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

mBio ◽  
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.

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 Kinetics of Early Innate Immune Activation during HIV-1 Infection of Humanized Mice

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Jessica Katy Skelton ◽  
Ana Maria Ortega-Prieto ◽  
Steve Kaye ◽  
Jose Manuel Jimenez-Guardeño ◽  
Jane Turner ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Activation ◽  
Innate Immune ◽  
Model Systems ◽  
Humanized Mice ◽  
Type I ◽  
Innate Immune Activation ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection is associated with aberrant immune activation; however, most model systems for HIV-1 have been used during established infection. Here, we utilize ultrasensitive HIV-1 quantification to delineate early events during the eclipse, burst, and chronic phases of HIV-1 infection in humanized mice. We show that very early in infection, HIV-1 suppresses peripheral type I interferon (IFN) and interferon-stimulated gene (ISG) responses, including the HIV-1 restriction factor IFI44. At the peak of innate immune activation, prior to CD4 T cell loss, HIV-1 infection differentially affects peripheral and lymphoid Toll-like receptor (TLR) expression profiles in T cells and macrophages. This results in a trend toward an altered activation of nuclear factor κB (NF-κB), TANK-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3). The subsequent type I and III IFN responses result in preferential induction of peripheral ISG responses. Following this initial innate immune activation, peripheral expression of the HIV-1 restriction factor SAM domain- and HD domain-containing protein 1 (SAMHD1) returns to levels below those observed in uninfected mice, suggesting that HIV-1 interferes with their basal expression. However, peripheral cells still retain their responsiveness to exogenous type I IFN, whereas splenic cells show a reduction in select ISGs in response to IFN. This demonstrates the highly dynamic nature of very early HIV-1 infection and suggests that blocks to the induction of HIV-1 restriction factors contribute to the establishment of viral persistence. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) infection is restricted to humans and some nonhuman primates (e.g., chimpanzee and gorilla). Alternative model systems based on simian immunodeficiency virus (SIV) infection of macaques are available but do not recapitulate all aspects of HIV-1 infection and disease. Humanized mice, which contain a human immune system, can be used to study HIV-1, but only limited information on early events and immune responses is available to date. Here, we describe very early immune responses to HIV-1 and demonstrate a suppression of cell-intrinsic innate immunity. Furthermore, we show that HIV-1 infection interacts differently with innate immune responses in blood and lymphoid organs.

scholarly journals LPS-induced down-regulation of signal regulatory protein α contributes to innate immune activation in macrophages

2007 ◽  
Vol 204 (11) ◽  
pp. 2719-2731 ◽  
Author(s):  
Xiao-Ni Kong ◽  
He-Xin Yan ◽  
Lei Chen ◽  
Li-Wei Dong ◽  
Wen Yang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Immune Activation ◽  
Endotoxic Shock ◽  
Regulatory Protein ◽  
Innate Immune ◽  
Host Cells ◽  
Type I ◽  
Innate Immune Responses ◽  
Innate Immune Activation

Activation of the mitogen-activated protein kinases (MAPKs) and nuclear factor κB (NF-κB) cascades after Toll-like receptor (TLR) stimulation contributes to innate immune responses. Signal regulatory protein (SIRP) α, a member of the SIRP family that is abundantly expressed in macrophages, has been implicated in regulating MAPK and NF-κB signaling pathways. In addition, SIRPα can negatively regulate the phagocytosis of host cells by macrophages, indicating an inhibitory role of SIRPα in innate immunity. We provide evidences that SIRPα is an essential endogenous regulator of the innate immune activation upon lipopolysaccharide (LPS) exposure. SIRPα expression was promptly reduced in macrophages after LPS stimulation. The decrease in SIRPα expression levels was required for initiation of LPS-induced innate immune responses because overexpression of SIRPα reduced macrophage responses to LPS. Knockdown of SIRPα caused prolonged activation of MAPKs and NF-κB pathways and augmented production of proinflammatory cytokines and type I interferon (IFN). Mice transferred with SIRPα-depleted macrophages were highly susceptible to endotoxic shock, developing multiple organ failure and exhibiting a remarkable increase in mortality. SIRPα may accomplish this mainly through its association and sequestration of the LPS signal transducer SHP-2. Thus, SIRPα functions as a biologically important modulator of TLR signaling and innate immunity.

