scholarly journals Ursodeoxycholic Acid (UDCA) Mitigates the Host Inflammatory Response during Clostridioides difficile Infection by Altering Gut Bile Acids

2020 ◽  
Vol 88 (6) ◽  
Author(s):  
Jenessa A. Winston ◽  
Alissa J. Rivera ◽  
Jingwei Cai ◽  
Rajani Thanissery ◽  
Stephanie A. Montgomery ◽  
...  
Keyword(s):  
Immune Response ◽  
Bile Acid ◽  
Inflammatory Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Colonization Resistance ◽  
Content Type ◽  
Clostridioides Difficile

ABSTRACT Clostridioides difficile infection (CDI) is associated with increasing morbidity and mortality posing an urgent threat to public health. Recurrence of CDI after successful treatment with antibiotics is high, thus necessitating discovery of novel therapeutics against this enteric pathogen. Administration of the secondary bile acid ursodeoxycholic acid (UDCA; ursodiol) inhibits the life cycles of various strains of C. difficile in vitro, suggesting that the FDA-approved formulation of UDCA, known as ursodiol, may be able to restore colonization resistance against C. difficile in vivo. However, the mechanism(s) by which ursodiol is able to restore colonization resistance against C. difficile remains unknown. Here, we confirmed that ursodiol inhibits C. difficile R20291 spore germination and outgrowth, growth, and toxin activity in a dose-dependent manner in vitro. In a murine model of CDI, exogenous administration of ursodiol resulted in significant alterations in the bile acid metabolome with little to no changes in gut microbial community structure. Ursodiol pretreatment resulted in attenuation of CDI pathogenesis early in the course of disease, which coincided with alterations in the cecal and colonic inflammatory transcriptome, bile acid-activated receptors nuclear farnesoid X receptor (FXR) and transmembrane G-protein-coupled membrane receptor 5 (TGR5), which are able to modulate the innate immune response through signaling pathways such as NF-κB. Although ursodiol pretreatment did not result in a consistent decrease in the C. difficile life cycle in vivo, it was able to attenuate an overly robust inflammatory response that is detrimental to the host during CDI. Ursodiol remains a viable nonantibiotic treatment and/or prevention strategy against CDI. Likewise, modulation of the host innate immune response via bile acid-activated receptors FXR and TGR5 represents a new potential treatment strategy for patients with CDI.

scholarly journals Ursodeoxycholic acid (UDCA) mitigates the host inflammatory response during Clostridioides difficile infection by altering gut bile acids which attenuates NF-κB signaling via bile acid activated receptors

2020 ◽  
Author(s):  
Jenessa A. Winston ◽  
Alissa J. Rivera ◽  
Jingwei Cai ◽  
Rajani Thanissery ◽  
Stephanie A. Montgomery ◽  
...  
Keyword(s):  
Immune Response ◽  
Bile Acid ◽  
Inflammatory Response ◽  
Ursodeoxycholic Acid ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Farnesoid X Receptor ◽  
Clostridioides Difficile

