A paucigranulocytic asthma host environment promotes the emergence of virulent influenza viral variants

Influenza virus has a high mutation rate, such that within one host different viral variants can emerge. Evidence suggests that influenza virus variants are more prevalent in pregnant and/or obese individuals due to their impaired interferon response. We have recently shown that the non-allergic, paucigranulocytic subtype of asthma is associated with impaired type I interferon production. Here, we seek to address if this is associated with an increased emergence of influenza virus variants. Compared to controls, mice with paucigranulocytic asthma had increased disease severity and an increased emergence of influenza virus variants. Specifically, PB1 mutations exclusively detected in asthmatic mice were associated with increased polymerase activity. Furthermore, asthmatic host-derived virus led to increased disease severity in wild-type mice. Taken together, these data suggest that at least a subset of patients with asthma may be more susceptible to severe influenza and may be a possible source of new influenza virus variants.

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Influenza Virus-Induced Type I Interferon Leads to Polyclonal B-Cell Activation but Does Not Break Down B-Cell Tolerance

Journal of Virology ◽

10.1128/jvi.00839-07 ◽

2007 ◽

Vol 81 (22) ◽

pp. 12525-12534 ◽

Cited By ~ 10

Author(s):

Anne Woods ◽

Fanny Monneaux ◽

Pauline Soulas-Sprauel ◽

Sylviane Muller ◽

Thierry Martin ◽

...

Keyword(s):

Influenza Virus ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Type I Interferon ◽

Type I ◽

Interferon Production ◽

B Cell Activation ◽

B Cell Tolerance

ABSTRACT The link between infection and autoimmunity is not yet well understood. This study was designed to evaluate if an acute viral infection known to induce type I interferon production, like influenza, can by itself be responsible for the breakdown of immune tolerance and for autoimmunity. We first tested the effects of influenza virus on B cells in vitro. We then infected different transgenic mice expressing human rheumatoid factors (RF) in the absence or in the constitutive presence of the autoantigen (human immunoglobulin G [IgG]) and young lupus-prone mice [(NZB × NZW)F1] with influenza virus and looked for B-cell activation. In vitro, the virus induces B-cell activation through type I interferon production by non-B cells but does not directly stimulate purified B cells. In vivo, both RF and non-RF B cells were activated in an autoantigen-independent manner. This activation was abortive since IgM and IgM-RF production levels were not increased in infected mice compared to uninfected controls, whether or not anti-influenza virus human IgG was detected and even after viral rechallenge. As in RF transgenic mice, acute viral infection of (NZB × NZW)F1 mice induced only an abortive activation of B cells and no increase in autoantibody production compared to uninfected animals. Taken together, these experiments show that virus-induced acute type I interferon production is not able by itself to break down B-cell tolerance in both normal and autoimmune genetic backgrounds.

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Involvement of Virus-Induced Interferon Production in IgG Autoantibody-Mediated Anemia

International Journal of Molecular Sciences ◽

10.3390/ijms22169027 ◽

2021 ◽

Vol 22 (16) ◽

pp. 9027

Author(s):

Sarah Legrain ◽

Dan Su ◽

Mélanie Gaignage ◽

Cor Breukel ◽

Jill Claassens ◽

...

Keyword(s):

Lactate Dehydrogenase ◽

Type I Interferon ◽

Type I ◽

Type Ii ◽

Interferon Production ◽

Activated Macrophages ◽

Wild Type ◽

Fcγ Receptors ◽

Interferon Receptor ◽

Deficient Mice

Infection with viruses, such as the lactate dehydrogenase-elevating virus (LDV), is known to trigger the onset of autoimmune anemia through the enhancement of the phagocytosis of autoantibody-opsonized erythrocytes by activated macrophages. Type I interferon receptor-deficient mice show enhanced anemia, which suggests a protective effect of these cytokines, partly through the control of type II interferon production. The development of anemia requires the expression of Fcγ receptors (FcγR) I, III, and IV. Whereas LDV infection decreases FcγR III expression, it enhances FcγR I and IV expression in wild-type animals. The LDV-associated increase in the expression of FcγR I and IV is largely reduced in type I interferon receptor-deficient mice, through both type II interferon-dependent and -independent mechanisms. Thus, the regulation of the expression of FcγR I and IV, but not III, by interferons may partly explain the exacerbating effect of LDV infection on anemia that results from the enhanced phagocytosis of IgG autoantibody-opsonized erythrocytes.

