Potent Inhibition of SARS-Associated Coronavirus (SCoV) Infection and Replication by Type I Interferons (IFN-α/β) but Not by Type II Interferon (IFN-γ)

ABSTRACTTrypanosoma cruzi, the protozoan parasite that causes human Chagas' disease, induces a type I interferon (IFN) (IFN-α/β) response during acute experimental infection in mice and in isolated primary cell types. To examine the potential impact of the type I IFN response in shaping outcomes in experimentalT. cruziinfection, groups of wild-type (WT) and type I IFN receptor-deficient (IFNAR−/−) 129sv/ev mice were infected with two differentT. cruzistrains under lethal and sublethal conditions and several parameters were measured during the acute stage of infection. The results demonstrate that type I IFNs are not required for early host protection againstT. cruzi. In contrast, under conditions of lethalT. cruzichallenge, WT mice succumbed to infection whereas IFNAR−/−mice were ultimately able to control parasite growth and survive.T. cruziclearance in and survival of IFNAR−/−mice were accompanied by higher levels of IFN-γ production by isolated splenocytes in response to parasite antigen. The suppression of IFN-γ in splenocytes from WT mice was independent of IL-10 levels. While the impact of type I IFNs on the production of IFN-γ and other cytokines/chemokines remains to be fully determined in the context ofT. cruziinfection, our data suggest that, under conditions of high parasite burden, type I IFNs negatively impact IFN-γ production, initiating a detrimental cycle that contributes to the ultimate failure to control infection. These findings are consistent with a growing theme in the microbial pathogenesis field in which type I IFNs can be detrimental to the host in a variety of nonviral pathogen infection models.

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Type I Interferons Promote Severe Disease in a Mouse Model of Lethal Ehrlichiosis

Infection and Immunity ◽

10.1128/iai.01564-13 ◽

2014 ◽

Vol 82 (4) ◽

pp. 1698-1709 ◽

Cited By ~ 15

Author(s):

Yubin Zhang ◽

Vinh Thai ◽

Amanda McCabe ◽

Maura Jones ◽

Katherine C. MacNamara

Keyword(s):

Mouse Model ◽

Severe Disease ◽

Type I Interferons ◽

Type I ◽

Bacterial Burden ◽

Chimeric Mice ◽

Content Type ◽

Type I Ifns ◽

Ifn Γ ◽

Deficient Mice

ABSTRACTHuman monocytic ehrlichiosis (HME) is caused by a tick-borne obligate intracellular pathogen of the orderRickettsiales. HME disease can range from mild to a fatal, toxic shock-like syndrome, yet the mechanisms regulating pathogenesis are not well understood. We define a central role for type I interferons (alpha interferon [IFN-α] and IFN-β) in severe disease in a mouse model of fatal ehrlichiosis caused byIxodes ovatusEhrlichia(IOE). IFN-α and IFN-β were induced by IOE infection but not in response to a less virulent strain,Ehrlichia muris. The major sources of type I IFNs during IOE infection were plasmacytoid dendritic cells and monocytes. Mice lacking the receptor for type I IFNs (Ifnardeficient) or neutralization of IFN-α and IFN-β resulted in a reduced bacterial burden.Ifnar-deficient mice exhibited significantly increased survival after IOE infection, relative to that of wild-type (WT) mice, that correlated with increased type II IFN (IFN-γ) production. Pathogen-specific antibody responses were also elevated inIfnar-deficient mice, and this required IFN-γ. Remarkably, increased IFN-γ and IgM were not essential for protection in the absence of type I IFN signaling. The direct effect of type I IFNs on hematopoietic and nonhematopoietic cells was evaluated in bone marrow chimeric mice. We observed that chimeric mice containingIfnar-deficient hematopoietic cells succumbed to infection early, whereasIfnar-deficient mice containing WT hematopoietic cells exhibited increased survival, despite having a higher bacterial burden. These data demonstrate that IFN-α receptor signaling in nonhematopoietic cells is important for pathogenesis. Thus, type I IFNs are induced during a rickettsial infectionin vivoand promote severe disease.

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Casein Kinase 1α Mediates the Degradation of Receptors for Type I and Type II Interferons Caused by Hemagglutinin of Influenza A Virus

Journal of Virology ◽

10.1128/jvi.00006-18 ◽

2018 ◽

Vol 92 (7) ◽

Cited By ~ 9

Author(s):

Chuan Xia ◽

Jennifer J. Wolf ◽

Madhuvanthi Vijayan ◽

Caleb J. Studstill ◽

Wenjun Ma ◽

...