AbstractClostridioides difficile infection (CDI) is associated with increasing morbidity and mortality posing an urgent threat to public health. Recurrence of CDI after successful treatment with antibiotics is high, thus necessitating discovery of novel therapeutics against this enteric pathogen. Administration of the secondary bile acid ursodeoxycholic acid (UDCA, ursodiol) inhibits the life cycle of various strains of C. difficile in vitro, suggesting the FDA approved formulation of UDCA, known as ursodiol, may be able to restore colonization resistance against C. difficile in vivo. However, the mechanism(s) by which ursodiol is able to restore colonization resistance against C. difficile remains unknown. Here, we confirmed that ursodiol inhibits C. difficile R20291 spore germination and outgrowth, growth, and toxin activity in a dose dependent manner in vitro. In a murine model of CDI, exogenous administration of ursodiol resulted in significant alterations in the bile acid metabolome with little to no changes in gut microbial community structure. Ursodiol pretreatment resulted in attenuation of CDI pathogenesis early in the course of disease, which coincided with alterations in the cecal and colonic inflammatory transcriptome, bile acid activated receptors nuclear farnesoid X receptor (FXR), and transmembrane G protein-coupled membrane receptor 5 (TGR5), which are able to modulate the innate immune response through signaling pathways such as NF-κB. Although ursodiol pretreatment did not result in a consistent decrease in the C. difficile life cycle in vivo, it was able to attenuate an overly robust inflammatory response that is detrimental to the host during CDI. Ursodiol remains a viable non-antibiotic treatment and/or prevention strategy against CDI. Likewise, modulation of the host innate immune response via bile acid activated receptors, FXR and TGR5, represents a new potential treatment strategy for patients with CDI.ImportanceThe clinical utility of ursodiol for prevention of recurrent CDI is currently in Phase 4 clinical trials. However, the mechanism by which ursodiol exerts its impacts on C. difficile pathogenesis is poorly understood. Herein, we demonstrated that ursodiol pretreatment attenuates CDI pathogenesis early in the course of disease in mice, which coincides with alterations in the cecal and colonic inflammatory transcriptome, bile acid activated receptors nuclear farnesoid X receptor (FXR), and transmembrane G protein-coupled membrane receptor 5 (TGR5), which are able to modulate the innate immune response through signaling pathways such as NF-κB. Ursodiol attenuated an overly robust inflammatory response that is detrimental to the host during CDI, and thus remains a viable non-antibiotic treatment and/or prevention strategy against CDI. Likewise, modulation of the host innate immune response via bile acid activated receptors, FXR and TGR5, represents a new potential treatment strategy for patients with CDI.AbbreviationsαMCA – α-Muricholic acid; βMCA –β-Muricholic acid; ωMCA –ω-Muricholic acid; CA – Cholic acid; CDCA – Chenodeoxycholic acid; DCA – Deoxycholic acid; GCDCA – Glycochenodeoxycholic acid; GDCA – Glycodeoxycholic acid; GLCA – Glycolithocholic acid; GUDCA – Glycoursodeoxycholic acid; HCA – Hyodeoxycholic acid; iDCA – Isodeoxycholic acid; iLCA – Isolithocholic acid; LCA – Lithocholic acid; TCA – Taurocholic acid; TCDCA – Taurochenodeoxycholic acid; TDCA – Taurodeoxycholic acid; THCA – Taurohyodeoxycholic acid; TUDCA – Tauroursodeoxycholic acid; TβMCA– Tauro-β-muricholic acid; TωMCA –Tauro ω-muricholic acid; UDCA Ursodeoxycholic acid.

scholarly journals Coxiella burnetii Interaction with Neutrophils and MacrophagesIn Vitroand in SCID Mice following Aerosol Infection

2013 ◽  
Vol 81 (12) ◽  
pp. 4604-4614 ◽  
Author(s):  
Alexandra Elliott ◽  
Ying Peng ◽  
Guoquan Zhang
Keyword(s):  
Immune Response ◽  
Coxiella Burnetii ◽  
Q Fever ◽  
Natural Infection ◽  
Scid Mice ◽  
Innate Immune ◽  
Content Type ◽  
Aerosol Infection

ABSTRACTCoxiella burnetiiis an obligate intracellular bacterium that causes acute and chronic Q fever in humans. Human Q fever is mainly transmitted by aerosol infection. However, there is a fundamental gap in the knowledge regarding the mechanisms of pulmonary immunity againstC. burnetiiinfection. This study focused on understanding the interaction betweenC. burnetiiand innate immune cellsin vitroandin vivo. Both virulentC. burnetiiNine Mile phase I (NMI) and avirulent Nine Mile phase II (NMII) were able to infect neutrophils, while the infection rates were lower than 29%, suggesting thatC. burnetiican infect neutrophils, but infection is limited. Interestingly,C. burnetiiinside neutrophils can infect and replicate within macrophages, suggesting that neutrophils cannot killC. burnetiiandC. burnetiimay be using infection of neutrophils as an evasive strategy to infect macrophages. To elucidate the mechanisms of the innate immune response toC. burnetiinatural infection, SCID mice were exposed to aerosolizedC. burnetii. Surprisingly, neutrophil influx into the lungs was delayed until day 7 postinfection in both NMI- and NMII-infected mice. This result suggests that neutrophils may play a unique role in the early immune response against aerosolizedC. burnetii. Studying the interaction betweenC. burnetiiand the innate immune system can provide a model system for understanding how the bacteria evade early immune responses to cause infection.

