scholarly journals Boosting Toll-like receptor 4 signaling enhances the therapeutic outcome of antibiotic therapy in pneumococcal pneumonia

2020 ◽  
Author(s):  
Fiordiligie Casilag ◽  
Sebastian Franck ◽  
Laura Matarazzo ◽  
Martin Figeac ◽  
Robin Michelet ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Antibiotic Therapy ◽  
Lung Tissue ◽  
Bacterial Load ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Term Survival ◽  
Monophosphoryl Lipid A ◽  
Host Innate Immunity

ABSTRACTThe emergence and spread of antibiotic resistance emphasize the need for alternative treatment strategies against bacterial infections. Boosting the host innate immunity is not only readily deployable in most individuals but can also mobilize many different antibacterial defenses. This study tested the hypothesis whereby stimulation of the innate immune receptor Toll-like receptor 4 (TLR4) can be combined with antibiotics in the treatment of invasive pneumonia. In a mouse model of Streptococcus pneumoniae infection, a single oral administration of low-dose amoxicillin (AMX) or the systemic delivery of monophosphoryl lipid A (MPLA, a clinically-approved TLR4 activator) decreased the bacterial load in lung and spleen, although this was not sufficient for long-term survival. In contrast, a single treatment with a combination of MPLA and AMX induced significant bacterial clearance with little to no regrowth over time, and was associated with longer survival. Upregulation of genes related to granulocyte infiltration in lung tissue and elevation of blood levels of pro-inflammatory cytokines was immediate and transient in MPLA-treated mice; this indicates activation of the innate immune system in a context of infection. Combination treatment was associated with a well-preserved lung tissue architecture and more rapid recovery from inflammation - suggesting that immune activation by MPLA does not exacerbate pneumonia-induced damage. After AMX administration, plasma AMX concentrations rapidly reached the maximum and declined, whereas the downstream effects of MPLA extended beyond AMX elimination; these findings suggested a two-step effect. Our results demonstrated that leveraging host innate immunity increases the efficacy of antibiotic therapy in bacterial pneumonia.

scholarly journals Fetal and Maternal Innate Immunity Receptors Have Opposing Effects on the Severity of Experimental Malaria in Pregnancy: Beneficial Roles for Fetus-Derived Toll-Like Receptor 4 and Type I Interferon Receptor 1

2018 ◽  
Vol 86 (5) ◽  
Author(s):  
Lurdes Rodrigues-Duarte ◽  
Yash Pandya ◽  
Rita Neres ◽  
Carlos Penha-Gonçalves
Keyword(s):  
Innate Immunity ◽  
Type I Interferon ◽  
Parasite Burden ◽  
Innate Immune ◽  
Malaria In Pregnancy ◽  
Type I ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Interferon Receptor ◽  
In Pregnancy

ABSTRACTMalaria in pregnancy (MiP) is a distinctive clinical form ofPlasmodiuminfection and is a cause of placental insufficiency leading to poor pregnancy outcomes. Maternal innate immunity responses play a decisive role in the development of placental inflammation, but the action of fetus-derived factors in MiP outcomes has been overlooked. We investigated the role of theTlr4andIfnar1genes, taking advantage of heterogenic mating strategies to dissect the effects mediated by maternally and fetally derived Toll-like receptor 4 (TLR4) or type I interferon receptor 1 (IFNAR1). Using a mouse infection system displaying severe MiP outcomes, we found that the expressions of TLR4 and IFNAR1 in the maternal compartment take part in deleterious MiP outcomes, but their fetal counterparts patently counteract these effects. We uncovered that fetal TLR4 contributes to thein vitrouptake of infected erythrocytes by trophoblasts and to the innate immune response in the placenta, offering robust protection of fetus viability, but had no sensible impact on the placental parasite burden. In contrast, we observed that the expression of IFNAR1 in the fetal compartment was associated with a reduced placental parasite burden but had little beneficial effect on fetus outcomes. Furthermore, the downregulation ofIfnar1expression in infected placentas and in trophoblasts exposed to infected erythrocytes indicated that the interferon-IFNAR1 pathway is involved in the trophoblast response to infection. This work unravels that maternal and fetal counterparts of innate immune pathways drive opposing responses in murine placental malaria and implicates the activation of innate receptors in fetal trophoblast cells in the control of placental infection and in the protection of the fetus.

