scholarly journals ADAR1 Function Regulates Innate Immune Activation and Susceptibility to Viral Infections

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 34
Author(s):  
Maria Pujantell ◽  
Eva Riveira-Muñoz ◽  
Edurne García-Vidal ◽  
Lucía Gutiérrez-Chamorro ◽  
Roger Badia ◽  
...  
Keyword(s):  
Genetic Association ◽  
Immune Activation ◽  
Viral Infections ◽  
Association Studies ◽  
Innate Immune ◽  
Viral Control ◽  
Innate Immune Activation ◽  
Hiv 1

Viral infection induces innate intracellular antiviral defenses, aimed at restricting virus replication and spread. Therefore, understanding the role and function of innate immune modulators can help to establish novel strategies for viral control. Here, we explore the role of ADAR1 as a regulator of the HIV, HCV, and HPV infections, both in vitro and in vivo, in a genetic association study. Depletion of ADAR1 induced innate immune activation, observed by a significant increase in IFNB1 mRNA and CXCL10 expression. Further characterization of ADAR1 knockdown also showed upregulation of the RNA sensors MDA5 and RIG-I, increased IRF7 expression, and phosphorylation of STAT1. ADAR1 deficiency had differential effects depending on the virus tested: siADAR1 cells showed a significant reduction in HIV-1 infection, whereas ADAR1 knockdown suggested a proviral role in HCV and HPV infections. In addition, genetic association studies were performed in a cohort of 155 HCV/HIV individuals with chronic coinfection, and a cohort of 173 HPV/HIV-infected individuals was followed for a median of six years (range 0.1–24). Polymorphisms within the ADAR1 gene were found to be significantly associated with poor clinical outcome of HCV therapy and advanced liver fibrosis in a cohort of HCV/HIV-1-coinfected patients. Moreover, we identified the low-frequency haplotype AACCAT to be significantly associated with recurrent HPV dysplasia, suggesting a role for ADAR1 in the outcome of HPV infection in HIV+ individuals. In conclusion, we show that ADAR1 regulates innate immune activation and plays a key role in susceptibility to viral infections by either limiting or enhancing viral replication. Overall, ADAR1 could be a potential target for designing immune-modulating therapeutic strategies.

scholarly journals ADAR1 function affects HPV replication and is associated to recurrent human papillomavirus-induced dysplasia in HIV coinfected individuals

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Maria Pujantell ◽  
Roger Badia ◽  
Iván Galván-Femenía ◽  
Edurne Garcia-Vidal ◽  
Rafael de Cid ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Immune Activation ◽  
Hpv Infection ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Activation ◽  
Enhanced Expression

AbstractInfection by human papillomavirus (HPV) alters the microenvironment of keratinocytes as a mechanism to evade the immune system. A-to-I editing by ADAR1 has been reported to regulate innate immunity in response to viral infections. Here, we evaluated the role of ADAR1 in HPV infection in vitro and in vivo. Innate immune activation was characterized in human keratinocyte cell lines constitutively infected or not with HPV. ADAR1 knockdown induced an innate immune response through enhanced expression of RIG-I-like receptors (RLR) signaling cascade, over-production of type-I IFNs and pro-inflammatory cytokines. ADAR1 knockdown enhanced expression of HPV proteins, a process dependent on innate immune function as no A-to-I editing could be identified in HPV transcripts. A genetic association study was performed in a cohort of HPV/HIV infected individuals followed for a median of 6 years (range 0.1–24). We identified the low frequency haplotype AACCAT significantly associated with recurrent HPV dysplasia, suggesting a role of ADAR1 in the outcome of HPV infection in HIV+ individuals. In summary, our results suggest that ADAR1-mediated innate immune activation may influence HPV disease outcome, therefore indicating that modification of innate immune effectors regulated by ADAR1 could be a therapeutic strategy against HPV infection.

Toll-Like Receptor and Autoimmunity.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-24-SCI-24
Author(s):  
Mark Shlomchik ◽  
Kevin Nickerson ◽  
Rebecca Sweet ◽  
Sean Christensen ◽  
Robin Herlands
Keyword(s):  
T Cells ◽  
B Cells ◽  
Immune Activation ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Autoreactive B Cells ◽  
Innate Immune Activation ◽  
Intrinsic Roles

