P136 Combined action of type I and type III IFN restricts initial replication of SARS-coronavirus in the lung but fails to inhibit systemic virus spread

STAT1-deficient mice are more susceptible to infection with severe acute respiratory syndrome coronavirus (SARS-CoV) than type I interferon (IFN) receptor-deficient mice. We used mice lacking functional receptors for both type I and type III IFN (double knockout, dKO) to evaluate the possibility that type III IFN plays a decisive role in SARS-CoV protection. We found that viral peak titres in lungs of dKO and STAT1-deficient mice were similar, but significantly higher than in wild-type mice. The kinetics of viral clearance from the lung were also comparable in dKO and STAT1-deficient mice. Surprisingly, however, infected dKO mice remained healthy, whereas infected STAT1-deficient mice developed liver pathology and eventually succumbed to neurological disease. Our data suggest that the failure of STAT1-deficient mice to control initial SARS-CoV replication efficiently in the lung is due to impaired type I and type III IFN signalling, whereas the failure to control subsequent systemic viral spread is due to unrelated defects in STAT1-deficient mice.

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Increased sensitivity of SARS-CoV-2 to type III interferon in human intestinal epithelial cells

10.1101/2021.06.14.448464 ◽

2021 ◽

Author(s):

Carmon Kee ◽

Camila Metz-Zumaran ◽

Patricio Doldan ◽

Cuncai Guo ◽

Megan Stanifer ◽

...

Keyword(s):

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Type I ◽

Intestinal Epithelial ◽

Human Intestine ◽

Virus Spread ◽

Type Iii ◽

Type I Ifns ◽

Human Intestinal Epithelial Cells ◽

Type Iii Ifn

The coronavirus SARS-CoV-2 caused the COVID-19 global pandemic leading to 3.5 million deaths worldwide as of June 2021. The human intestine was found to be a major viral target which could have a strong impact on virus spread and pathogenesis since it is one of the largest organs. While type I interferons (IFNs) are key cytokines acting against systemic virus spread, in the human intestine type III IFNs play a major role by restricting virus infection and dissemination without disturbing homeostasis. Recent studies showed that both type I and III IFNs can inhibit SARS-CoV-2 infection, but it is not clear if one IFN controls SARS-CoV-2 infection of the human intestine better or with a faster kinetics. In this study, we could show that both type I and III IFNs possess antiviral activity against SARS-CoV-2 in human intestinal epithelial cells (hIECs), however type III IFN is more potent. Shorter type III IFN pretreatment times and lower concentrations were required to efficiently reduce virus load when compared to type I IFNs. Moreover, type III IFNs significantly inhibited SARS-CoV-2 even 4 hours post-infection and induced a long-lasting antiviral effect in hIECs. Importantly, the sensitivity of SARS-CoV-2 to type III IFNs was virus-specific since type III IFN did not control VSV infection as efficiently. Together these results suggest that type III IFNs have a higher potential for IFN-based treatment of SARS-CoV-2 intestinal infection as compared to type I IFNs.

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Lambda Interferon Renders Epithelial Cells of the Respiratory and Gastrointestinal Tracts Resistant to Viral Infections

Journal of Virology ◽

10.1128/jvi.00272-10 ◽

2010 ◽

Vol 84 (11) ◽

pp. 5670-5677 ◽

Cited By ~ 243

Author(s):

Markus Mordstein ◽

Eva Neugebauer ◽

Vanessa Ditt ◽

Birthe Jessen ◽

Toni Rieger ◽

...

