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

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
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.

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

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.

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

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Katina D Hulme ◽  
Anjana C Karawita ◽  
Cassandra Pegg ◽  
Myrna JM Bunte ◽  
Helle Bielefeldt-Ohmann ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Disease Severity ◽  
Type I Interferon ◽  
Polymerase Activity ◽  
Interferon Response ◽  
Type I ◽  
Interferon Production ◽  
Wild Type ◽  
Host Environment ◽  
Severe Influenza

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.

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

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
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.

scholarly journals Inhibition of retrotransposition improves health and extends lifespan of SIRT6 knockout mice

2018 ◽  
Author(s):  
Matthew Simon ◽  
Michael Van Meter ◽  
Julia Ablaeva ◽  
Zhonghe Ke ◽  
Raul S. Gonzalez ◽  
...  
Keyword(s):  
Dna Damage ◽  
Reverse Transcriptase ◽  
Knockout Mice ◽  
Type I Interferon ◽  
Display Type ◽  
Interferon Response ◽  
Type I ◽  
Wild Type ◽  
Reverse Transcriptase Inhibitors ◽  
Aged Mice

SUMMARYMice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6 deficient cells and tissues accumulate abundant cytoplasmic L1 cDNA which triggers massive type I interferon response via activation of cGAS. Remarkably, nucleoside reverse transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number and type I interferons were elevated in the wild type aged mice. As sterile inflammation is a hallmark of aging we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies.HighlightsSIRT6 KO mice accumulate L1 cDNA triggering type I interferon response via cGAS pathwayWild type aged mice accumulate L1 cDNA and display type I interferon responseReverse transcriptase inhibitors rescue type I interferon response and DNA damageReverse transcriptase inhibitors extend lifespan and improve health of SIRT6 KO mice

scholarly journals Spatial Profiling of Lung SARS-CoV-2 and Influenza Virus Infection Dissects Virus-Specific Host Responses and Gene Signatures

2020 ◽  
Author(s):  
Arutha Kulasinghe ◽  
Chin Wee Tan ◽  
Anna Flavia Ribeiro dos Santos Miggiolaro ◽  
James Monkman ◽  
Dharmesh Bhuva ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Influenza Virus Infection ◽  
Respiratory Illness ◽  
High Viral Load ◽  
Host Responses ◽  
Interferon Response ◽  
Type I ◽  
Gene Signatures ◽  
Spatial Profiling ◽  
Novel Biomarkers

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019 has spread globally, causing a pandemic of respiratory illness designated coronavirus disease 2019 (COVID-19). Robust blood biomarkers that reflect tissue damage are urgently needed to better stratify and triage infected patients. Here, we use spatial transcriptomics to generate an in-depth picture of the pulmonary transcriptional landscape of COVID-19 (10 patients), pandemic H1N1 (pH1N1) influenza (5) and uninfected control patients (4). Host transcriptomics showed a significant upregulation of genes associated with inflammation, type I interferon production, coagulation and angiogenesis in the lungs of COVID-19 patients compared to non-infected controls. SARS-CoV-2 was non-uniformly distributed in lungs with few areas of high viral load and these were largely only associated with an increased type I interferon response. A very limited number of genes were differentially expressed between the lungs of influenza and COVID-19 patients. Specific interferon-associated genes (including IFI27) were identified as candidate novel biomarkers for COVID-19 differentiating this COVID-19 from influenza. Collectively, these data demonstrate that spatial transcriptomics is a powerful tool to identify novel gene signatures within tissues, offering new insights into the pathogenesis of SARS-COV-2 to aid in patient triage and treatment.

scholarly journals Early Control of H5N1 Influenza Virus Replication by the Type I Interferon Response in Mice

2009 ◽  
Vol 83 (11) ◽  
pp. 5825-5834 ◽  
Author(s):  
Kristy J. Szretter ◽  
Shivaprakash Gangappa ◽  
Jessica A. Belser ◽  
Hui Zeng ◽  
Hualan Chen ◽  
...  
Keyword(s):  
H5n1 Virus ◽  
Type I Interferon ◽  
Influenza Viruses ◽  
Interferon Response ◽  
Type I ◽  
Wild Type ◽  
H5n1 Influenza ◽  
Deficient Mice