Innate immune responses to toll-like receptor stimulation are altered during the course of pregnancy

2018 ◽  
Vol 128 ◽  
pp. 30-37 ◽  
Author(s):  
Susanne Maria Ziegler ◽  
Cai Niklaas Feldmann ◽  
Sven Hendrik Hagen ◽  
Laura Richert ◽  
Tanja Barkhausen ◽  
...  
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Receptor Stimulation

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

2014 ◽  
Vol 82 (12) ◽  
pp. 5076-5085 ◽  
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.

scholarly journals Toll-like Receptor 7 Contributes to Inflammation, Organ Injury, and Mortality in Murine Sepsis

2019 ◽  
Vol 131 (1) ◽  
pp. 105-118 ◽  
Author(s):  
Wenling Jian ◽  
Lili Gu ◽  
Brittney Williams ◽  
Yan Feng ◽  
Wei Chao ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Immune Responses ◽  
Knockout Mice ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Innate Immune ◽  
Organ Injury ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Wild Type

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Sepsis remains a critical illness with high mortality. The authors have recently reported that mouse plasma RNA concentrations are markedly increased during sepsis and closely associated with its severity. Toll-like receptor 7, originally identified as the sensor for single-stranded RNA virus, also mediates host extracellular RNA-induced innate immune responses in vitro and in vivo. Here, the authors hypothesize that innate immune signaling via Toll-like receptor 7 contributes to inflammatory response, organ injury, and mortality during polymicrobial sepsis. Methods Sepsis was created by (1) cecal ligation and puncture or (2) stool slurry peritoneal injection. Wild-type and Toll-like receptor 7 knockout mice, both in C57BL/6J background, were used. The following endpoints were measured: mortality, acute kidney injury biomarkers, plasma and peritoneal cytokines, blood bacterial loading, peritoneal leukocyte counts, and neutrophil phagocytic function. Results The 11-day overall mortality was 81% in wild-type mice and 48% in Toll-like receptor 7 knockout mice after cecal ligation and puncture (N = 27 per group, P = 0.0031). Compared with wild-type septic mice, Toll-like receptor 7 knockout septic mice also had lower sepsis severity, attenuated plasma cytokine storm (wild-type vs. Toll-like receptor 7 knockout, interleukin-6: 43.2 [24.5, 162.7] vs. 4.4 [3.1, 12.0] ng/ml, P = 0.003) and peritoneal inflammation, alleviated acute kidney injury (wild-type vs. Toll-like receptor 7 knockout, neutrophil gelatinase-associated lipocalin: 307 ± 184 vs.139 ± 41-fold, P = 0.0364; kidney injury molecule-1: 40 [16, 49] vs.13 [4, 223]-fold, P = 0.0704), lower bacterial loading, and enhanced leukocyte peritoneal recruitment and phagocytic activities at 24 h. Moreover, stool slurry from wild-type and Toll-like receptor 7 knockout mice resulted in similar level of sepsis severity, peritoneal cytokines, and leukocyte recruitment in wild-type animals after peritoneal injection. Conclusions Toll-like receptor 7 plays an important role in the pathogenesis of polymicrobial sepsis by mediating host innate immune responses and contributes to acute kidney injury and mortality.

scholarly journals Toll-Like Receptor 4 Mediates Innate Immune Responses to Haemophilus influenzae Infection in Mouse Lung

2002 ◽  
Vol 168 (2) ◽  
pp. 810-815 ◽  
Author(s):  
Xiaorong Wang ◽  
Christian Moser ◽  
Jean-Pierre Louboutin ◽  
Elena S. Lysenko ◽  
Daniel J. Weiner ◽  
...  
Keyword(s):  
Immune Responses ◽  
Haemophilus Influenzae ◽  
Innate Immune ◽  
Mouse Lung ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4
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