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The Interferon-Induced Exonuclease ISG20 Exerts Antiviral Activity through Upregulation of Type I Interferon Response Proteins

mSphere ◽

10.1128/msphere.00209-18 ◽

2018 ◽

Vol 3 (5) ◽

Cited By ~ 12

Author(s):

Christopher M. Weiss ◽

Derek W. Trobaugh ◽

Chengqun Sun ◽

Tiffany M. Lucas ◽

Michael S. Diamond ◽

...

Keyword(s):

Virus Replication ◽

Type I Interferon ◽

Rna Virus ◽

Ectopic Expression ◽

Viral Rna ◽

Interferon Response ◽

Type I ◽

Venezuelan Equine Encephalitis ◽

Wild Type ◽

In Cells

ABSTRACTType I interferon (IFN)-stimulated genes (ISGs) have critical roles in inhibiting virus replication and dissemination. Despite advances in understanding the molecular basis of ISG restriction, the antiviral mechanisms of many remain unclear. The 20-kDa ISG ISG20 is a nuclear 3′–5′ exonuclease with preference for single-stranded RNA (ssRNA) and has been implicated in the IFN-mediated restriction of several RNA viruses. Although the exonuclease activity of ISG20 has been shown to degrade viral RNAin vitro, evidence has yet to be presented that virus inhibition in cells requires this activity. Here, we utilized a combination of an inducible, ectopic expression system and newly generatedIsg20−/−mice to investigate mechanisms and consequences of ISG20-mediated restriction. Ectopically expressed ISG20 localized primarily to Cajal bodies in the nucleus and restricted replication of chikungunya and Venezuelan equine encephalitis viruses. Although restriction by ISG20 was associated with inhibition of translation of infecting genomic RNA, degradation of viral RNAs was not observed. Instead, translation inhibition of viral RNA was associated with ISG20-induced upregulation of over 100 other genes, many of which encode known antiviral effectors. ISG20 modulated the production of IFIT1, an ISG that suppresses translation of alphavirus RNAs. Consistent with this observation, the pathogenicity of IFIT1-sensitive alphaviruses was increased inIsg20−/−mice compared to that of wild-type viruses but not in cells ectopically expressing ISG20. Our findings establish an indirect role for ISG20 in the early restriction of RNA virus replication by regulating expression of other ISGs that inhibit translation and possibly other activities in the replication cycle.IMPORTANCEThe host immune responses to infection lead to the production of type I interferon (IFN), and the upregulation of interferon-stimulated genes (ISGs) reduces virus replication and virus dissemination within a host. Ectopic expression of the interferon-induced 20-kDa exonuclease ISG20 suppressed replication of chikungunya virus and Venezuelan equine encephalitis virus, two mosquito-vectored RNA alphaviruses. Since the replication of alphavirus genomes occurs exclusively in the cytoplasm, the mechanism of nucleus-localized ISG20 inhibition of replication is unclear. In this study, we determined that ISG20 acts as a master regulator of over 100 genes, many of which are ISGs. Specifically, ISG20 upregulated IFIT1 genes and inhibited translation of the alphavirus genome. Furthermore, IFIT1-sensitive alphavirus replication was increased inIsg20−/−mice compared to the replication of wild-type viruses but not in cells ectopically expressing ISG20. We propose that ISG20 acts as an indirect regulator of RNA virus replication in the cytoplasm through the upregulation of many other ISGs.

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Transcriptomic profile of cystic fibrosis patients identifies type I interferon response and ribosomal stalk proteins as potential modifiers of disease severity

PLoS ONE ◽

10.1371/journal.pone.0183526 ◽

2017 ◽

Vol 12 (8) ◽

pp. e0183526 ◽

Cited By ~ 18

Author(s):

Michael S. D. Kormann ◽

Alexander Dewerth ◽

Felizitas Eichner ◽

Praveen Baskaran ◽

Andreas Hector ◽

...

