Smoking Products Suppress Type I IFN During SARS-Cov-2 Infection

E3S Web of Conferences ◽

10.1051/e3sconf/202129203095 ◽

2021 ◽

Vol 292 ◽

pp. 03095

Author(s):

Zhenni Lu

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Molecular Level ◽

Severe Pneumonia ◽

Type I Interferons ◽

Type I ◽

Hospital Data ◽

Type I Ifns ◽

Global Pandemic ◽

Negative Effect

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), which can lead to the development severe pneumonia. While some hospital data shows a positive correlation between smoking and severe pneumonia, more molecular-level mechanisms need to be determined. The previous study investigates the mechanism of the negative effect of smoking on anti-viral infection on Type I interferons (IFNs). Research has shown that Type I IFNs play an important role in defending against SARS-Cov-2. Here, we want to investigate smoking components’ effects on SARS-CoV-2 at the molecular level in vitro and give some ideas on the correlation between smoking and syndrome.

Download Full-text

Inhibition of Angiogenesis by Type I Interferons in Models of Kaposi'S Sarcoma

The International Journal of Biological Markers ◽

10.1177/172460089901400411 ◽

1999 ◽

Vol 14 (4) ◽

pp. 257-262 ◽

Cited By ~ 11

Author(s):

C. Marchisone ◽

R. Benelli ◽

A. Albini ◽

L. Santi ◽

D. M. Noonan

Keyword(s):

Kaposi's Sarcoma ◽

Kaposi’S Sarcoma ◽

Inhibitory Effect ◽

Type I Interferons ◽

Endothelial Cell Migration ◽

Type I ◽

Type I Ifns ◽

Hiv 1

Kaposi's Sarcoma (KS) is a pathology which occurs with increased frequency and in a particularly aggressive form in AIDS patients. The HIV-1 Tat protein appears to be an important co-factor in the induction of the extensive neo-vascularization associated with AIDS-KS. Tat acts as a chemoattractant for endothelial cells in vitro, inducing both chemotactic and invasive responses. Several clinical trials have been performed testing the effectiveness of diverse biological agents in therapy of KS, among these the type I interferons. Type I IFNs have diverse biological functions besides their anti-viral activity, including anti-angiogenic properties. We have shown that IFNα and IFNβ are potent inhibitors of both primary and immortalized endothelial cell migration and morphogenesis in vitro as well as neo-angiogenesis induced by HIV-1 Tat in vivo. The inhibitory effect of IFN class I on HIV-Tat associated angiogenesis further supports its use as a therapy for epidemic Kaposi's sarcoma. The use of recombinant IFNs at the levels required to obtain a therapeutic effect are associated with side effects and toxicity, therefore we are now developing a gene therapy approach for constant and local delivery type I IFNs.

Download Full-text

Type I interferons produced by dendritic cells promote their phenotypic and functional activation

Blood ◽

10.1182/blood.v99.9.3263 ◽

2002 ◽

Vol 99 (9) ◽

pp. 3263-3271 ◽

Cited By ~ 332

Author(s):

Maria Montoya ◽

Giovanna Schiavoni ◽

Fabrizio Mattei ◽

Ion Gresser ◽

Filippo Belardelli ◽

...

Keyword(s):

Bone Marrow ◽

Dendritic Cells ◽

T Cell ◽

Bone Marrow Cells ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Type I Ifns

Abstract Resting dendritic cells (DCs) are resident in most tissues and can be activated by environmental stimuli to mature into potent antigen-presenting cells. One important stimulus for DC activation is infection; DCs can be triggered through receptors that recognize microbial components directly or by contact with infection-induced cytokines. We show here that murine DCs undergo phenotypic maturation upon exposure to type I interferons (type I IFNs) in vivo or in vitro. Moreover, DCs either derived from bone marrow cells in vitro or isolated from the spleens of normal animals express IFN-α and IFN-β, suggesting that type I IFNs can act in an autocrine manner to activate DCs. Consistent with this idea, the ability to respond to type I IFN was required for the generation of fully activated DCs from bone marrow precursors, as DCs derived from the bone marrow of mice lacking a functional receptor for type I IFN had reduced expression of costimulatory and adhesion molecules and a diminished ability to stimulate naive T-cell proliferation compared with DCs derived from control bone marrow. Furthermore, the addition of neutralizing anti–IFN-α/β antibody to purified splenic DCs in vitro partially blocked the “spontaneous” activation of these cells, inhibiting the up-regulation of costimulatory molecules, secretion of IFN-γ, and T-cell stimulatory activity. These results show that DCs both secrete and respond to type I IFN, identifying type I interferons as autocrine DC activators.