Abstract Abstract SCI-24 While the paradigm that adaptive immunity to pathogens requires innate immune activation via pattern recognition receptors is well accepted, until recently how autoimmune responses are initiated and propagated has been less clear. In principle, it is less obvious how the requisite innate immune activation might occur. In 2002 landmark results demonstrated that autoreactive B cells could be activated in vitro by a self-Ags that contained both a BCR and a Toll-like receptor (TLR) ligand; the ability of endogenous chromatin antigens to engage TLR9, a DNA sensor, could explain how anti-DNA type antibodies were generated. We have extended these results in two ways. First, we have evaluated the roles of TLR9 and TLR7 (a ssRNA receptor) in vivo. We backcrossed TLR9 (DNA) and TLR7 (ssRNA) knockout alleles onto the MRL/lpr lupus-prone background. We found that TLR9 was required to generate the anti-chromatin response and TLR7 was required for anti-RNA associated responses. With respect to disease, TLR9 had an unexpected regulatory role: KO mice get more severe lupus, hypergammaglobulinemia, and die prematurely. Whereas, TLR7-deficient mice demonstrate ameliorated disease. This is surprising as TLR7 and TLR9 are highly homologous, are expressed in similar cells, and signal through the same pathway. To investigate the mechanism behind these differences, we have made TLR7 KO and TLR7/9 double KO MRL/lpr mice and I will discuss their phenotypes. In addition, we have used these animals to investigate B cell intrinsic roles for TLR9, and these data will be presented. These results suggest that innate immunity contributes to initiation and specificity of autoimmunity. In the second line of investigation, we have used a mouse that expresses an autoreactive BCR, specific for self-IgG (rheumatoid factor, RF) to investigate the roles of TLRs and T cells in the initial activation of these cells. Taken together, our results indicate that autoreactive B cells are activated in a TLR-dependent, T cell-independent fashion, but only by self molecules that provide a simultaneous BCR and TLR ligand. These cells then differentiate into autoantibody secreting plasmablasts and also are a vector for activating autoreactive T cells. Once this occurs, we propose that full-blown autoimmune disease is initiated and maintained by positive feedback between autoreactive B and T cells. The implications of this model for therapeutic approaches that target both B cells and TLRs will be discussed. Disclosures Shlomchik: Coley Pharmaceuticals: Patents & Royalties.

scholarly journals Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin

2005 ◽  
Vol 201 (1) ◽  
pp. 19-25 ◽  
Author(s):  
Cevayir Coban ◽  
Ken J. Ishii ◽  
Taro Kawai ◽  
Hiroaki Hemmi ◽  
Shintaro Sato ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Activation ◽  
Interleukin 1 ◽  
Innate Immune ◽  
Dependent Manner ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Innate Immune Activation

Malaria parasites within red blood cells digest host hemoglobin into a hydrophobic heme polymer, known as hemozoin (HZ), which is subsequently released into the blood stream and then captured by and concentrated in the reticulo-endothelial system. Accumulating evidence suggests that HZ is immunologically active, but the molecular mechanism(s) through which HZ modulates the innate immune system has not been elucidated. This work demonstrates that HZ purified from Plasmodium falciparum is a novel non-DNA ligand for Toll-like receptor (TLR)9. HZ activated innate immune responses in vivo and in vitro, resulting in the production of cytokines, chemokines, and up-regulation of costimulatory molecules. Such responses were severely impaired in TLR9−/− and myeloid differentiation factor 88 (MyD88)−/−, but not in TLR2, TLR4, TLR7, or Toll/interleukin 1 receptor domain–containing adaptor-inducing interferon β−/− mice. Synthetic HZ, which is free of the other contaminants, also activated innate immune responses in vivo in a TLR9-dependent manner. Chloroquine (CQ), an antimalarial drug, abrogated HZ-induced cytokine production. These data suggest that TLR9-mediated, MyD88-dependent, and CQ-sensitive innate immune activation by HZ may play an important role in malaria parasite–host interactions.

scholarly journals Author response: HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

2020 ◽  
Author(s):  
Hataf Khan ◽  
Rebecca P Sumner ◽  
Jane Rasaiyaah ◽  
Choon Ping Tan ◽  
Maria Teresa Rodriguez-Plata ◽  
...  
Keyword(s):  
Immune Activation ◽  
Nuclear Transport ◽  
Innate Immune ◽  
Author Response ◽  
Innate Immune Activation ◽  
Hiv 1

scholarly journals Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine

2021 ◽  
Author(s):  
Leetah Senkpeil ◽  
Jyoti Bhardwaj ◽  
Morgan Little ◽  
Prasida Holla ◽  
Aditi Upadhye ◽  
...  
Keyword(s):  
Immune Activation ◽  
Malaria Infection ◽  
Protective Immunity ◽  
Molecular Mechanisms ◽  
Protective Efficacy ◽  
T Cell Response ◽  
Innate Immune ◽  
Transcriptional Analysis ◽  
Innate Immune Activation

Baseline innate immune signatures can influence protective immunity following vaccination. Here, we used systems transcriptional analysis to assess the molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole sporozoite PfSPZ Vaccine in African infants. Innate immune activation and myeloid signatures at pre-vaccination baseline correlated with protection from Plasmodium falciparum infection in placebo controls, while the same signatures predicted susceptibility to infection among infants who received the highest and most protective dose of the PfSPZ Vaccine. Machine learning identified monocytes and an antigen presentation signature as pre-vaccination features predictive of malaria infection after highest-dose PfSPZ vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against malaria infection in mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data establish a dichotomous role of innate stimulation for malaria protection and induction of protective immunity of whole-sporozoite malaria vaccines.

scholarly journals Maedi-visna virus Vif protein uses motifs distinct from HIV-1 Vif to bind zinc and cofactor required for A3 degradation