Keyword(s):

Cystic Fibrosis ◽

Disease Severity ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

Transcriptomic Profile ◽

Ribosomal Stalk

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The LymphotoxinβReceptor Is Essential for Upregulation of IFN-Induced Guanylate-Binding Proteins and Survival afterToxoplasma gondiiInfection

Mediators of Inflammation ◽

10.1155/2017/7375818 ◽

2017 ◽

Vol 2017 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Kristina Behnke ◽

Ursula R. Sorg ◽

Helmut E. Gabbert ◽

Klaus Pfeffer

Keyword(s):

Type I Interferon ◽

Parasite Load ◽

Mortality Rates ◽

Host Responses ◽

Interferon Response ◽

Transcriptional Level ◽

Type I ◽

Type Ii ◽

Wild Type ◽

Guanylate Binding Protein

Lymphotoxinβreceptor (LTβR) signaling plays an important role in efficient initiation of host responses to a variety of pathogens, encompassing viruses, bacteria, and protozoans via induction of the type I interferon response. The present study reveals that afterToxoplasma gondiiinfection, LTβR−/−mice show a substantially reduced survival rate when compared to wild-type mice. LTβR−/−mice exhibit an increased parasite load and a more pronounced organ pathology. Also, a delayed increase of serum IL-12p40 and a failure of the protective IFNγresponse in LTβR−/−mice were observed. Serum NO levels in LTβR−/−animals rose later and were markedly decreased compared to wild-type animals. At the transcriptional level, LTβR−/−animals exhibited a deregulated expression profile of several cytokines known to play a role in activation of innate immunity inT. gondiiinfection. Importantly, expression of the IFNγ-regulated murine guanylate-binding protein (mGBP) genes was virtually absent in the lungs of LTβR−/−mice. This demonstrates clearly that the LTβR is essential for the induction of a type II IFN-mediated immune response againstT. gondii. The pronounced inability to effectively upregulate host defense effector molecules such as GBPs explains the high mortality rates of LTβR−/−animals afterT. gondiiinfection.

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Oral administration of heat-killed Lactobacillus plantarum L-137 enhances protection against influenza virus infection by stimulation of type I interferon production in mice

International Immunopharmacology ◽

10.1016/j.intimp.2009.04.015 ◽

2009 ◽

Vol 9 (9) ◽

pp. 1122-1125 ◽

Cited By ~ 80

Author(s):

Naoyoshi Maeda ◽

Risa Nakamura ◽

Yoshitaka Hirose ◽

Shinji Murosaki ◽

Yoshihiro Yamamoto ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Oral Administration ◽

Lactobacillus Plantarum ◽

Type I Interferon ◽

Influenza Virus Infection ◽

Type I ◽

Interferon Production ◽

Stimulation Of

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The γ134.5 Protein of Herpes Simplex Virus 1 Is Required To Interfere with Dendritic Cell Maturation during Productive Infection

Journal of Virology ◽

10.1128/jvi.02535-08 ◽

2009 ◽

Vol 83 (10) ◽

pp. 4984-4994 ◽

Cited By ~ 25

Author(s):

Huali Jin ◽

Yijie Ma ◽

Bellur S. Prabhakar ◽

Zongdi Feng ◽

Tibor Valyi-Nagy ◽

...

Keyword(s):

Type I Interferon ◽

Wild Type Virus ◽

Type I ◽

Interferon Production ◽

Type Virus ◽

Null Mutant ◽

Wild Type ◽

Herpes Simplex Virus 1 ◽

Mhc Ii ◽

Simplex Virus

ABSTRACT The γ134.5 protein of herpes simplex virus 1 is an essential factor for viral virulence. In infected cells, this viral protein prevents the translation arrest mediated by double-stranded RNA-dependent protein kinase R. Additionally, it associates with and inhibits TANK-binding kinase 1, an essential component of Toll-like receptor-dependent and -independent pathways that activate interferon regulatory factor 3 and cytokine expression. Here, we show that γ134.5 is required to block the maturation of conventional dendritic cells (DCs) that initiate adaptive immune responses. Unlike wild-type virus, the γ134.5 null mutant stimulates the expression of CD86, major histocompatibility complex class II (MHC-II), and cytokines such as alpha/beta interferon in immature DCs. Viral replication in DCs inversely correlates with interferon production. These phenotypes are also mirrored in a mouse ocular infection model. Further, DCs infected with the γ134.5 null mutant effectively activate naïve T cells whereas DCs infected with wild-type virus fail to do so. Type I interferon-neutralizing antibodies partially reverse virus-induced upregulation of CD86 and MHC-II, suggesting that γ134.5 acts through interferon-dependent and -independent mechanisms. These data indicate that γ134.5 is involved in the impairment of innate immunity by inhibiting both type I interferon production and DC maturation, leading to defective T-cell activation.

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