Keyword(s):

Epithelial Cells ◽

Respiratory Tract ◽

Viral Infections ◽

Influenza B Virus ◽

Influenza B ◽

Type I ◽

Type I Ifn ◽

Sars Coronavirus ◽

Type Iii ◽

Type Iii Ifn

ABSTRACT Virus-infected cells secrete a broad range of interferons (IFN) which confer resistance to yet uninfected cells by triggering the synthesis of antiviral factors. The relative contributions of the various IFN subtypes to innate immunity against virus infections remain elusive. IFN-α, IFN-β, and other type I IFN molecules signal through a common, universally expressed cell surface receptor, whereas type III IFN (IFN-λ) uses a distinct cell-type-specific receptor complex for signaling. Using mice lacking functional receptors for type I IFN, type III IFN, or both, we found that IFN-λ plays an important role in the defense against several human pathogens that infect the respiratory tract, such as influenza A virus, influenza B virus, respiratory syncytial virus, human metapneumovirus, and severe acute respiratory syndrome (SARS) coronavirus. These viruses were more pathogenic and replicated to higher titers in the lungs of mice lacking both IFN receptors than in mice with single IFN receptor defects. In contrast, Lassa fever virus, which infects via the respiratory tract but primarily replicates in the liver, was not influenced by the IFN-λ receptor defect. Careful analysis revealed that expression of functional IFN-λ receptor complexes in the lung and intestinal tract is restricted to epithelial cells and a few other, undefined cell types. Interestingly, we found that SARS coronavirus was present in feces from infected mice lacking receptors for both type I and type III IFN but not in those from mice lacking single receptors, supporting the view that IFN-λ contributes to the control of viral infections in epithelial cells of both respiratory and gastrointestinal tracts.

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SAMHD1 Phosphorylation Coordinates the Anti-HIV-1 Response by Diverse Interferons and Tyrosine Kinase Inhibition

mBio ◽

10.1128/mbio.00819-18 ◽

2018 ◽

Vol 9 (3) ◽

Cited By ~ 15

Author(s):

Matthew A. Szaniawski ◽

Adam M. Spivak ◽

James E. Cox ◽

Jonathan L. Catrow ◽

Timothy Hanley ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Restriction Factor ◽

Type I ◽

Dependent Manner ◽

Type Ii ◽

Type Iii ◽

Type Iii Ifn ◽

Hiv 1

ABSTRACTMacrophages are susceptible to human immunodeficiency virus type 1 (HIV-1) infection despite abundant expression of antiviral proteins. Perhaps the most important antiviral protein is the restriction factor sterile alpha motif domain and histidine/aspartic acid domain-containing protein 1 (SAMHD1). We investigated the role of SAMHD1 and its phospho-dependent regulation in the context of HIV-1 infection in primary human monocyte-derived macrophages and the ability of various interferons (IFNs) and pharmacologic agents to modulate SAMHD1. Here we show that stimulation by type I, type II, and to a lesser degree, type III interferons share activation of SAMHD1 via dephosphorylation at threonine-592 as a consequence of signaling. Cyclin-dependent kinase 1 (CDK1), a known effector kinase for SAMHD1, was downregulated at the protein level by all IFN types tested. Pharmacologic inhibition or small interfering RNA (siRNA)-mediated knockdown of CDK1 phenocopied the effects of IFN on SAMHD1. A panel of FDA-approved tyrosine kinase inhibitors potently induced activation of SAMHD1 and subsequent HIV-1 inhibition. The viral restriction imposed via IFNs or dasatinib could be overcome through depletion of SAMHD1, indicating that their effects are exerted primarily through this pathway. Our results demonstrate that SAMHD1 activation, but not transcriptional upregulation or protein induction, is the predominant mechanism of HIV-1 restriction induced by type I, type II, and type III IFN signaling in macrophages. Furthermore, SAMHD1 activation presents a pharmacologically actionable target through which HIV-1 infection can be subverted.IMPORTANCEOur experimental results demonstrate that SAMHD1 dephosphorylation at threonine-592 represents a central mechanism of HIV-1 restriction that is common to the three known families of IFNs. While IFN types I and II were potent inhibitors of HIV-1, type III IFN showed modest to undetectable activity. Regulation of SAMHD1 by IFNs involved changes in phosphorylation status but not in protein levels. Phosphorylation of SAMHD1 in macrophages occurred at least in part via CDK1. Tyrosine kinase inhibitors similarly induced SAMHD1 dephosphorylation, which protects macrophages from HIV-1 in a SAMHD1-dependent manner. SAMHD1 is a critical restriction factor regulating HIV-1 infection of macrophages.

