and dysfunction. This study aimed to evaluate if hsa-miR-145-5p modulates MUC1 and TLR4 overexpression in SG from SS-patients in a type I IFN dependent manner. Labial SG (LSG) biopsies from 9 SS-patients and 6 controls were analyzed. We determined hsa-miR-145-5p levels by TaqMan assays and the mRNA levels of MUC1, TLR4, IFN-α, IFN-β, and IFN-stimulated genes (MX1, IFIT1, IFI44, and IFI44L) by real time-PCR. We also performed in vitro assays using type I IFNs and chemically synthesized hsa-miR-145-5p mimics and inhibitors. We validated the decreased hsa-miR-145-5p levels in LSG from SS-patients, which inversely correlated with the type I IFN score, mRNA levels of IFN-β, MUC1, TLR4, and clinical parameters of SS-patients (Ro/La autoantibodies and focus score). IFN-α or IFN-β stimulation downregulated hsa-miR-145-5p and increased MUC1 and TLR4 mRNA levels. Hsa-miR-145-5p overexpression decreased MUC1 and TLR4 mRNA levels, while transfection with a hsa-miR-145-5p inhibitor increased mRNA levels. Our findings show that type I IFNs decrease hsa-miR-145-5p expression leading to upregulation of MUC1 and TLR4. Together, this suggests that type I interferon-dependent hsa-miR-145-5p downregulation contributes to the perpetuation of inflammation in LSG from SS-patients.

scholarly journals Mycobacterium tuberculosis MmsA (Rv0753c) Interacts with STING and Blunts the Type I Interferon Response

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Yifan Sun ◽  
Wei Zhang ◽  
Chunsheng Dong ◽  
Sidong Xiong
Keyword(s):  
Mass Spectrometry ◽  
Mycobacterium Tuberculosis ◽  
Proteomic Analysis ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn ◽  
Content Type ◽  
C Terminus ◽  
Autophagic Degradation

ABSTRACT Type I interferon (IFN) plays an important role in Mycobacterium tuberculosis persistence and disease pathogenesis. M. tuberculosis has evolved a number of mechanisms to evade host immune surveillance. However, it is unclear how the type I IFN response is tightly regulated by the M. tuberculosis determinants. Stimulator of interferon genes (STING) is an essential adaptor for type I IFN production triggered by M. tuberculosis genomic DNA or cyclic dinucleotides upon infection. To investigate how the type I IFN response is regulated by M. tuberculosis determinants, immunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis was performed to screen proteins interacting with STING in the context of M. tuberculosis infection. Among the many predicted candidates interacting with STING, the M. tuberculosis coding protein Rv0753c (MmsA) was identified. We confirmed that MmsA binds and colocalizes with STING, and the N-terminal regions of MmsA (amino acids [aa] 1 to 251) and STING (aa 1 TO 190) are responsible for MmsA-STING interaction. Type I IFN production was impaired with exogenous expression of MmsA in RAW264.7 cells. MmsA inhibited the STING-TBK1-IRF3 pathway, as evidenced by reduced STING levelS and subsequent IRF3 activation. Furthermore, MmsA facilitated p62-mediated STING autophagic degradation by binding p62 with its C terminus (aa 252 to 455), which may account for the negative regulation of M. tuberculosis MmsA in STING-mediated type I IFN production. Additionally, the M. tuberculosis mmsA R138W mutation, detected in a hypervirulent clinical isolate, enhanced the degradation of STING, implying the important relevance of MmsA in disease outcome. Together, we report a novel mechanism where M. tuberculosis MmsA serves as an antagonist of type I IFN response by targeting STING with p62-mediated autophagic degradation. IMPORTANCE It is unclear how the type I IFN response is regulated by mycobacterial determinants. Here, we characterized the previously unreported role of M. tuberculosis MmsA in immunological regulation of type I IFN response by targeting the central adaptor STING in the DNA sensing pathway. We identified STING-interacting MmsA by coimmunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis and showed MmsA interacting with STING and autophagy receptor p62 via its N terminus and C terminus, respectively. We also showed that MmsA downregulated type I IFN by promoting p62-mediated STING degradation. Moreover, the MmsA mutant R138W is potentially associated with the virulence of M. tuberculosis clinical strains owing to the modulation of STING protein. Our results provide novel insights into the regulatory mechanism of type I IFN response manipulated by mycobacterial MmsA and the additional cross talk between autophagy and STING in M. tuberculosis infection, wherein a protein from microbial pathogens induces autophagic degradation of host innate immune molecules.