ABSTRACT Widespread distribution of highly pathogenic avian H5N1 influenza viruses in domesticated and wild birds continues to pose a threat to public health, as interspecies transmission of virus has resulted in increasing numbers of human disease cases. Although the pathogenic mechanism(s) of H5N1 influenza viruses has not been fully elucidated, it has been suggested that the ability to evade host innate responses, such as the type I interferon response, may contribute to the virulence of these viruses in mammals. We investigated the role that type I interferons (alpha/beta interferon [IFN-α/β]) might play in H5N1 pathogenicity in vivo, by comparing the kinetics and outcomes of H5N1 virus infection in IFN-α/β receptor (IFN-α/βR)-deficient and SvEv129 wild-type mice using two avian influenza A viruses isolated from humans, A/Hong Kong/483/97 (HK/483) and A/Hong Kong/486/97 (HK/486), which exhibit high and low lethality in mice, respectively. IFN-α/βR-deficient mice experienced significantly more weight loss and more rapid time to death than did wild-type mice. HK/486 virus caused a systemic infection similar to that with HK/483 virus in IFN-α/βR-deficient mice, suggesting a role for IFN-α/β in controlling the systemic spread of this H5N1 virus. HK/483 virus replicated more efficiently than HK/486 virus both in vivo and in vitro. However, replication of both viruses was significantly reduced following pretreatment with IFN-α/β. These results suggest a role for the IFN-α/β response in the control of H5N1 virus replication both in vivo and in vitro, and as such it may provide some degree of protection to the host in the early stages of infection.

scholarly journals Exploring zebrafish larvae as a COVID-19 model: probable SARS-COV-2 replication in the swim bladder

2021 ◽  
Author(s):  
Valerio Laghi ◽  
Veronica Rezelj ◽  
Laurent Boucontet ◽  
Pierre Boudinot ◽  
Irene Salinas ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Swim Bladder ◽  
Wild Type ◽  
Zebrafish Larvae ◽  
Cytokine Responses ◽  
Successful Infection ◽  
Plasmid Injection ◽  
Brain Ventricle

Animal models are essential to understand COVID-19 pathophysiology and for pre-clinical assessment of drugs and other therapeutic or prophylactic interventions. We explored the small, cheap and transparent zebrafish larva as a potential host for the SARS-CoV-2 virus. Bath exposure, as well as microinjection in the coelom, pericardium, brain ventricle, bloodstream, or yolk, did not result in detectable SARS-CoV-2 replication in wild-type larvae. However, when the virus was inoculated in the swim bladder, a modest increase in viral RNA was observed after 24 hours, suggesting a successful infection in some animals. The low infectivity of SARS- CoV-2 in zebrafish was not due to the host type I interferon response, as similar results were observed in type I interferon-deficient animals. We could not detect the induction of transcriptional type I interferon or inflammatory cytokine responses following infection. Overexpression of human ACE2 in a mosaic fashion by plasmid injection in eggs was not sufficient to increase SARS-CoV-2 infectivity. In conclusion, wild-type zebrafish larvae appear mostly non-permissive to SARS-CoV-2, except in the swim bladder, an aerial organ sharing similarities with lungs.

scholarly journals Profiling of lung SARS-CoV-2 and influenza virus infection dissects virus-specific host responses and gene signatures

2021 ◽  
pp. 2101881
Author(s):  
Arutha Kulasinghe ◽  
Chin Wee Tan ◽  
Anna Flavia Ribeiro dos Santos Miggiolaro ◽  
James Monkman ◽  
Habib SadeghiRad ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Influenza Virus Infection ◽  
Respiratory Illness ◽  
High Viral Load ◽  
H1n1 Influenza ◽  
Host Responses ◽  
Interferon Response ◽  
Type I ◽  
Gene Signatures ◽  
Definition Of