scholarly journals From benchtop to clinic: a translational analysis of the immune response to submicron topography and its relevance to bone healing

2021 ◽  
Vol 41 ◽  
pp. 756-773
Author(s):  
LA van Dijk ◽  
◽  
F de Groot ◽  
H Yuan ◽  
C Campion ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Bone Healing ◽  
Interbody Fusion ◽  
Case Series ◽  
Innate Immune ◽  
Surface Features ◽  
Healing Response

Proper regulation of the innate immune response to bone biomaterials after implantation is pivotal for successful bone healing. Pro-inflammatory M1 and anti-inflammatory M2 macrophages are known to have an important role in regulating the healing response to biomaterials. Materials with defined structural and topographical features have recently been found to favourably modulate the innate immune response, leading to improved healing outcomes. Calcium phosphate bone grafts with submicron-sized needle-shaped surface features have been shown to trigger a pro-healing response through upregulation of M2 polarised macrophages, leading to accelerated and enhanced bone regeneration. The present review describes the recent research on these and other materials, all the way from benchtop to the clinic, including in vitro and in vivo fundamental studies, evaluation in clinically relevant spinal fusion models and clinical validation in a case series of 77 patients with posterolateral and/or interbody fusion in the lumbar and cervical spine. This research demonstrates the feasibility of enhancing biomaterial-directed bone formation by modulating the innate immune response through topographic surface features.

scholarly journals Regulation of Innate Immune Response toCandida albicansInfections by αMβ2-Pra1p Interaction

2011 ◽  
Vol 79 (4) ◽  
pp. 1546-1558 ◽  
Author(s):  
Dmitry A. Soloviev ◽  
Samir Jawhara ◽  
William A. Fonzi
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Cell Mediated Immunity ◽  
Fungal Virulence ◽  
Opportunistic Fungal Pathogen ◽  
Organ Invasion ◽  
Increased Susceptibility

ABSTRACTCandida albicansis a common opportunistic fungal pathogen and is the leading cause of invasive fungal diseases in immunocompromised individuals. The induction of cell-mediated immunity toC. albicansis one of the main tasks of cells of the innate immune system, andin vitroevidence suggests that integrin αMβ2(CR3, Mac-1, and CD11b/CD18) is the principal leukocyte receptor involved in recognition of the fungus. Using αMβ2-KO mice and mutated strains ofC. albicansin two models of murine candidiasis, we demonstrate that neutrophils derived from mice deficient in αMβ2have a reduced ability to killC. albicansand that the deficient mice themselves exhibit increased susceptibility to fungal infection. Disruption of thePRA1gene ofC. albicans, the primary ligand for αMβ2, protects the fungus against leukocyte killingin vitroandin vivo, impedes the innate immune response to the infection, and increases fungal virulence and organ invasionin vivo. Thus, recognition of pH-regulated antigen 1 protein (Pra1p) by αMβ2plays a pivotal role in determining fungal virulence and host response and protection againstC. albicansinfection.

scholarly journals Kdo Hydrolase Is Required for Francisella tularensis Virulence and Evasion of TLR2-Mediated Innate Immunity

mBio ◽  
2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Nihal A. Okan ◽  
Sabina Chalabaev ◽  
Tae-Hyun Kim ◽  
Avner Fink ◽  
Robin A. Ross ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Innate Immune Response ◽  
Francisella Tularensis ◽  
Innate Immune ◽  
Content Type ◽  
Tnf Α ◽  
Schu S4 ◽  
Highly Virulent