Keyword(s):

Influenza Virus ◽

Influenza A Virus ◽

Influenza A ◽

P38 Map Kinase ◽

Casein Kinase ◽

Type I ◽

Type Ii ◽

Ifn Γ ◽

Cellular Responsiveness ◽

Novel Strategy

ABSTRACTAlthough influenza A virus (IAV) evades cellular defense systems to effectively propagate in the host, the viral immune-evasive mechanisms are incompletely understood. Our recent data showed that hemagglutinin (HA) of IAV induces degradation of type I IFN receptor 1 (IFNAR1). Here, we demonstrate that IAV HA induces degradation of type II IFN (IFN-γ) receptor 1 (IFNGR1), as well as IFNAR1, via casein kinase 1α (CK1α), resulting in the impairment of cellular responsiveness to both type I and II IFNs. IAV infection or transient HA expression induced degradation of both IFNGR1 and IFNAR1, whereas HA gene-deficient IAV failed to downregulate the receptors. IAV HA caused the phosphorylation and ubiquitination of IFNGR1, leading to the lysosome-dependent degradation of IFNGR1. Influenza viral HA strongly decreased cellular sensitivity to type II IFNs, as it suppressed the activation of STAT1 and the induction of IFN-γ-stimulated genes in response to exogenously supplied recombinant IFN-γ. Importantly, CK1α, but not p38 MAP kinase or protein kinase D2, was proven to be critical for HA-induced degradation of both IFNGR1 and IFNAR1. Pharmacologic inhibition of CK1α or small interfering RNA (siRNA)-based knockdown of CK1α repressed the degradation processes of both IFNGR1 and IFNAR1 triggered by IAV infection. Further, CK1α was shown to be pivotal for proficient replication of IAV. Collectively, the results suggest that IAV HA induces degradation of IFN receptors via CK1α, creating conditions favorable for viral propagation. Therefore, the study uncovers a new immune-evasive pathway of influenza virus.IMPORTANCEInfluenza A virus (IAV) remains a grave threat to humans, causing seasonal and pandemic influenza. Upon infection, innate and adaptive immunity, such as the interferon (IFN) response, is induced to protect hosts against IAV infection. However, IAV seems to be equipped with tactics to evade the IFN-mediated antiviral responses, although the detailed mechanisms need to be elucidated. In the present study, we show that IAV HA induces the degradation of the type II IFN receptor IFNGR1 and thereby substantially attenuates cellular responses to IFN-γ. Of note, a cellular kinase, casein kinase 1α (CK1α), is crucial for IAV HA-induced degradation of both IFNGR1 and IFNAR1. Accordingly, CK1α is proven to positively regulate IAV propagation. Thus, this study unveils a novel strategy employed by IAV to evade IFN-mediated antiviral activities. These findings may provide new insights into the interplay between IAV and host immunity to impact influenza virus pathogenicity.

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The Polybasic Cleavage Site in SARS-CoV-2 Spike Modulates Viral Sensitivity to Type I Interferon and IFITM2

Journal of Virology ◽

10.1128/jvi.02422-20 ◽

2021 ◽

Vol 95 (9) ◽

Cited By ~ 4

Author(s):

Helena Winstone ◽

Maria Jose Lista ◽

Alisha C. Reid ◽

Clement Bouton ◽

Suzanne Pickering ◽

...

Keyword(s):

