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 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 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 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.

scholarly journals Corticosteroids and cellulose purification improve respectively the in vivo translation and vaccination efficacy of self-amplifying mRNAs

2020 ◽  
Author(s):  
Zifu Zhong ◽  
Séan Mc Cafferty ◽  
Lisa Opsomer ◽  
Haixiu Wang ◽  
Hanne Huysmans ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Biomedical Applications ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Therapeutic Platform ◽  
By Products

AbstractSynthetic mRNAs are an appealing therapeutic platform with multiple biomedical applications ranging from protein replacement therapy to vaccination. In comparison to conventional mRNA, synthetic self-amplifying mRNAs (sa-mRNAs) are gaining increased interest due to their higher and longer-lasting expression. However, sa-mRNAs also elicit an innate immune response, which may complicate the clinical translation of this platform. Approaches to reduce the innate immunity of sa-mRNAs have not been studied in detail. In this work we investigated the effect of several innate immune inhibitors and a novel cellulose-based mRNA purification approach on the type I interferon (IFN) response, translation and vaccination efficacy of our formerly developed sa-mRNA vaccine against Zika virus. Among the investigated inhibitors, we found that topical application of clobetasol at the sa-mRNA injection site was the most efficient in suppressing the type I IFN response and increasing the translation of sa-mRNA. However, clobetasol prevented the formation of antibodies against sa-mRNA encoded antigens and should therefore be avoided in a vaccination context. Residual dsRNA by-products of the in vitro transcription reaction are known inducers of immediate type I IFN responses. We additionally demonstrate drastic reduction of these dsRNA by-products upon cellulose-based purification, consequently reducing the innate immune response and improving sa-mRNA vaccination efficacy.

scholarly journals Cyprinus carpio TRIF Participates in the Innate Immune Response by Inducing NF-κB and IFN Activation and Promoting Apoptosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Rongrong Liu ◽  
Xiaoye Liu ◽  
Meijiao Song ◽  
Yue Qi ◽  
Hua Li ◽  
...  
Keyword(s):  
Immune Response ◽  
Common Carp ◽  
Innate Immune Response ◽  
Cyprinus Carpio ◽  
Critical Role ◽  
Innate Immune ◽  
Poly I:C ◽  
Luciferase Reporter

TRIF, an important adaptor downstream of Toll-like receptor signaling, plays a critical role in the innate immune response. In this study, the full-length coding sequence of TRIF from common carp (Cyprinus carpio L.) was cloned and characterized. Bioinformatics analysis showed that common carp TRIF exhibited a conserved TIR domain and had the closest relationship with grass carp TRIF. Expression analysis revealed that TRIF was constitutively expressed in the examined tissues of common carp, with the highest expression in the spleen and the lowest expression in the head kidney, and could be upregulated under Aeromonas hydrophila and poly(I:C) stimulation in vivo and under poly(I:C), LPS, PGN, flagellin, and Pam3CSK4 stimulation in vitro. Laser confocal microscopy showed that common carp TRIF colocalized with the Golgi apparatus. A luciferase reporter assay showed that carp TRIF elicited the activity of ifn-1 and nf-κb through the C-terminal domain. Additionally, crystal violet staining and qPCR assays revealed that carp TRIF inhibited the replication of SVCV in epithelioma papulosum cyprini (EPC) cells. Then, the signaling downstream of carp TRIF was investigated. Coimmunoprecipitation and Western blotting analysis demonstrated that carp TRIF interacted with TBK1 and augmented the expression of TRAF6 and phosphorylation of TBK1. Overexpression of carp TRIF significantly enhanced the expression of interferon-stimulated genes and inflammatory cytokines. Furthermore, flow cytometric (FCM) analysis suggested that carp TRIF induced apoptosis through the activation of caspase-8. In summary, our study indicated that TRIF plays an essential role in the innate immune responses of common carp against bacterial and viral infection.

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 Effects of antibiotics on acquired immunity in vivo – current state of knowledge

2012 ◽  
Vol 15 (3) ◽  
pp. 583-588 ◽  
Author(s):  
M. Pomorska-Mól ◽  
Z. Pejsak
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Innate Immune Response ◽  
Ex Vivo ◽  
Animal Experiments ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Antimicrobial Drugs

AbstractAntibiotics are widely used in the therapy of infections. Besides the respective interactions between antibiotics and pathogens it seems that antibiotics also directly interact with the immune system. Some commonly used antibiotics are currently known to have effects on the innate immune response, as shown byin vitro, ex vivoand alsoin vivoanimal experiments and clinical studies. Most of the experimental papers published to date, as well as most reviews, relate to how antibiotics affect the innate immune response or non-specific monocyte or lymphocyte proliferation. However the effects of antibiotics on the adaptive immune response are still not well characterized. This review of the literature considering differentin vivoexperiments indicate the real importance of interrelations existing between acquired immune responses and antibiotics, however, the mechanism of immunomodulatory effects of antibiotics are still poorly understood. Currently, data on the immunomodulating effects of antibiotics often remain heterogeneous, contradictory or insufficient, but most results published to date revealed the immunosuppressive effect of antibiotics on the antigen- specific immune responsein vivo. In pigs as well as in poultry herds, it is not uncommon practice to add antibiotics to drinking water or feed at the time of vaccination. Information on the effects of such practices on the immune system of animals is restricted and morein vivostudies are needed to investigate the effects of antimicrobial drugs on the immune system, especially in the field conditions.

High content screening and computational prediction reveal viral genes that suppress innate immune response

2021 ◽  
Author(s):  
Tai L Ng ◽  
Erika J Olson ◽  
Tae Yeon Yoo ◽  
H. Sloane Weiss ◽  
Yukiye Koide ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Nuclear Transport ◽  
Computational Prediction ◽  
Viral Proteins ◽  
Innate Immune ◽  
Type I ◽  
Viral Genes ◽  
Genes Encoding

Suppression of the host innate immune response is a critical aspect of viral replication. Upon infection, viruses may introduce one or more proteins that inhibit key immune pathways, such as the type I interferon pathway. However, the ability to predict and evaluate viral protein bioactivity on targeted pathways remains challenging and is typically done on a single virus/gene basis. Here, we present a medium-throughput high-content cell-based assay to reveal the immunosuppressive effects of viral proteins. To test the predictive power of our approach, we developed a library of 800 genes encoding known, predicted, and uncharacterized human viral genes. We find that previously known immune suppressors from numerous viral families such as Picornaviridae and Flaviviridae recorded positive responses. These include a number of viral proteases for which we further confirmed that innate immune suppression depends on protease activity. A class of predicted inhibitors encoded by Rhabdoviridae viruses was demonstrated to block nuclear transport, and several previously uncharacterized proteins from uncultivated viruses were shown to inhibit nuclear transport of the transcription factors NF-kB and IRF3. We propose that this pathway-based assay, together with early sequencing, gene synthesis, and viral infection studies, could partly serve as the basis for rapid in vitro characterization of novel viral proteins.

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