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019 has spread globally, causing a pandemic of respiratory illness designated coronavirus disease 2019 (COVID-19). A better definition of the pulmonary host response to SARS-CoV-2 infection is required to understand viral pathogenesis and to validate putative COVID-19 biomarkers that have been proposed in clinical studies. Here, we use targeted transcriptomics of FFPE tissue using the Nanostring GeoMX™ platform to generate an in-depth picture of the pulmonary transcriptional landscape of COVID-19, pandemic H1N1 influenza and uninfected control patients. Host transcriptomics showed a significant upregulation of genes associated with inflammation, type I interferon production, coagulation and angiogenesis in the lungs of COVID-19 patients compared to non-infected controls. SARS-CoV-2 was non-uniformly distributed in lungs (emphasising the advantages of spatial transcriptomics) with the areas of high viral load associated with an increased type I interferon response. Once the dominant cell type present in the sample, within patient correlations and patient-patient variation had been controlled for, only a very limited number of genes were differentially expressed between the lungs of fatal influenza and COVID-19 patients. Strikingly, the interferon-associated gene IFI27, previously identified as a useful blood biomarker to differentiate bacterial and viral lung infections, was significantly upregulated in the lungs of COVID-19 patients compared to patients with influenza. Collectively, these data demonstrate that spatial transcriptomics is a powerful tool to identify novel gene signatures within tissues, offering new insights into the pathogenesis of SARS-COV-2 to aid in patient triage and treatment.

Two Different UGT1A1 Mutations causing Crigler–Najjar Syndrome types I and II in an Iranian Family

2015 ◽  
Vol 24 (4) ◽  
pp. 523-526 ◽  
Author(s):  
Yoshihiro Maruo ◽  
Mahdiyeh Behnam ◽  
Shinichi Ikushiro ◽  
Sayuri Nakahara ◽  
Narges Nouri ◽  
...  
Keyword(s):  
Serum Bilirubin ◽  
Total Serum Bilirubin ◽  
Total Serum ◽  
Compound Heterozygous ◽  
Type I ◽  
Syndrome Type ◽  
Type Ii ◽  
Wild Type ◽  
Iranian Family ◽  
Udp Glucuronosyltransferase

Background: Crigler–Najjar syndrome type I (CN-1) and type II (CN-2) are rare hereditary unconjugated hyperbilirubinemia disorders. However, there have been no reports regarding the co-existence of CN-1 and CN-2 in one family. We experienced a case of an Iranian family that included members with either CN-1 or CN-2. Genetic analysis revealed a mutation in the bilirubin UDP-glucuronosyltransferase (UGT1A1) gene that resulted in residual enzymatic activity.Case report: The female proband developed severe hyperbilirubinemia [total serum bilirubin concentration (TB) = 34.8 mg/dL] with bilirubin encephalopathy (kernicterus) and died after liver transplantation. Her family history included a cousin with kernicterus (TB = 30.0 mg/dL) diagnosed as CN-1. Her great grandfather (TB unknown) and uncle (TB = 23.0 mg/dL) developed jaundice, but without any treatment, they remained healthy as CN-2. Results: The affected cousin was homozygous for a novel frameshift mutation (c.381insGG, p.C127WfsX23). The affected uncle was compound heterozygous for p.C127WfsX23 and p.V225G linked with A(TA)7TAA. p.V225G-UGT1A1 reduced glucuronidation activity to 60% of wild-type. Thus, linkage of A(TA)7TAA and p.V225G might reduce UGT1A1 activity to 18%–36 % of the wild-type. Conclusion: Genetic and in vitro expression analyses are useful for accurate genetic counseling for a family with a history of both CN-1 and CN-2. Abbreviations: CN-1: Crigler–Najjar syndrome type I; CN-2: Crigler–Najjar syndrome type II; GS: Gilbert syndrome; UGT1A1: bilirubin UDP-glucuronosyltransferase; WT: Wild type; TB: total serum bilirubin.

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