2020 ◽  
pp. jbc.RA120.015828
Author(s):  
Kirsten M. Knecht ◽  
Yingxia Hu ◽  
Diana Rubene ◽  
Matthew Cook ◽  
Samantha J Ziegler ◽  
...  
Keyword(s):  
Viral Infections ◽  
Zinc Ion ◽  
Binding Motif ◽  
Cytidine Deaminases ◽  
Visna Virus ◽  
Primate Lentiviruses ◽  
Maedi Visna Virus ◽  
Hiv 1

The mammalian apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3 or A3) family of cytidine deaminases restrict viral infections by mutating viral DNA and impeding reverse transcription. To overcome this antiviral activity, most lentiviruses express a viral accessory protein called Vif, which recruits A3 proteins to Cullin-RING E3 ubiquitin ligases such as Cul5 for ubiquitylation and subsequent proteasomal degradation. While Vif proteins from primate lentiviruses like HIV-1 utilize the transcription factor CBFβ as a non-canonical cofactor to stabilize the complex, maedi-visna virus (MVV) Vif hijacks cyclophilin A (CypA) instead. Since CBFβ and CypA are both highly conserved among mammals, the requirement for two different cellular cofactors suggests that these two A3-targeting Vif proteins have different biochemical and structural properties. To investigate this topic, we used a combination of in vitro biochemical assays and in vivo A3 degradation assays to study motifs required for MVV Vif to bind zinc ion, Cul5, and the cofactor CypA. Our results demonstrate that while some common motifs between HIV-1 Vif and MVV Vif are involved in recruiting Cul5, different determinants in MVV Vif are required for cofactor binding and stabilization of the E3 ligase complex, such as the zinc-binding motif and N- and C-terminal regions of the protein. Results from this study advance our understanding of the mechanism of MVV Vif recruitment of cellular factors and the evolution of lentiviral Vif proteins.

scholarly journals HIV-1 gp120 signaling through TLR4 modulates innate immune activation in human macrophages and the biology of hepatic stellate cells

2016 ◽  
Vol 100 (3) ◽  
pp. 599-606 ◽  
Author(s):  
Manuela Del Cornò ◽  
Andrea Cappon ◽  
Gloria Donninelli ◽  
Barbara Varano ◽  
Fabio Marra ◽  
...  
Keyword(s):  
Immune Activation ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Innate Immune ◽  
Human Macrophages ◽  
Innate Immune Activation ◽  
Hiv 1

scholarly journals Chronic innate immune activation as a cause of HIV-1 immunopathogenesis

2008 ◽  
Vol 126 (3) ◽  
pp. 235-242 ◽  
Author(s):  
Adriano Boasso ◽  
Gene M. Shearer
Keyword(s):  
Immune Activation ◽  
Innate Immune ◽  
Innate Immune Activation ◽  
Hiv 1

scholarly journals HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

2020 ◽  
Author(s):  
Hataf Khan ◽  
Rebecca P. Sumner ◽  
Jane Rasaiyaah ◽  
Choon Ping Tan ◽  
Maria Teresa Rodriguez-Plata ◽  
...  
Keyword(s):  
Immune Activation ◽  
Nuclear Import ◽  
Nuclear Transport ◽  
Innate Immune ◽  
Human Macrophages ◽  
Innate Immune Activation ◽  
Immune Sensing ◽  
Molecular Patterns ◽  
Innate Immune Sensing ◽  
Hiv 1

AbstractHIV-1 must replicate in cells that are equipped to defend themselves from infection through intracellular innate immune systems. HIV-1 evades innate immune sensing through encapsidated DNA synthesis and encodes accessory genes that antagonize specific antiviral effectors. Here we show that both particle associated, and expressed HIV-1 Vpr, antagonize the stimulatory effect of a variety of pathogen associated molecular patterns by inhibiting IRF3 and NF-κB nuclear transport. Phosphorylation of IRF3 at S396, but not S386, was also inhibited. We propose that, rather than promoting HIV-1 nuclear import, Vpr interacts with karyopherins to disturb their import of IRF3 and NF-κB to promote replication in macrophages. Concordantly, we demonstrate Vpr dependent rescue of HIV-1 replication in human macrophages from inhibition by cGAMP, the product of activated cGAS. We propose a model that unifies Vpr manipulation of nuclear import and inhibition of innate immune activation to promote HIV-1 replication and transmission.

scholarly journals HIV-1 gp120 Induces TLR2- and TLR4-Mediated Innate Immune Activation in Human Female Genital Epithelium

2013 ◽  
Vol 191 (8) ◽  
pp. 4246-4258 ◽  
Author(s):  
Aisha Nazli ◽  
Jessica K. Kafka ◽  
Victor H. Ferreira ◽  
Varun Anipindi ◽  
Kristen Mueller ◽  
...  
Keyword(s):  
Immune Activation ◽  
Innate Immune ◽  
Human Female ◽  
Innate Immune Activation ◽  
Hiv 1 ◽  
Female Genital
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