Conversion of Adenines to Inosines in RNA During Virus Infections Activates Innate Immune Responses

ABSTRACT We describe a novel function for the interferon (IFN)-induced protein 44-like (IFI44L) gene in negatively modulating innate immune responses induced after virus infections. Furthermore, we show that decreasing IFI44L expression impairs virus production and that IFI44L expression negatively modulates the antiviral state induced by an analog of double-stranded RNA (dsRNA) or by IFN treatment. The mechanism likely involves the interaction of IFI44L with cellular FK506-binding protein 5 (FKBP5), which in turn interacts with kinases essential for type I and III IFN responses, such as inhibitor of nuclear factor kappa B (IκB) kinase alpha (IKKα), IKKβ, and IKKε. Consequently, binding of IFI44L to FKBP5 decreased interferon regulatory factor 3 (IRF-3)-mediated and nuclear factor kappa-B (NF-κB) inhibitor (IκBα)-mediated phosphorylation by IKKε and IKKβ, respectively. According to these results, IFI44L is a good target for treatment of diseases associated with excessive IFN levels and/or proinflammatory responses and for reduction of viral replication. IMPORTANCE Excessive innate immune responses can be deleterious for the host, and therefore, negative feedback is needed. Here, we describe a completely novel function for IFI44L in negatively modulating innate immune responses induced after virus infections. In addition, we show that decreasing IFI44L expression impairs virus production and that IFI44L expression negatively modulates the antiviral state induced by an analog of dsRNA or by IFN treatment. IFI44L binds to the cellular protein FKBP5, which in turn interacts with kinases essential for type I and III IFN induction and signaling, such as the kinases IKKα, IKKβ, and IKKε. IFI44L binding to FKBP5 decreased the phosphorylation of IRF-3 and IκBα mediated by IKKε and IKKβ, respectively, providing an explanation for the function of IFI44L in negatively modulating IFN responses. Therefore, IFI44L is a candidate target for reducing virus replication.

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Sex differences in innate anti-viral immune responses to respiratory viruses and in their clinical outcomes in a birth cohort study

Scientific Reports ◽

10.1038/s41598-021-03044-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Eteri Regis ◽

Sara Fontanella ◽

Lijing Lin ◽

Rebecca Howard ◽

Sadia Haider ◽

...

Keyword(s):

Sex Differences ◽

Immune Responses ◽

Birth Cohort ◽

Respiratory Virus ◽

Respiratory Infections ◽

Respiratory Viruses ◽

Innate Immune ◽

Innate Immune Responses ◽

Virus Infections ◽

Respiratory Virus Infections

AbstractThe mechanisms explaining excess morbidity and mortality in respiratory infections among males are poorly understood. Innate immune responses are critical in protection against respiratory virus infections. We hypothesised that innate immune responses to respiratory viruses may be deficient in males. We stimulated peripheral blood mononuclear cells from 345 participants at age 16 years in a population-based birth cohort with three live respiratory viruses (rhinoviruses A16 and A1, and respiratory syncytial virus) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2) and investigated sex differences in interferon (IFN) responses. IFN-α responses to all viruses and stimuli were 1.34–2.06-fold lower in males than females (P = 0.018 − < 0.001). IFN-β, IFN-γ and IFN-induced chemokines were also deficient in males across all stimuli/viruses. Healthcare records revealed 12.1% of males and 6.6% of females were hospitalized with respiratory infections in infancy (P = 0.017). In conclusion, impaired innate anti-viral immunity in males likely results in high male morbidity and mortality from respiratory virus infections.

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Innate immune responses elicited by Sin Nombre virus or type I IFN agonists protect hamsters from lethal Andes virus infections

Journal of General Virology ◽

10.1099/jgv.0.001131 ◽

2018 ◽

Vol 99 (10) ◽

pp. 1359-1366 ◽

Cited By ~ 3

Author(s):

Rebecca L. Brocato ◽

Victoria Wahl ◽

Christopher D. Hammerbeck ◽

Matthew D. Josleyn ◽

Anita K. McElroy ◽

...

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Sin Nombre Virus ◽

Type I ◽

Type I Ifn ◽

Innate Immune Responses ◽

Virus Infections ◽

Andes Virus

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Cellular Signaling and Innate Immune Responses to RNA Virus Infections

10.1128/9781555815561 ◽

2008 ◽

Cited By ~ 12

Keyword(s):

Immune Responses ◽

Rna Virus ◽

Cellular Signaling ◽

Innate Immune ◽

Innate Immune Responses ◽

Virus Infections

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Shared Molecular Signatures Across Neurodegenerative Diseases and Herpes Virus Infections Highlights Potential Mechanisms for Maladaptive Innate Immune Responses

Scientific Reports ◽

10.1038/s41598-019-45129-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 8

Author(s):

Ana Caroline Costa Sa ◽

Heather Madsen ◽

James R. Brown

Keyword(s):

Immune Responses ◽

Neurodegenerative Diseases ◽

Herpes Virus ◽

Innate Immune ◽

Molecular Signatures ◽

Innate Immune Responses ◽

Virus Infections ◽

Herpes Virus Infections ◽

Herpès Virus

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Innate Immune Responses in Respiratory Syncytial Virus Infections

Viral Immunology ◽

10.1089/0882824041310612 ◽

2004 ◽

Vol 17 (2) ◽

pp. 220-233 ◽

Cited By ~ 35

Author(s):

Subramaniam Krishnan ◽

Marilyn Halonen ◽

Robert C. Welliver

Keyword(s):

Respiratory Syncytial Virus ◽

Immune Responses ◽

Innate Immune ◽

Innate Immune Responses ◽

Virus Infections ◽

Respiratory Syncytial Virus Infections ◽

Syncytial Virus

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Oral Immune Activation by Disgust and Disease-Related Pictures

Journal of Psychophysiology ◽

10.1027/0269-8803/a000143 ◽

2015 ◽

Vol 29 (3) ◽

pp. 119-129 ◽

Cited By ~ 4

Author(s):

Richard J. Stevenson ◽

Deborah Hodgson ◽

Megan J. Oaten ◽

Luba Sominsky ◽

Mehmet Mahmut ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Negative Control ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Markers ◽

Before And After ◽

Secondary Analyses ◽

Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

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