Download Full-text

Type I interferons protect mice against enterovirus 71 infection

Journal of General Virology ◽

10.1099/vir.0.81195-0 ◽

2005 ◽

Vol 86 (12) ◽

pp. 3263-3269 ◽

Cited By ~ 111

Author(s):

Ming-Liang Liu ◽

Yi-Ping Lee ◽

Ya-Fang Wang ◽

Huan-Yao Lei ◽

Ching-Chuan Liu ◽

...

Keyword(s):

Clinical Symptoms ◽

Enterovirus 71 ◽

Neutralizing Antibody ◽

Oral Route ◽

Type I Interferons ◽

Ev71 Infection ◽

Type I ◽

Type I Ifns ◽

Protection Against Infection

In this study, the contribution of type I interferons (IFNs) to protection against infection with enterovirus 71 (EV71) was investigated using a murine model where the virus was administrated to neonatal Institute of Cancer Research (ICR) mice by either the intraperitoneal (i.p.) or the oral route. In i.p. inoculated mice, post-infection treatment of dexamethasone (5 mg kg−1 at 2 or 3 days after infection) exacerbated clinical symptoms and increased the tissue viral titre. In contrast, polyriboinosinic : polyribocytidylic acid [poly(I : C); 10 or 100 μg per mouse at 12 h before infection], a potent IFN inducer, improved the survival rate and decreased the tissue viral titres after EV71 challenge, which correlated with an increase in serum IFN-α concentration, the percentage of dendritic cells, their expression of major histocompatibility complex class II molecule and IFN-α in spleen. Treatment with a neutralizing antibody for type I IFNs (104 neutralizing units per mouse, 6 h before and 12 h after infection) resulted in frequent deaths and higher tissue viral load in infected mice compared with control mice. In contrast, an early administration of recombinant mouse IFN-αA (104 U per mouse for 3 days starting at 0, 1 or 3 days after infection) protected the mice against EV71 infection. In vitro analysis of virus-induced death in three human cell lines showed that human type I IFNs exerted a direct protective effect on EV71. It was concluded that type I IFNs play an important role in controlling EV71 infection and replication.

Download Full-text

Type-I Interferon Receptor Deficiency Reduces Lupus-like Disease in NZB Mice

Journal of Experimental Medicine ◽

10.1084/jem.20021996 ◽

2003 ◽

Vol 197 (6) ◽

pp. 777-788 ◽

Cited By ~ 390

Author(s):

Marie-Laure Santiago-Raber ◽

Roberto Baccala ◽

Katarina M. Haraldsson ◽

Divaker Choubey ◽

Timothy A. Stewart ◽

...

Keyword(s):

T Cell ◽

Immune Cell ◽

Indirect Evidence ◽

Dendritic Cell Maturation ◽

Type I Interferons ◽

Type I ◽

Type I Ifns ◽

Common Receptor

Indirect evidence suggests that type-I interferons (IFN-α/β) play a significant role in the pathogenesis of lupus. To directly examine the contribution of these pleiotropic molecules, we created congenic NZB mice lacking the α-chain of IFN-α/βR, the common receptor for the multiple IFN-α/β species. Compared with littermate controls, homozygous IFN-α/βR-deleted NZB mice had significantly reduced anti-erythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease, and mortality. These reductions were intermediate in the heterozygous-deleted mice. The disease-ameliorating effects were accompanied by reductions in splenomegaly and in several immune cell subsets, including B-1 cells, the major producers of anti-erythrocyte autoantibodies. Decreases of B and T cell proliferation in vitro and in vivo, and of dendritic cell maturation and T cell stimulatory activity in vitro were also detected. Absence of signaling through the IFN-α/βR, however, did not affect increased basal levels of the IFN-responsive p202 phosphoprotein, encoded by a polymorphic variant of the Ifi202 gene associated with the Nba2 predisposing locus in NZB mice. The data indicate that type-I IFNs are important mediators in the pathogenesis of murine lupus, and that reducing their activity in the human counterpart may be beneficial.

Download Full-text

Neutralizing autoantibodies to type I IFNs in >10% of patients with severe COVID-19 pneumonia hospitalized in Madrid, Spain

10.21203/rs.3.rs-290977/v1 ◽

2021 ◽

Author(s):

Jesús Troya García ◽

Paul Bastard ◽

Laura Planas-Serra ◽

Pablo Ryan ◽

Montse Ruíz ◽

...