Viral Entry ◽

Cleavage Site ◽

Type I Interferons ◽

Spike Protein ◽

Type I ◽

Furin Cleavage ◽

Independent Manner ◽

Type I Ifns ◽

Furin Cleavage Site ◽

Potent Inhibition

ABSTRACT The cellular entry of severe acute respiratory syndrome-associated coronaviruses types 1 and 2 (SARS-CoV-1 and -2) requires sequential protease processing of the viral spike glycoprotein. The presence of a polybasic cleavage site in SARS-CoV-2 spike at the S1/S2 boundary has been suggested to be a factor in the increased transmissibility of SARS-CoV-2 compared to SARS-CoV-1 by facilitating maturation of the spike precursor by furin-like proteases in the producer cells rather than endosomal cathepsins in the target. We investigate the relevance of the polybasic cleavage site in the route of entry of SARS-CoV-2 and the consequences this has for sensitivity to interferons (IFNs) and, more specifically, the IFN-induced transmembrane (IFITM) protein family that inhibit entry of diverse enveloped viruses. We found that SARS-CoV-2 is restricted predominantly by IFITM2, rather than IFITM3, and the degree of this restriction is governed by route of viral entry. Importantly, removal of the cleavage site in the spike protein renders SARS-CoV-2 entry highly pH and cathepsin dependent in late endosomes, where, like SARS-CoV-1 spike, it is more sensitive to IFITM2 restriction. Furthermore, we found that potent inhibition of SARS-CoV-2 replication by type I but not type II IFNs is alleviated by targeted depletion of IFITM2 expression. We propose that the polybasic cleavage site allows SARS-CoV-2 to mediate viral entry in a pH-independent manner, in part to mitigate against IFITM-mediated restriction and promote replication and transmission. This suggests that therapeutic strategies that target furin-mediated cleavage of SARS-CoV-2 spike may reduce viral replication through the activity of type I IFNs. IMPORTANCE The furin cleavage site in the spike protein is a distinguishing feature of SARS-CoV-2 and has been proposed to be a determinant for the higher transmissibility between individuals, compared to SARS-CoV-1. One explanation for this is that it permits more efficient activation of fusion at or near the cell surface rather than requiring processing in the endosome of the target cell. Here, we show that SARS-CoV-2 is inhibited by antiviral membrane protein IFITM2 and that the sensitivity is exacerbated by deletion of the furin cleavage site, which restricts viral entry to low pH compartments. Furthermore, we find that IFITM2 is a significant effector of the antiviral activity of type I interferons against SARS-CoV-2 replication. We suggest that one role of the furin cleavage site is to reduce SARS-CoV-2 sensitivity to innate immune restriction, and thus, it may represent a potential therapeutic target for COVID-19 treatment development.

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Type I interferons are essential while type II interferon is dispensable for protection against St. Louis encephalitis virus infection in the mouse brain

Virulence ◽

10.1080/21505594.2020.1869392 ◽

2021 ◽

Vol 12 (1) ◽

pp. 244-259

Author(s):

Rebeca Froes Rocha ◽

Juliana L. Del Sarto ◽

Giovanni F. Gomes ◽

Mariana P. Gonçalves ◽

Milene A. Rachid ◽

...

Keyword(s):

Virus Infection ◽

Mouse Brain ◽

Encephalitis Virus ◽

Type I Interferons ◽

Type I ◽

Type Ii

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Activation of the Transcription Factor ISGF3 by Interferon-gamma

Biological Chemistry ◽

10.1515/bc.1999.087 ◽

1999 ◽

Vol 380 (6) ◽

pp. 699-703 ◽

Cited By ~ 79

Author(s):

M. Matsumoto ◽

N. Tanaka ◽

H. Harada ◽

T. Kimura ◽

T. Yokochi ◽

...

Keyword(s):

Transcription Factor ◽

Type I ◽

Type Ii ◽

Additional Mechanism ◽

Embryonic Fibroblasts ◽

Signal Transducers ◽

Stat Proteins ◽

Antiviral Activities ◽

Ifn Γ ◽

Binding Component

AbstractThe interferon-stimulated gene factor 3 (ISGF3) transcription factor has been extensively studied in the context of the type I interferon (IFN-α/β)-mediated antiviral response; it consists of the major DNA-binding component p48, and the signal transducers and activators of transcription (Stat)1 and Stat2. We show here that type II IFN (IFN-γ) can also invoke the activation of ISGF3 in mouse primary embryonic fibroblasts. In fact, the two Stat proteins were tyrosine phosphorylated in IFN-γ stimulated cells. Our present findings reveal an additional mechanism by which these two distinct types of cytokines, IFN-α/β and -γ, can commonly elicit antiviral activities.

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Stat-mediated Signaling Induced by Type I and Type II Interferons (IFNs) Is Differentially Controlled through Lipid Microdomain Association and Clathrin-dependent Endocytosis of IFN Receptors

Molecular Biology of the Cell ◽

10.1091/mbc.e06-01-0076 ◽

2006 ◽

Vol 17 (7) ◽

pp. 2896-2909 ◽

Cited By ~ 74

Author(s):

Marta Marchetti ◽

Marie-Noelle Monier ◽

Alexandre Fradagrada ◽

Keith Mitchell ◽

Florence Baychelier ◽

...

Keyword(s):

Plasma Membrane ◽

Biological Activities ◽

Critical Role ◽

Membrane Lipid ◽

Endocytic Pathway ◽

Type I ◽

Type Ii ◽

Biological Responses ◽

Signal Specificity ◽

Ifn Γ

Type I (α/β) and type II (γ) interferons (IFNs) bind to distinct receptors, although they activate the same signal transducer and activator of transcription, Stat1, raising the question of how signal specificity is maintained. Here, we have characterized the sorting of IFN receptors (IFN-Rs) at the plasma membrane and the role it plays in IFN-dependent signaling and biological activities. We show that both IFN-α and IFN-γ receptors are internalized by a classical clathrin- and dynamin-dependent endocytic pathway. Although inhibition of clathrin-dependent endocytosis blocked the uptake of IFN-α and IFN-γ receptors, this inhibition only affected IFN-α–induced Stat1 and Stat2 signaling. Furthermore, the antiviral and antiproliferative activities induced by IFN-α but not IFN-γ were also affected. Finally, we show that, unlike IFN-α receptors, activated IFN-γ receptors rapidly become enriched in plasma membrane lipid microdomains. We conclude that IFN-R compartmentalization at the plasma membrane, through clathrin-dependent endocytosis and lipid-based microdomains, plays a critical role in the signaling and biological responses induced by IFNs and contributes to establishing specificity within the Jak/Stat signaling pathway.

