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 ISG15 counteracts Listeria monocytogenes infection

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Lilliana Radoshevich ◽  
Francis Impens ◽  
David Ribet ◽  
Juan J Quereda ◽  
To Nam Tham ◽  
...  
Keyword(s):  
Isotope Labeling ◽  
Innate Immune ◽  
Type I ◽  
Bacterial Dna ◽  
Listeria Monocytogenes Infection ◽  
Isg15 Expression ◽  
Listeria Infection

ISG15 is an interferon-stimulated, linear di-ubiquitin-like protein, with anti-viral activity. The role of ISG15 during bacterial infection remains elusive. We show that ISG15 expression in nonphagocytic cells is dramatically induced upon Listeria infection. Surprisingly this induction can be type I interferon independent and depends on the cytosolic surveillance pathway, which senses bacterial DNA and signals through STING, TBK1, IRF3 and IRF7. Most importantly, we observed that ISG15 expression restricts Listeria infection in vitro and in vivo. We made use of stable isotope labeling in tissue culture (SILAC) to identify ISGylated proteins that could be responsible for the protective effect. Strikingly, infection or overexpression of ISG15 leads to ISGylation of ER and Golgi proteins, which correlates with increased secretion of cytokines known to counteract infection. Together, our data reveal a previously uncharacterized ISG15-dependent restriction of Listeria infection, reinforcing the view that ISG15 is a key component of the innate immune response.

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 STAT2 Limits Host Species Specificity of Human Metapneumovirus

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 724
Author(s):  
Meredith C. Rogers ◽  
Margot Miranda-Katz ◽  
Yu Zhang ◽  
Tim D. Oury ◽  
Melissa B. Uccellini ◽  
...  
Keyword(s):  
Human Infection ◽  
Human Metapneumovirus ◽  
Innate Immune ◽  
Type I ◽  
Immune Recognition ◽  
Surface Receptors ◽  
Hmpv Infection

The host tropism of viral infection is determined by a variety of factors, from cell surface receptors to innate immune signaling. Many viruses encode proteins that interfere with host innate immune recognition in order to promote infection. STAT2 is divergent between species and therefore has a role in species restriction of some viruses. To understand the role of STAT2 in human metapneumovirus (HMPV) infection of human and murine tissues, we first infected STAT2−/− mice and found that HMPV could be serially passaged in STAT2−/−, but not WT, mice. We then used in vitro methods to show that HMPV inhibits expression of both STAT1 and STAT2 in human and primate cells, but not in mouse cells. Transfection of the murine form of STAT2 into STAT2-deficient human cells conferred resistance to STAT2 inhibition. Finally, we sought to understand the in vivo role of STAT2 by infecting hSTAT2 knock-in mice with HMPV, and found that mice had increased weight loss, inhibition of type I interferon signaling, and a Th2-polarized cytokine profile compared to WT mice. These results indicate that STAT2 is a target of HMPV in human infection, while the murine version of STAT2 restricts tropism of HMPV for murine cells and tissue.

scholarly journals WNT-5A regulates TGF-β-related activities in liver fibrosis

2017 ◽  
Vol 312 (3) ◽  
pp. G219-G227 ◽  
Author(s):  
Leonie Beljaars ◽  
Sara Daliri ◽  
Christa Dijkhuizen ◽  
Klaas Poelstra ◽  
Reinoud Gosens
Keyword(s):  
Liver Fibrosis ◽  
Functional Role ◽  
Collagen Type ◽  
Collagen Type I ◽  
Matrix Proteins ◽  
Type I ◽  
Human Livers

WNT-5A is a secreted growth factor that belongs to the noncanonical members of the Wingless-related MMTV-integration family. Previous studies pointed to a connection between WNT-5A and the fibrogenic factor TGF-β warranting further studies into the functional role of WNT-5A in liver fibrosis. Therefore, we studied WNT-5A expressions in mouse and human fibrotic livers and examined the relation between WNT-5A and various fibrosis-associated growth factors, cytokines, and extracellular matrix proteins. WNT-5A gene and protein expressions were significantly increased in fibrotic mouse and human livers compared with healthy livers. Regression or therapeutic intervention in mice resulted in decreased hepatic WNT-5A levels paralleled by lower collagen levels. Immunohistochemical analysis showed WNT-5A staining in fibrotic septa colocalizing with desmin staining indicating WNT-5A expression in myofibroblasts. In vitro studies confirmed WNT-5A expression in this cell type and showed that TGF-β significantly enhanced WNT-5A expression in contrast to PDGF-BB and proinflammatory cytokines IL-1β and TNF-α. Additionally, TGF-β induces the expression of the WNT receptors FZD2 and FZD8. After silencing of WNT-5A, reduced levels of collagen type I, vimentin, and fibronectin in TGF-β-stimulated myofibroblasts were measured compared with nonsilencing siRNA-treated controls. Interestingly, the antifibrotic cytokine IFNγ suppressed WNT-5A in vitro and in vivo. IFNγ-treated fibrotic mice showed significantly less WNT-5A expression compared with untreated fibrotic mice. In conclusion, WNT-5A paralleled collagen I levels in fibrotic mouse and human livers. WNT-5A expression in myofibroblasts is induced by the profibrotic factor TGF-β and plays an important role in TGF-β-induced regulation of fibrotic matrix proteins, whereas its expression can be reversed upon treatment, both in vitro and in vivo. NEW & NOTEWORTHY This study describes the localization and functional role of WNT-5A in human and mouse fibrotic livers. Hepatic WNT-5A expression parallels collagen type I expression. In vivo and in vitro, the myofibroblasts were identified as the key hepatic cells producing WNT-5A. WNT-5A is under control of TGF-β and its activities are primarily profibrotic.