scholarly journals Getting “Inside” Type I IFNs: Type I IFNs in Intracellular Bacterial Infections

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Deann T. Snyder ◽  
Jodi F. Hedges ◽  
Mark A. Jutila
Keyword(s):  
Host Cell ◽  
Legionella Pneumophila ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Type I Interferons ◽  
Intracellular Bacteria ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns ◽  
Serovar Typhimurium

Type I interferons represent a unique and complex group of cytokines, serving many purposes during innate and adaptive immunity. Discovered in the context of viral infections, type I IFNs are now known to have myriad effects in infectious and autoimmune disease settings. Type I IFN signaling during bacterial infections is dependent on many factors including whether the infecting bacterium is intracellular or extracellular, as different signaling pathways are activated. As such, the repercussions of type I IFN induction can positively or negatively impact the disease outcome. This review focuses on type I IFN induction and downstream consequences during infection with the following intracellular bacteria:Chlamydia trachomatis,Listeria monocytogenes,Mycobacterium tuberculosis,Salmonella entericaserovar Typhimurium,Francisella tularensis,Brucella abortus,Legionella pneumophila, andCoxiella burnetii. Intracellular bacterial infections are unique because the bacteria must avoid, circumvent, and even co-opt microbial “sensing” mechanisms in order to reside and replicate within a host cell. Furthermore, life inside a host cell makes intracellular bacteria more difficult to target with antibiotics. Because type I IFNs are important immune effectors, modulating this pathway may improve disease outcomes. But first, it is critical to understand the context-dependent effects of the type I IFN pathway in intracellular bacterial infections.

scholarly journals Arenaviral Nucleoproteins Suppress PACT-Induced Augmentation of RIG-I Function To Inhibit Type I Interferon Production

2018 ◽  
Vol 92 (13) ◽  
pp. e00482-18 ◽  
Author(s):  
Junjie Shao ◽  
Qinfeng Huang ◽  
Xiaoying Liu ◽  
Da Di ◽  
Yuying Liang ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Hemorrhagic Fever ◽  
Cellular Protein ◽  
Rnase Activity ◽  
Block Type ◽  
Type I ◽  
Type I Ifn ◽  
Viral Pathogen ◽  
Virus Growth ◽  
Type I Ifns

ABSTRACT RIG-I is a major cytoplasmic sensor of viral pathogen-associated molecular pattern (PAMP) RNA and induces type I interferon (IFN) production upon viral infection. A double-stranded RNA (dsRNA)-binding protein, PACT, plays an important role in potentiating RIG-I function. We have shown previously that arenaviral nucleoproteins (NPs) suppress type I IFN production via their RNase activity to degrade PAMP RNA. We report here that NPs of arenaviruses block the PACT-induced enhancement of RIG-I function to mediate type I IFN production and that this inhibition is dependent on the RNase function of NPs, which is different from that of a known mechanism of other viral proteins to abolish the interaction between PACT and RIG-I. To understand the biological roles of PACT and RIG-I in authentic arenavirus infection, we analyze growth kinetics of recombinant Pichinde virus (PICV), a prototypical arenavirus, in RIG-I knockout (KO) and PACT KO mouse embryonic fibroblast (MEF) cells. Wild-type (WT) PICV grew at higher titers in both KO MEF lines than in normal MEFs, suggesting the important roles of these cellular proteins in restricting virus replication. PICV carrying the NP RNase catalytically inactive mutation could not grow in normal MEFs but could replicate to some extent in both KO MEF lines. The level of virus growth was inversely correlated with the amount of type I IFNs produced. These results suggest that PACT plays an important role in potentiating RIG-I function to produce type I IFNs in order to restrict arenavirus replication and that viral NP RNase activity is essential for optimal viral replication by suppressing PACT-induced RIG-I activation. IMPORTANCE We report here a new role of the nucleoproteins of arenaviruses that can block type I IFN production via their specific inhibition of the cellular protein sensors of virus infection (RIG-I and PACT). Our results suggest that PACT plays an important role in potentiating RIG-I function to produce type I IFNs in order to restrict arenavirus replication. This new knowledge can be exploited for the development of novel antiviral treatments and/or vaccines against some arenaviruses that can cause severe and lethal hemorrhagic fever diseases in humans.

Sign in / Sign up

Export Citation Format

Share Document