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

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.

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194 A Non-Gluten Component of Wheat is a Strong Stimulator of Innate Immune Responses In Vitro and In Vivo and Acts via Toll Like Receptor 4

Gastroenterology ◽

10.1016/s0016-5085(10)60165-5 ◽

2010 ◽

Vol 138 (5) ◽

pp. S-36

Author(s):

Yvonne Junker ◽

Donatella Barisani ◽

Daniel A. Leffler ◽

Towia Libermann ◽

Simon T. Dillon ◽

...

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Innate Immune Responses ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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Toll-Like Receptor and Autoimmunity.

Blood ◽

10.1182/blood.v114.22.sci-24.sci-24 ◽

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.

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Toll-Like Receptor (TLR) Signaling Enables Cyclic GMP-AMP Synthase (cGAS) Sensing of HIV-1 Infection in Macrophages

mBio ◽

10.1128/mbio.02817-21 ◽

2021 ◽

Author(s):

Mohammad Adnan Siddiqui ◽

Masahiro Yamashita

Keyword(s):

Immune Responses ◽

Cyclic Gmp ◽

Immune Activation ◽

Innate Immune ◽

Innate Immune Responses ◽

Toll Like Receptor ◽

Tlr Signaling ◽

Innate Immune Activation ◽

Hiv 1

Innate immune activation is a hallmark of HIV-1 pathogenesis. Thus, it is critical to understand how HIV-1 infection elicits innate immune responses.

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

Scientific Reports ◽

10.1038/s41598-019-56422-x ◽

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.

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Toll-Like Receptor-Triggered Calcium Mobilization Protects Mice against Bacterial Infection through Extracellular ATP Release

Infection and Immunity ◽

10.1128/iai.02546-14 ◽

2014 ◽

Vol 82 (12) ◽

pp. 5076-5085 ◽

Cited By ~ 29

Author(s):

Hua Ren ◽

Yunfei Teng ◽

Binghe Tan ◽

Xiaoyu Zhang ◽

Wei Jiang ◽

...

Keyword(s):

Immune Responses ◽

Pyridoxal Phosphate ◽

Atp Release ◽

Extracellular Atp ◽

Calcium Mobilization ◽

Innate Immune ◽

Disulfonic Acid ◽

Dependent Manner ◽

Innate Immune Responses ◽

Toll Like Receptor

ABSTRACTExtracellular ATP (eATP), released as a “danger signal” by injured or stressed cells, plays an important role in the regulation of immune responses, but the relationship between ATP release and innate immune responses is still uncertain. In this study, we demonstrated that ATP was released through Toll-like receptor (TLR)-associated signaling in bothEscherichia coli-infected mice and lipopolysaccharide (LPS)- or Pam3CSK4-treated macrophages. This ATP release could be blocked completely only byN-ethylmaleimide (NEM), not by carbenoxolone (CBX), flufenamic acid (FFA), or probenecid, suggesting the key role of exocytosis in this process. Furthermore, LPS-induced ATP release could also be reduced dramatically through suppressing calcium mobilization by use of U73122, caffeine, and thapsigargin (TG). In addition, the secretion of interleukin-1β (IL-1β) and CCL-2 was enhanced significantly by ATP, in a time- and dose-dependent manner. Meanwhile, macrophage-mediated phagocytosis of bacteria was also promoted significantly by ATP stimulation. Furthermore, extracellular ATP reduced the number of invading bacteria and protected mice from peritonitis by activating purinergic receptors. Mechanistically, phosphorylation of AKT and ERK was overtly increased by ATP in antibacterial immune responses. Accordingly, if we blocked the P2X- and P2Y-associated signaling pathway by using suramin and pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid), tetrasodium salt (PPADS), the ATP-enhanced immune response was restrained significantly. Taken together, our findings reveal an internal relationship between danger signals and TLR signaling in innate immune responses, which suggests a potential therapeutic significance of calcium mobilization-mediated ATP release in infectious diseases.

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High-Resolution Profiling of Innate Immune Responses by Porcine Dendritic Cell Subsets in vitro and in vivo

Frontiers in Immunology ◽

10.3389/fimmu.2020.01429 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 1

Author(s):

Gaël Auray ◽

Stephanie C. Talker ◽

Irene Keller ◽

Sylvie Python ◽

Markus Gerber ◽

...