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 Transcriptional role of p53 in interferon-mediated antiviral immunity

2008 ◽  
Vol 205 (8) ◽  
pp. 1929-1938 ◽  
Author(s):  
César Muñoz-Fontela ◽  
Salvador Macip ◽  
Luis Martínez-Sobrido ◽  
Lauren Brown ◽  
Joseph Ashour ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Viral Replication ◽  
Viral Infections ◽  
Suppressor Gene ◽  
Central Component ◽  
Type I ◽  
Infected Cells

Tumor suppressor p53 is activated by several stimuli, including DNA damage and oncogenic stress. Previous studies (Takaoka, A., S. Hayakawa, H. Yanai, D. Stoiber, H. Negishi, H. Kikuchi, S. Sasaki, K. Imai, T. Shibue, K. Honda, and T. Taniguchi. 2003. Nature. 424:516–523) have shown that p53 is also induced in response to viral infections as a downstream transcriptional target of type I interferon (IFN) signaling. Moreover, many viruses, including SV40, human papillomavirus, Kaposi's sarcoma herpesvirus, adenoviruses, and even RNA viruses such as polioviruses, have evolved mechanisms designated to abrogate p53 responses. We describe a novel p53 function in the activation of the IFN pathway. We observed that infected mouse and human cells with functional p53 exhibited markedly decreased viral replication early after infection. This early inhibition of viral replication was mediated both in vitro and in vivo by a p53-dependent enhancement of IFN signaling, specifically the induction of genes containing IFN-stimulated response elements. Of note, p53 also contributed to an increase in IFN release from infected cells. We established that this p53-dependent enhancement of IFN signaling is dependent to a great extent on the ability of p53 to activate the transcription of IFN regulatory factor 9, a central component of the IFN-stimulated gene factor 3 complex. Our results demonstrate that p53 contributes to innate immunity by enhancing IFN-dependent antiviral activity independent of its functions as a proapoptotic and tumor suppressor gene.

scholarly journals Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice

2018 ◽  
Vol 115 (20) ◽  
pp. 5253-5258 ◽  
Author(s):  
Hideyuki Yanai ◽  
Shiho Chiba ◽  
Sho Hangai ◽  
Kohei Kometani ◽  
Asuka Inoue ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Types ◽  
Type I ◽  
Type I Ifn ◽  
Cell Type ◽  
Gene Ablation ◽  
Cell Type Specific

IFN regulatory factor 3 (IRF3) is a transcription regulator of cellular responses in many cell types that is known to be essential for innate immunity. To confirm IRF3’s broad role in immunity and to more fully discern its role in various cellular subsets, we engineered Irf3-floxed mice to allow for the cell type-specific ablation of Irf3. Analysis of these mice confirmed the general requirement of IRF3 for the evocation of type I IFN responses in vitro and in vivo. Furthermore, immune cell ontogeny and frequencies of immune cell types were unaffected when Irf3 was selectively inactivated in either T cells or B cells in the mice. Interestingly, in a model of lipopolysaccharide-induced septic shock, selective Irf3 deficiency in myeloid cells led to reduced levels of type I IFN in the sera and increased survival of these mice, indicating the myeloid-specific, pathogenic role of the Toll-like receptor 4–IRF3 type I IFN axis in this model of sepsis. Thus, Irf3-floxed mice can serve as useful tool for further exploring the cell type-specific functions of this transcription factor.

scholarly journals The central role of inflammatory signaling in the pathogenesis of myelodysplastic syndromes

Blood ◽  
2019 ◽  
Vol 133 (10) ◽  
pp. 1039-1048 ◽  
Author(s):  
David A. Sallman ◽  
Alan List
Keyword(s):  
Myelodysplastic Syndromes ◽  
Immune Activation ◽  
Nlrp3 Inflammasome ◽  
Cancer Biology ◽  
Innate Immune ◽  
Cell Swelling ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Innate Immune Activation

Abstract In cancer biology, tumor-promoting inflammation and an inflammatory microenvironment play a vital role in disease pathogenesis. In the past decade, aberrant innate immune activation and proinflammatory signaling within the malignant clone and the bone marrow (BM) microenvironment were identified as key pathogenic drivers of myelodysplastic syndromes (MDS). In particular, S100A9-mediated NOD-like receptor protein 3 (NLRP3) inflammasome activation directs an inflammatory, lytic form of cell death termed pyroptosis that underlies many of the hallmark features of the disease. This circuit and accompanying release of other danger-associated molecular patterns expands BM myeloid-derived suppressor cells, creating a feed-forward process propagating inflammasome activation. Furthermore, somatic gene mutations of varied functional classes license the NLRP3 inflammasome to generate a common phenotype with excess reactive oxygen species generation, Wnt/β-catenin–induced proliferation, cation flux-induced cell swelling, and caspase-1 activation. Recent investigations have shown that activation of the NLRP3 inflammasome complex has more broad-reaching importance, particularly as a possible disease-specific biomarker for MDS, and, mechanistically, as a driver of cardiovascular morbidity/mortality in individuals with age-related, clonal hematopoiesis. Recognition of the mechanistic role of aberrant innate immune activation in MDS provides a new perspective for therapeutic development that could usher in a novel class of disease-modifying agents.

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