ABSTRACT The highly virulent Francisella tularensis subsp. tularensis has been classified as a category A bioterrorism agent. A live vaccine strain (LVS) has been developed but remains unlicensed in the United States because of an incomplete understanding of its attenuation. Lipopolysaccharide (LPS) modification is a common strategy employed by bacterial pathogens to avoid innate immunity. A novel modification enzyme has recently been identified in F. tularensis and Helicobacter pylori. This enzyme, a two-component Kdo (3-deoxy-d-manno-octulosonic acid) hydrolase, catalyzes the removal of a side chain Kdo sugar from LPS precursors. The biological significance of this modification has not yet been studied. To address the role of the two-component Kdo hydrolase KdhAB in F. tularensis pathogenesis, a ΔkdhAB deletion mutant was constructed from the LVS strain. In intranasal infection of mice, the ΔkdhAB mutant strain had a 50% lethal dose (LD50) 2 log10 units higher than that of the parental LVS strain. The levels of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) in bronchoalveolar lavage fluid were significantly higher (2-fold) in mice infected with the ΔkdhAB mutant than in mice infected with LVS. In vitro stimulation of bone marrow-derived macrophages with the ΔkdhAB mutant induced higher levels of TNF-α and IL-1β in a TLR2-dependent manner. In addition, TLR2−/− mice were more susceptible than wild-type mice to ΔkdhAB bacterial infection. Finally, immunization of mice with ΔkdhAB bacteria elicited a high level of protection against the highly virulent F. tularensis subsp. tularensis strain Schu S4. These findings suggest an important role for the Francisella Kdo hydrolase system in virulence and offer a novel mutant as a candidate vaccine. IMPORTANCE The first line of defense against a bacterial pathogen is innate immunity, which slows the progress of infection and allows time for adaptive immunity to develop. Some bacterial pathogens, such as Francisella tularensis, suppress the early innate immune response, killing the host before adaptive immunity can mature. To avoid an innate immune response, F. tularensis enzymatically modifies its lipopolysaccharide (LPS). A novel LPS modification—Kdo (3-deoxy-d-manno-octulosonic acid) saccharide removal—has recently been reported in F. tularensis. We found that the ∆kdhAB mutant was significantly attenuated in mice. Additionally, the mutant strain induced an early innate immune response in mice both in vitro and in vivo. Immunization of mice with this mutant provided protection against the highly virulent F. tularensis strain Schu S4. Thus, our study has identified a novel LPS modification important for microbial virulence. A mutant lacking this modification may be used as a live attenuated vaccine against tularemia.

scholarly journals TLR3-mediated NF-κB signaling in human esophageal epithelial cells

2009 ◽  
Vol 297 (6) ◽  
pp. G1172-G1180 ◽  
Author(s):  
Diana M. Lim ◽  
Sneha Narasimhan ◽  
Carmen Z. Michaylira ◽  
Mei-Lun Wang
Keyword(s):  
Immune Response ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Poly I:C ◽  
Esophageal Epithelium ◽  
Esophageal Epithelial Cells ◽  
Stimulation Of

Despite its position at the front line against ingested pathogens, very little is presently known about the role of the esophageal epithelium in host innate immune defense. As a key player in the innate immune response, Toll-like receptor (TLR) signaling has not been well characterized in human esophageal epithelial cells. In the present study, we investigated the inflammatory response and signaling pathways activated by TLR stimulation of human esophageal cells in vitro. Using quantitative RT-PCR, we profiled the expression pattern of human TLRs 1–10 in primary esophageal keratinocytes (EPC2), immortalized nontransformed esophageal keratinocytes (EPC2-hTERT), and normal human esophageal mucosal biopsies and found that TLRs 1, 2, 3, and 5 were expressed both in vivo and in vitro. Using the cytokine IL-8 as a physiological read out of the inflammatory response, we found that TLR3 is the most functional of the expressed TLRs in both primary and immortalized esophageal epithelial cell lines in response to its synthetic ligand polyinosinic polycytidylic acid [poly(I:C)]. Through reporter gene studies, we show that poly(I:C)-induced NF-κB activation is critical for the transactivation of the IL-8 promoter in vitro and that nuclear translocation of NF-κB occurs at an early time point following poly(I:C) stimulation of esophageal epithelial cells. Importantly, we also show that poly(I:C) stimulation induces the NF-κB-dependent esophageal epithelial expression of TLR2, leading to enhanced epithelial responsiveness of EPC2-hTERT cells to TLR2 ligand stimulation, suggesting an important regulatory role for TLR3-mediated NF-κB signaling in the innate immune response of esophageal epithelial cells. Our findings demonstrate for the first time that TLR3 is highly functional in the human esophageal epithelium and that TLR3-mediated NF-κB signaling may play an important regulatory role in esophageal epithelial homeostasis.