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Acute Liver Failure Following Minocycline Treatment – A Case Report and Review of the Literature

Zeitschrift für Gastroenterologie ◽

10.1055/s-0031-1299443 ◽

2012 ◽

Vol 50 (08) ◽

pp. 771-775 ◽

Cited By ~ 4

Author(s):

A. Kuhn ◽

C. Weiler-Normann ◽

C. Schramm ◽

S. Kluge ◽

M. Behne ◽

...

Keyword(s):

Liver Failure ◽

Acute Liver Failure ◽

Experimental Studies ◽

Type I ◽

Type Ii ◽

Minocycline Treatment ◽

Tnf Α ◽

Ige Mediated ◽

Ifn Γ

AbstractWe present the case of a 23-year-old female patient with acute liver failure following intake of minocycline. This patient had severe hypereosinophilia and massively increased IgE levels. Experimental studies in this case revealed elevated IFN-γ-, as well as TNF-α-producing CD4+ and CD8+ T-cells after in vitro stimulation with minocycline, indicating a type I/IgE-mediated as well as type II/cytotoxic reaction in the pathogenesis of minocycline-induced liver failure. Although mild forms of liver involvement are well known side effects of minocycline, only 8 cases with acute liver failure have been reported, and we present a review of all cases.

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Expression of Interferon Gamma by a Recombinant Rabies Virus Strongly Attenuates the Pathogenicity of the Virus via Induction of Type I Interferon

Journal of Virology ◽

10.1128/jvi.01572-14 ◽

2014 ◽

Vol 89 (1) ◽

pp. 312-322 ◽

Cited By ~ 26

Author(s):

Darryll A. Barkhouse ◽

Samantha A. Garcia ◽

Emily K. Bongiorno ◽

Aurore Lebrun ◽

Milosz Faber ◽

...

Keyword(s):

Rabies Virus ◽

Interferon Gamma ◽

Virus Replication ◽

Neutralizing Antibodies ◽

Type I Interferon ◽

Lethal Dose ◽

Type I Interferons ◽

Type I ◽

Antiviral Effects ◽

Ifn Γ

ABSTRACTPrevious animal model experiments have shown a correlation between interferon gamma (IFN-γ) expression and both survival from infection with attenuated rabies virus (RABV) and reduction of neurological sequelae. Therefore, we hypothesized that rapid production of murine IFN-γ by the rabies virus itself would induce a more robust antiviral response than would occur naturally in mice. To test this hypothesis, we used reverse engineering to clone the mouse IFN-γ gene into a pathogenic rabies virus backbone, SPBN, to produce the recombinant rabies virus designated SPBNγ. Morbidity and mortality were monitored in mice infected intranasally with SPBNγ or SPBN(−) control virus to determine the degree of attenuation caused by the expression of IFN-γ. Incorporation of IFN-γ into the rabies virus genome highly attenuated the virus. SPBNγ has a 50% lethal dose (LD50)more than 100-fold greater than SPBN(−).In vitroandin vivomouse experiments show that SPBNγ infection enhances the production of type I interferons. Furthermore, knockout mice lacking the ability to signal through the type I interferon receptor (IFNAR−/−) cannot control the SPBNγ infection and rapidly die. These data suggest that IFN-γ production has antiviral effects in rabies, largely due to the induction of type I interferons.IMPORTANCESurvival from rabies is dependent upon the early control of virus replication and spread. Once the virus reaches the central nervous system (CNS), this becomes highly problematic. Studies of CNS immunity to RABV have shown that control of replication begins at the onset of T cell entry and IFN-γ production in the CNS prior to the appearance of virus-neutralizing antibodies. Moreover, antibody-deficient mice are able to control but not clear attenuated RABV from the CNS. We find here that IFN-γ triggers the early production of type I interferons with the expected antiviral effects. We also show that engineering a lethal rabies virus to express IFN-γ directly in the infected tissue reduces rabies virus replication and spread, limiting its pathogenicity in normal and immunocompromised mice. Therefore, vector delivery of IFN-γ to the brain may have the potential to treat individuals who would otherwise succumb to infection with rabies virus.

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