scholarly journals The Toll-Like Receptor 4 Agonist Monophosphoryl Lipid A Augments Innate Host Resistance to Systemic Bacterial Infection

2011 ◽  
Vol 79 (9) ◽  
pp. 3576-3587 ◽  
Author(s):  
Christopher D. Romero ◽  
Tushar K. Varma ◽  
Jason B. Hobbs ◽  
Aimee Reyes ◽  
Brandon Driver ◽  
...  
Keyword(s):  
Lipid A ◽  
Cytokine Production ◽  
Myeloid Cells ◽  
Innate Immune ◽  
Bacterial Clearance ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Systemic Dissemination

ABSTRACTMonophosphoryl lipid A (MPLA) is a Toll-like receptor 4 (TLR4) agonist that is currently used as a vaccine adjuvant in humans. In this study, we evaluated the effect of MPLA treatment on the innate immune response to systemic bacterial infections in mice. Mice treated with MPLA after burn injury showed improved survival and less local and systemic dissemination of bacteria in a model ofPseudomonas aeruginosaburn wound infection. Prophylactic treatment with MPLA significantly enhanced bacterial clearance at the site of infection and reduced systemic dissemination of bacteria despite causing attenuation of proinflammatory cytokine production during acute intra-abdominal infection caused by cecal ligation and puncture. Administration of MPLA at 1 h after CLP also improved bacterial clearance but did not alter cytokine production. MPLA treatment increased the numbers of granulocytes, double-positive myeloid cells, and macrophages at sites of infection and increased the percentage and total numbers of myeloid cells mediating phagocytosis of bacteria. Depletion of Ly6G+neutrophils, but not macrophages, eliminated the ability of MPLA treatment to improve bacterial clearance. The immunomodulatory effects of MPLA were absent in TLR4-deficient mice. In conclusion, these studies show that MPLA treatment significantly augments the innate immune response to bacterial infection by enhancing bacterial clearance despite the attenuation of proinflammatory cytokine production. The enhanced bacterial clearance is mediated, in part, by increased numbers of myeloid cells with effective phagocytic functions at sites of infection and is TLR4 dependent.

scholarly journals The contribution of miR-122 to the innate immunity by regulating toll-like receptor 4 in hepatoma cells

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Liyu Shi ◽  
Xiaoqiu Zheng ◽  
Yuzhuo Fan ◽  
Xiaolan Yang ◽  
Aimei Li ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Hepatoma Cells ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Toll-like receptor 4 ablation in mdx mice reveals innate immunity as a therapeutic target in Duchenne muscular dystrophy

2014 ◽  
Vol 24 (8) ◽  
pp. 2147-2162 ◽  
Author(s):  
Christian Giordano ◽  
Kamalika Mojumdar ◽  
Feng Liang ◽  
Christian Lemaire ◽  
Tong Li ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Therapeutic Target ◽  
Mdx Mice ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Variability among Macaca fascicularis in the innate immune response to Toll‐like receptor 4 (TLR4) agonists

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Charles Wayne Frevert ◽  
Renee Hukkanen ◽  
Steve Mongovin ◽  
Kay Larsen ◽  
Mike Agy ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Macaca Fascicularis ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

2017 ◽  
Vol 91 (6) ◽  
Author(s):  
Nicholas L. Cianciola ◽  
Stacey Chung ◽  
Danny Manor ◽  
Cathleen R. Carlin
Keyword(s):  
Innate Immunity ◽  
Endoplasmic Reticulum ◽  
Membrane Protein ◽  
Lipid Droplets ◽  
Cholesterol Transport ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Human Adenoviruses ◽  
Early Region ◽  
Early Region 3