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Impairment of Type I but Not Type III IFN Signaling by Hepatitis C Virus Infection Influences Antiviral Responses in Primary Human Hepatocytes

PLoS ONE ◽

10.1371/journal.pone.0121734 ◽

2015 ◽

Vol 10 (3) ◽

pp. e0121734 ◽

Cited By ~ 7

Author(s):

Jacques Friborg ◽

Petra Ross-Macdonald ◽

Jian Cao ◽

Ryan Willard ◽

Baiqing Lin ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Virus Infection ◽

Human Hepatocytes ◽

Type I ◽

Hepatitis C Virus Infection ◽

Type Iii ◽

Antiviral Responses ◽

Primary Human Hepatocytes ◽

Type Iii Ifn

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975. Roles of Type I and III Interferon in Severe Pathogenesis of Human Metapneumovirus

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz359.077 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S34-S35

Author(s):

John V Williams ◽

Yu Zhang ◽

Jiuyang Xu ◽

Margot Miranda-Katz ◽

Helen Rich ◽

...

Keyword(s):

Weight Loss ◽

Disease Severity ◽

Severe Disease ◽

Human Metapneumovirus ◽

Mouse Strains ◽

Type I ◽

Viral Titer ◽

Type I Ifn ◽

Type Iii ◽

Type Iii Ifn

Abstract Background Human metapneumovirus (HMPV) is a leading cause of respiratory tract infection in children and adults. However, mechanisms of pathogenesis are not fully understood. Methods We tested HMPV clinical and laboratory isolates in an established C57BL/6 mouse model and measured weight loss, airway function, and viral titers. Immune responses were determined using cytokine quantitation and flow cytometry. Results HMPV clinical isolates induced variable disease severity ranging from mild to fatal disease. Laboratory strain TN/94-49 did not cause weight loss, but mice infected with clinical isolate C2-202 showed dramatic weight loss and 40% mortality within 5 days post-infection (Figure 1). These findings were confirmed in other inbred mouse strains. C2-202-infected mice also suffered from impaired pulmonary function post-recovery. Lung viral titer did not correlate with disease severity, suggesting immune-mediated pathogenesis. C2-202-infected mice exhibited increased production of type I and III interferons (IFN) and pro-inflammatory cytokines, and lung neutrophil infiltration. However, neutrophil depletion or inflammasome inactivation did not reduce disease. Stat1/Stat2 double knockout (KO) mice lacking type I and III IFN signaling exhibited reduced weight loss but increased lung viral titer after C2-202 infection (Figure 2). Type I IFN receptor (IFNAR) KO mice infected with C2-202 had reduced weight loss but unchanged lung viral titer (Figure 3), while the addition of type III IFN blockade to C2-202-infected IFNAR mice had no effect on disease but increased lung viral titer (Figure 4). Conclusion These results suggest that severe disease caused by virulent HMPV was due to exuberant IFN response. Moreover, type I IFN was primarily associated with disease, while type III IFN was associated with viral clearance. These data suggest that IFN signaling plays an important role in HMPV pathogenesis, and thus serves as a potential therapeutic target. Disclosures All Authors: No reported Disclosures.

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The RNA binding protein La/SS-B promotes RIG-I-mediated type I and type III IFN responses following Sendai viral infection

Scientific Reports ◽

10.1038/s41598-017-15197-9 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 3

Author(s):

Rebecca Mahony ◽

Lindsay Broadbent ◽

Jacen S. Maier-Moore ◽

Ultan F. Power ◽

Caroline A. Jefferies

Keyword(s):

Viral Infection ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Type I ◽

Type Iii ◽

Type Iii Ifn

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Interferon-λ Attenuates Rabies Virus Infection by Inducing Interferon-Stimulated Genes and Alleviating Neurological Inflammation

Viruses ◽

10.3390/v12040405 ◽

2020 ◽

Vol 12 (4) ◽

pp. 405

Author(s):

Yingying Li ◽

Ling Zhao ◽

Zhaochen Luo ◽

Yachun Zhang ◽

Lei Lv ◽

...