scholarly journals Analysis of the Human Mucosal Response to Cholera Reveals Sustained Activation of Innate Immune Signaling Pathways

2017 ◽  
Vol 86 (2) ◽  
Author(s):  
Daniel L. Bourque ◽  
Taufiqur Rahman Bhuiyan ◽  
Diane P. Genereux ◽  
Rasheduzzaman Rashu ◽  
Crystal N. Ellis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Signaling Pathways ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Immune Signaling ◽  
Content Type ◽  
Upstream Regulators

ABSTRACTTo better understand the innate immune response toVibrio choleraeinfection, we tracked gene expression in the duodenal mucosa of 11 Bangladeshi adults with cholera, using biopsy specimens obtained immediately after rehydration and 30 and 180 days later. We identified differentially expressed genes and performed an analysis to predict differentially regulated pathways and upstream regulators. During acute cholera, there was a broad increase in the expression of genes associated with innate immunity, including activation of the NF-κB, mitogen-activated protein kinase (MAPK), and Toll-like receptor (TLR)-mediated signaling pathways, which, unexpectedly, persisted even 30 days after infection. Focusing on early differences in gene expression, we identified 37 genes that were differentially expressed on days 2 and 30 across the 11 participants. These genes included the endosomal Toll-like receptor geneTLR8, which was expressed in lamina propria cells. Underscoring a potential role for endosomal TLR-mediated signalingin vivo, our pathway analysis found that interferon regulatory factor 7 and beta 1 and alpha 2 interferons were among the top upstream regulators activated during cholera. Among the innate immune effectors, we found that the gene for DUOX2, an NADPH oxidase involved in the maintenance of intestinal homeostasis, was upregulated in intestinal epithelial cells during cholera. Notably, the observed increases inDUOX2andTLR8expression were also modeledin vitrowhen Caco-2 or THP-1 cells, respectively, were stimulated with liveV. choleraebut not with heat-killed organisms or cholera toxin alone. These previously unidentified features of the innate immune response toV. choleraeextend our understanding of the mucosal immune signaling pathways and effectors activatedin vivofollowing cholera.

scholarly journals Vaccinia virus gene F3L encodes an intracellular protein that affects the innate immune response

2007 ◽  
Vol 88 (7) ◽  
pp. 1917-1921 ◽  
Author(s):  
Graham C. Froggatt ◽  
Geoffrey L. Smith ◽  
Philippa M. Beard
Keyword(s):  
Immune Response ◽  
Vaccinia Virus ◽  
Innate Immune Response ◽  
Cytopathic Effect ◽  
Innate Immune ◽  
Intracellular Protein ◽  
Virus Growth ◽  
Plaque Phenotype

The Vaccinia virus BTB/kelch protein F3 has been characterized and its effects on virus replication in vitro and virus virulence in vivo have been determined. The loss of the F3L gene had no effect on virus growth, plaque phenotype or cytopathic effect in cell culture under the conditions tested. However, the virulence of a virus lacking F3L in an intradermal model was reduced compared with controls, and this was demonstrated by a significantly smaller lesion and alterations to the innate immune response to infection. The predicted molecular mass of the F3 protein is 56 kDa; however, immunoblotting of infected cell lysates using an antibody directed against recombinant F3 revealed two proteins of estimated sizes 37 and 25 kDa.

Experimental in vitro and in vivo systems for studying the innate immune response during dengue virus infections

2018 ◽  
Vol 163 (7) ◽  
pp. 1717-1726
Author(s):  
Bouchra Kitab ◽  
Michinori Kohara ◽  
Kyoko Tsukiyama-Kohara
Keyword(s):  
Immune Response ◽  
Dengue Virus ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Virus Infections
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