ABSTRACT Human adenoviruses (Ads) generally cause mild self-limiting infections but can lead to serious disease and even be fatal in high-risk individuals, underscoring the importance of understanding how the virus counteracts host defense mechanisms. This study had two goals. First, we wished to determine the molecular basis of cholesterol homeostatic responses induced by the early region 3 membrane protein RIDα via its direct interaction with the sterol-binding protein ORP1L, a member of the evolutionarily conserved family of oxysterol-binding protein (OSBP)-related proteins (ORPs). Second, we wished to determine how this interaction regulates innate immunity to adenovirus. ORP1L is known to form highly dynamic contacts with endoplasmic reticulum-resident VAP proteins that regulate late endosome function under regulation of Rab7-GTP. Our studies have demonstrated that ORP1L-VAP complexes also support transport of LDL-derived cholesterol from endosomes to the endoplasmic reticulum, where it was converted to cholesteryl esters stored in lipid droplets when ORP1L was bound to RIDα. The virally induced mechanism counteracted defects in the predominant cholesterol transport pathway regulated by the late endosomal membrane protein Niemann-Pick disease type C protein 1 (NPC1) arising during early stages of viral infection. However, unlike NPC1, RIDα did not reconstitute transport to endoplasmic reticulum pools that regulate SREBP transcription factors. RIDα-induced lipid trafficking also attenuated proinflammatory signaling by Toll-like receptor 4, which has a central role in Ad pathogenesis and is known to be tightly regulated by cholesterol-rich “lipid rafts.” Collectively, these data show that RIDα utilizes ORP1L in a way that is distinct from its normal function in uninfected cells to fine-tune lipid raft cholesterol that regulates innate immunity to adenovirus in endosomes. IMPORTANCE Early region 3 proteins encoded by human adenoviruses that attenuate immune-mediated pathology have been a particularly rich source of information regarding intracellular protein trafficking. Our studies with the early region 3-encoded RIDα protein also provided fundamental new information regarding mechanisms of nonvesicular lipid transport and the flow of molecular information at membrane contacts between different organelles. We describe a new pathway that delivers cholesterol from endosomes to the endoplasmic reticulum, where it is esterified and stored in lipid droplets. Although lipid droplets are attracting renewed interest from the standpoint of normal physiology and human diseases, including those resulting from viral infections, experimental model systems for evaluating how and why they accumulate are still limited. Our studies also revealed an intriguing relationship between lipid droplets and innate immunity that may represent a new paradigm for viruses utilizing these organelles.

scholarly journals Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Zhijuan Qiu ◽  
Jorge L. Cervantes ◽  
Basak B. Cicek ◽  
Subhajit Mukherjee ◽  
Madhukumar Venkatesh ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Bacterial Infection ◽  
Host Defense ◽  
Negative Impact ◽  
Pregnane X Receptor ◽  
Negative Regulator ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Chemokine Production ◽  
Inflammatory Monocytes

Abstract The nuclear pregnane X receptor (PXR) plays a central role in regulating xenobiotic metabolism. We now report a novel role for PXR as a critical negative regulator of innate immunity after infection. Pxr −/− mice exhibited remarkably elevated pro-inflammatory cytokine and chemokine production following infection with Listeria monocytogenes (Lm). Despite the more robust innate immune response, Pxr −/− mice were highly susceptible to Lm infection. Surprisingly, disruption of the Toll-like receptor 4 (TLR4) but not TLR2 signaling restored the inflammation to normal levels and the ability to clear Lm in Pxr −/− mice. Mechanistically, the heightened inflammation in Pxr −/− mice resulted in the death of inflammatory monocytes that led to the enhanced susceptibility to Lm infection. These data demonstrated that PXR regulated pathogen-induced inflammation and host defense against Lm infection through modulating the TLR4 pathway. In summary, we discovered an apical role for PXR in regulating innate immunity. In addition, we uncovered a remarkable negative impact of the TLR4 pathway in controlling the quality of the inflammatory response and host defense against a gram-positive bacterial infection.

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