Keyword(s):

Rabies Virus ◽

Neuronal Damage ◽

Inflammatory Cells ◽

Inhibitory Effect ◽

Type I ◽

Type Iii ◽

Interferon Stimulated Genes ◽

Viral Spread ◽

Type Iii Ifn

Rabies, caused by rabies virus (RABV), is a fatal neurological disease that still causes more than 59,000 human deaths each year. Type III interferon IFN-λs are cytokines with type I IFN-like antiviral activities. Although IFN-λ can restrict the infection for some viruses, especially intestinal viruses, the inhibitory effect against RABV infection remains undefined. In this study, the function of type III IFN against RABV infection was investigated. Initially, we found that IFN-λ2 and IFN-λ3 could inhibit RABV replication in cells. To characterize the role of IFN-λ in RABV infection in a mouse model, recombinant RABVs expressing murine IFN-λ2 or IFN-λ3, termed as rB2c-IFNλ2 or rB2c-IFNλ3, respectively, were constructed and rescued. It was found that expression of IFN-λ could reduce the pathogenicity of RABV and limit viral spread in the brains by different infection routes. Furthermore, expression of IFN-λ could induce the activation of the JAK-STAT pathway, resulting in the production of interferon-stimulated genes (ISGs). It was also found that rRABVs expressing IFN-λ could reduce the production of inflammatory cytokines in primary astrocytes and microgila cells, restrict the opening of the blood-brain barrier (BBB), and prevent excessive infiltration of inflammatory cells into the brain, which could be responsible for the neuronal damage caused by RABV. Consistently, IFN-λ was found to maintain the integrity of tight junction (TJ) protein ZO-1 of BBB to alleviate neuroinflammation in a transwell model. Our study underscores the role of IFN-λ in inhibiting RABV infection, which potentiates IFN-λ as a possible therapeutic agent for the treatment of RABV infection.

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Inhibition of SARS–CoV-2 by type I and type III interferons

Journal of Biological Chemistry ◽

10.1074/jbc.ac120.013788 ◽

2020 ◽

Vol 295 (41) ◽

pp. 13958-13964 ◽

Cited By ~ 31

Author(s):

Ulrike Felgenhauer ◽

Andreas Schoen ◽

Hans Henrik Gad ◽

Rune Hartmann ◽

Andreas R. Schaubmar ◽

...

Keyword(s):

Adverse Effect ◽

Epithelial Cell ◽

Cell Lines ◽

Janus Kinase ◽

Type I ◽

Signal Transducer ◽

Type Iii ◽

Epithelial Cell Lines ◽

Inhibitory Activities ◽

Type Iii Ifn

The recently emerged severe acute respiratory syndrome coronavirus-2 (SARS–CoV-2) is the causative agent of the devastating COVID-19 lung disease pandemic. Here, we tested the inhibitory activities of the antiviral interferons of type I (IFN-α) and type III (IFN-λ) against SARS–CoV-2 and compared them with those against SARS–CoV-1, which emerged in 2003. Using two mammalian epithelial cell lines (human Calu-3 and simian Vero E6), we found that both IFNs dose-dependently inhibit SARS–CoV-2. In contrast, SARS–CoV-1 was restricted only by IFN-α in these cell lines. SARS–CoV-2 generally exhibited a broader IFN sensitivity than SARS–CoV-1. Moreover, ruxolitinib, an inhibitor of IFN-triggered Janus kinase/signal transducer and activator of transcription signaling, boosted SARS–CoV-2 replication in the IFN-competent Calu-3 cells. We conclude that SARS–CoV-2 is sensitive to exogenously added IFNs. This finding suggests that type I and especially the less adverse effect–prone type III IFN are good candidates for the management of COVID-19.

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