Keyword(s):

Severe Pneumonia ◽

University Hospital ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Protein Levels ◽

Reactive Protein ◽

Risk Of Death ◽

Type I Ifns ◽

Increased Risk

Abstract Background: In a recent study, autoantibodies neutralizing type I interferons (IFNs) were present in at least 10% of cases of critical COVID-19 pneumonia. These autoantibodies neutralized most type I IFNs but rarely IFN-beta.Objectives: We aimed to define the prevalence of autoantibodies neutralizing type I IFN in a cohort of patients with severe COVID-19 pneumonia treated with IFN-beta-1b during hospitalization and to analyze their impact on various clinical variables and outcomes.Methods: We analyzed stored serum/plasma samples and clinical data of COVID-19 patients treated subcutaneously with IFN-beta-1b from March to May 2020, at the Infanta Leonor University Hospital in Madrid, Spain. Results: The cohort comprised 47 COVID-19 patients with severe pneumonia, 16 of whom (34%) had a critical progression requiring ICU admission. The median age was 71 years, with 28 men (58.6%). Type I IFN-alpha- and omega-neutralizing autoantibodies were found in 5 of 47 patients with severe pneumonia or critical disease (10.6%). The autoantibodies did not neutralize IFN-beta. No demographic, comorbidity, or clinical differences were seen between individuals with or without autoantibodies. We found a significant correlation between the presence of neutralizing autoantibodies and higher C-reactive protein levels (p=5.10e-03) and lower lymphocyte counts (p=1.80e-02). Survival analysis suggested that neutralizing autoantibodies may increase the risk of death (4/5, 80% vs 12/42, 28.5%).Conclusion: Autoantibodies neutralizing type I IFN underlie severe/critical COVID-19 stages in at least 10% of cases, correlate with increased C-RP and lower lymphocyte counts, and confer a trend towards increased risk of death. Subcutaneous IFN-beta treatment of hospitalized patients did not seem to improve clinical outcome. Studies of earlier, ambulatory IFN-beta treatment are warranted.

Download Full-text

Differential Role of Anti-Viral Sensing Pathway for the Production of Type I Interferon β in Dendritic Cells and Macrophages Against Respiratory Syncytial Virus A2 Strain Infection

Viruses ◽

10.3390/v11010062 ◽

2019 ◽

Vol 11 (1) ◽

pp. 62 ◽

Cited By ~ 6

Author(s):

Dong Oh ◽

Tae Kim ◽

Heung Lee

Keyword(s):

Dendritic Cells ◽

Respiratory Syncytial Virus ◽

Primary Response ◽

Type I Interferons ◽

Type I ◽

Type I Ifns ◽

Rsv Infection ◽

Syncytial Virus ◽

Mitochondrial Antiviral Signaling

Respiratory syncytial virus (RSV) is a major cause of respiratory infectious disease in infants and young children. Dendritic cells (DCs) and macrophages (MACs) are known to play important roles in RSV recognition, and in the production of type I interferons (IFNs) and pro-inflammatory cytokine in RSV infection. Toll-like receptor 7 (TLR7), myeloid differentiation primary response 88 (MyD88), and mitochondrial antiviral-signaling protein (MAVS) are known to be important for the RSV sensing pathway in DCs and MACs. However, despite the critical roles of type I IFNs in the anti-RSV immune response, the pattern recognition receptors (PRRs) that are required for RSV sensing in DCs and MACs remain unclear. Here, we investigate the pathway activated by RSV A2 strain infection using an IFN-β/YFP reporter mouse model to visualize IFN-β-producing cells and in vitro RSV infection in bone marrow-derived DCs (BM-DCs) and macrophages (BM-DMs). We present our finding that MyD88, but not TLR7, are important for RSV recognition and type I IFN and pro-inflammatory production in DCs and MACs. MAVS-deficient BM-DCs and BM-DMs show impaired induction of IFN-β production upon RSV stimulation, and this effect is RSV replication-dependent. Our study provides information on cell type-specific PRR requirements in innate immune responses against RSV infection.