Keyword(s):

Dendritic Cell ◽

High Resolution ◽

Immune Responses ◽

Innate Immune ◽

Innate Immune Responses ◽

Dendritic Cell Subsets

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Decoding the role of CBLB for innate immune responses regulating systemic dissemination during Non-Tuberculous Mycobacteria infection

10.1101/2020.05.28.117663 ◽

2020 ◽

Author(s):

Srinivasu Mudalagiriyappa ◽

Jaishree Sharma ◽

Hazem F. M. Abdelaal ◽

Thomas C. Kelly ◽

Woosuk Choi ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Granulomatous Inflammation ◽

Innate Immune ◽

Dependent Manner ◽

Innate Immune Responses ◽

Inflammatory Monocytes ◽

Cell Immunity

AbstractNon-Tuberculous Mycobacteria (NTM) are ubiquitous in nature, present in soil and water, and cause primary leading to disseminated infections in immunocompromised individuals. NTM infections are surging in recent years due to an increase in an immune-suppressed population, medical interventions, and patients with underlying lung diseases. Host regulators of innate immune responses, frontiers for controlling infections and dissemination, are poorly defined during NTM infections. Here, we describe the role of CBLB, an E3-ubiquitin ligase, for innate immune responses and disease progression in a mouse model of NTM infection under compromised T-cell immunity. We found that CBLB thwarted NTM growth and dissemination in a time- and infection route- dependent manner. Mechanistically, we uncovered defects in many innate immune cells in the absence of Cblb, including poor responses of NK cells, inflammatory monocytes, and conventional dendritic cells. Strikingly, Cblb-deficient macrophages were competent to control NTM growth in vitro. Histopathology suggested the lack of early formation of granulomatous inflammation in the absence of CBLB. Collectively, CBLB is essential to mount productive innate immune responses and help prevent the dissemination during an NTM infection under T-cell deficiency.

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Polysaccharides derived from Yamoa™ (Funtumia elastica) prime γδ T cells in vitro and enhance innate immune responses in vivo

International Immunopharmacology ◽

10.1016/j.intimp.2009.07.015 ◽

2009 ◽

Vol 9 (11) ◽

pp. 1313-1322 ◽

Cited By ~ 18

Author(s):

Jill C. Graff ◽

Emily M. Kimmel ◽

Brett Freedman ◽

Igor A. Schepetkin ◽

Jeff Holderness ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Γδ T Cells ◽

Innate Immune ◽

Innate Immune Responses

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IFNα and IFNγ Impede Marek’s Disease Progression

Viruses ◽

10.3390/v11121103 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1103 ◽

Cited By ~ 4

Author(s):

Luca D. Bertzbach ◽

Olof Harlin ◽

Sonja Härtle ◽

Frank Fehler ◽

Tereza Vychodil ◽

...

Keyword(s):

Immune Responses ◽

Disease Onset ◽

Antiviral Effect ◽

Lymphoproliferative Disease ◽

Innate Immune ◽

Marek's Disease ◽

Marek’S Disease ◽

Innate Immune Responses

Marek’s disease virus (MDV) is an alphaherpesvirus that causes Marek’s disease, a malignant lymphoproliferative disease of domestic chickens. While MDV vaccines protect animals from clinical disease, they do not provide sterilizing immunity and allow field strains to circulate and evolve in vaccinated flocks. Therefore, there is a need for improved vaccines and for a better understanding of innate and adaptive immune responses against MDV infections. Interferons (IFNs) play important roles in the innate immune defenses against viruses and induce upregulation of a cellular antiviral state. In this report, we quantified the potent antiviral effect of IFNα and IFNγ against MDV infections in vitro. Moreover, we demonstrate that both cytokines can delay Marek’s disease onset and progression in vivo. Additionally, blocking of endogenous IFNα using a specific monoclonal antibody, in turn, accelerated disease. In summary, our data reveal the effects of IFNα and IFNγ on MDV infection and improve our understanding of innate immune responses against this oncogenic virus.

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