Download Full-text

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Science ◽

10.1126/science.abd4585 ◽

2020 ◽

Vol 370 (6515) ◽

pp. eabd4585 ◽

Cited By ~ 124

Author(s):

Paul Bastard ◽

Lindsey B. Rosen ◽

Qian Zhang ◽

Eleftherios Michailidis ◽

Hans-Heinrich Hoffmann ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

B Cell ◽

Immunoglobulin G ◽

The Other ◽

Type I ◽

Healthy Individuals ◽

Inborn Errors ◽

Type I Ifns ◽

Life Threatening

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Download Full-text

Type I Interferon Signaling Exacerbates Chlamydia muridarum Genital Infection in a Murine Model

Infection and Immunity ◽

10.1128/iai.00629-08 ◽

2008 ◽

Vol 76 (10) ◽

pp. 4642-4648 ◽

Cited By ~ 71

Author(s):

Uma M. Nagarajan ◽

Daniel Prantner ◽

James D. Sikes ◽

Charles W. Andrews ◽

Anna M. Goodwin ◽

...

Keyword(s):

T Cell ◽

T Cell Response ◽

Type I Interferons ◽

Cd4 T Cell ◽

Genital Infection ◽

Type I ◽

Genital Tract Infection ◽

Chlamydia Muridarum ◽

Type I Ifns

ABSTRACT Type I interferons (IFNs) induced during in vitro chlamydial infection exert bactericidal and immunomodulatory functions. To determine the precise role of type I IFNs during in vivo chlamydial genital infection, we examined the course and outcome of Chlamydia muridarum genital infection in mice genetically deficient in the receptor for type I IFNs (IFNAR−/− mice). A significant reduction in chlamydial shedding and duration of lower genital tract infection was observed in IFNAR−/− mice in comparison to the level of chlamydial shedding and duration of infection in wild-type (WT) mice. Furthermore, IFNAR−/− mice developed less chronic oviduct pathology in comparison to that in WT mice. Compared to the WT, IFNAR−/− mice had a greater number of chlamydial-specific T cells in their iliac lymph nodes 21 days postinfection. IFNAR−/− mice also exhibited earlier and enhanced CD4 T-cell recruitment to the cervical tissues, which was associated with increased expression of CXCL9 in the genital secretions of IFNAR−/− mice, but not with expression of CXCL10, which was reduced in the genital secretions of IFNAR−/− mice. These data suggest that type I IFNs exacerbate C. muridarum genital infection through an inhibition of the chlamydial-specific CD4 T-cell response.

Download Full-text

In VivoConditions Enable IFNAR-Independent Type I Interferon Production by Peritoneal CD11b+Cells upon Thogoto Virus Infection

Journal of Virology ◽

10.1128/jvi.00744-16 ◽

2016 ◽

Vol 90 (20) ◽

pp. 9330-9337 ◽

Cited By ~ 5

Author(s):

Georg Kochs ◽

Martina Anzaghe ◽

Stefanie Kronhart ◽

Valentina Wagner ◽

Patricia Gogesch ◽

...

Keyword(s):

Virus Infection ◽

Positive Feedback ◽

Molecular Mechanisms ◽

Viral Infections ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Cell Type ◽

Type I Ifns

ABSTRACTType I interferons (IFNs) crucially contribute to host survival upon viral infections. Robust expression of type I IFNs (IFN-α/β) and induction of an antiviral state critically depend on amplification of the IFN signal via the type I IFN receptor (IFNAR). A small amount of type I IFN produced early upon virus infection binds the IFNAR and activates a self-enhancing positive feedback loop, resulting in induction of large, protective amounts of IFN-α. Unexpectedly, we found robust, systemic IFN-α expression upon infection of IFNAR knockout mice with the orthomyxovirus Thogoto virus (THOV). The IFNAR-independent IFN-α production requiredin vivoconditions and was not achieved duringin vitroinfection. Using replication-incompetent THOV-derived virus-like particles, we demonstrate that IFNAR-independent type I IFN induction depends on viral polymerase activity but is largely independent of viral replication. To discover the cell type responsible for this effect, we used type I IFN reporter mice and identified CD11b+F4/80+myeloid cells within the peritoneal cavity of infected animals as the main source of IFNAR-independent type I IFN, corresponding to the particular tropism of THOV for this cell type.IMPORTANCEType I IFNs are crucial for the survival of a host upon most viral infections, and, moreover, they shape subsequent adaptive immune responses. Production of protective amounts of type I IFN critically depends on the positive feedback amplification via the IFNAR. Unexpectedly, we observed robust IFNAR-independent type I IFN expression upon THOV infection and unraveled molecular mechanisms and determined the tissue and cell type involved. Our data indicate that the host can effectively use alternative pathways to induce type I IFN responses if the classical feedback amplification is not available. Understanding how type I IFN can be produced in large amounts independently of IFNAR-dependent enhancement will identify mechanisms which might contribute to novel therapeutic strategies to fight viral pathogens.

Download Full-text