492. Adenovirus Vectors With Large Substitutions in the Penton Base RGD Loop Retain Infectivity and Elicit a Diminished Innate Immune Response In Vivo

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.

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Biofunctionalization of 3D-printed silicone implants with immunomodulatory hydrogels for controlling the innate immune response: An in vivo model of tracheal defect repair

Biomaterials ◽

10.1016/j.biomaterials.2020.120549 ◽

2021 ◽

Vol 268 ◽

pp. 120549

Author(s):

J. Barthes ◽

P. Lagarrigue ◽

V. Riabov ◽

G. Lutzweiler ◽

J. Kirsch ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Innate Immune ◽

In Vivo Model ◽

Silicone Implants ◽

Tracheal Defect ◽

Defect Repair ◽

3D Printed

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Effects of Regulatory T Cell Depletion on NK Cell Responses against Listeria monocytogenes in Feline Immunodeficiency Virus Infected Cats

Viruses ◽

10.3390/v11110984 ◽

2019 ◽

Vol 11 (11) ◽

pp. 984

Author(s):

Simões ◽

LaVoy ◽

Dean

Keyword(s):

Immune Response ◽

Listeria Monocytogenes ◽

Dendritic Cell ◽

Innate Immune Response ◽

Feline Immunodeficiency Virus ◽

Innate Immune ◽

Treg Depletion ◽

Cell Responses ◽

Immunodeficiency Virus

Regulatory T cells (Treg) are key players in the maintenance of peripheral tolerance, preventing autoimmune diseases and restraining chronic inflammatory diseases. Evidence suggests Treg cells and NK cells have important roles in feline immunodeficiency virus (FIV) pathogenesis; however, in vivo studies investigating the interplay between these two cell populations are lacking. We previously described innate immune defects in FIV-infected cats characterized by cytokine deficits and impaired natural killer cell (NK) and NK T cell (NKT) functions. In this study, we investigated whether in vivo Treg depletion by treatment with an anti-feline CD25 monoclonal antibody would improve the innate immune response against subcutaneous challenge with Listeria monocytogenes (Lm). Treg depletion resulted in an increased overall number of cells in Lm-draining lymph nodes and increased proliferation of NK and NKT cells in FIV-infected cats. Treg depletion did not normalize expression of perforin or granzyme A by NK and NKT cells, nor did Treg depletion result in improved clearance of Lm. Thus, despite the quantitative improvements in the NK and NKT cell responses to Lm, there was no functional improvement in the early control of Lm. CD1a+ dendritic cell percentages in the lymph nodes of FIV-infected cats were lower than in specific-pathogen-free control cats and failed to upregulate CD80 even when Treg were depleted. Taken together, Treg depletion failed to improve the innate immune response of FIV-infected cats against Lm and this may be due to dendritic cell dysfunction.

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Fulvestrant-Mediated Attenuation of the Innate Immune Response Decreases ER+ Breast Cancer Growth In Vivo More Effectively than Tamoxifen

Cancer Research ◽

10.1158/0008-5472.can-20-1705 ◽

2020 ◽

Vol 80 (20) ◽

pp. 4487-4499

Author(s):

Annelie Abrahamsson ◽

Gabriela Vazquez Rodriguez ◽

Charlotta Dabrosin

Keyword(s):

Breast Cancer ◽

Immune Response ◽

Innate Immune Response ◽

Innate Immune ◽

Cancer Growth ◽

Breast Cancer Growth

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The Exopolysaccharide of Lactobacillus fermentum UCO-979C Is Partially Involved in Its Immunomodulatory Effect and Its Ability to Improve the Resistance against Helicobacter pylori Infection

Microorganisms ◽

10.3390/microorganisms8040479 ◽

2020 ◽

Vol 8 (4) ◽

pp. 479

Author(s):

Valeria Garcia-Castillo ◽

Guillermo Marcial ◽

Leonardo Albarracín ◽

Mikado Tomokiyo ◽

Patricia Clua ◽

...

Keyword(s):

Immune Response ◽

Helicobacter Pylori ◽

Gastric Mucosa ◽

Innate Immune Response ◽

Innate Immune ◽

Helicobacter Pylori Infection ◽

Beneficial Effects ◽

Ifn Γ ◽

H Pylori

Lactobacillus fermentum UCO-979C (Lf979C) beneficially modulates the cytokine response of gastric epithelial cells and macrophages after Helicobacter pylori infection in vitro. Nevertheless, no in vivo studies were performed with this strain to confirm its beneficial immunomodulatory effects. This work evaluated whether Lf979C improves protection against H. pylori infection in mice by modulating the innate immune response. In addition, we evaluated whether its exopolysaccharide (EPS) was involved in its beneficial effects. Lf979C significantly reduced TNF-α, IL-8, and MCP-1 and augmented IFN-γ and IL-10 in the gastric mucosa of H. pylori-infected mice. The differential cytokine profile induced by Lf979C in H. pylori-infected mice correlated with an improved reduction in the pathogen gastric colonization and protection against inflammatory damage. The purified EPS of Lf979C reduced IL-8 and enhanced IL-10 levels in the gastric mucosa of infected mice, while no effect was observed for IFN-γ. This work demonstrates for the first time the in vivo ability of Lf979C to increase resistance against H. pylori infection by modulating the gastric innate immune response. In addition, we advanced knowledge of the mechanisms involved in the beneficial effects of Lf979C by demonstrating that its EPS is partially responsible for its immunomodulatory effect.

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

10.22203/ecm.v041a48 ◽

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.

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Bladder urothelial BK channel activity is a critical mediator for innate immune response in urinary tract infection pathogenesis

AJP Renal Physiology ◽

10.1152/ajprenal.00554.2018 ◽

2019 ◽

Vol 316 (4) ◽

pp. F617-F623 ◽

Cited By ~ 3

Author(s):

Judy Yeh ◽

Ming Lu ◽

Lery Alvarez-Lugo ◽

Toby C. Chai

Keyword(s):

Immune Response ◽

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Innate Immune Response ◽

Bk Channel ◽

Innate Immune ◽

Separate Experiment ◽

Channel Activity

The open probability of calcium-activated voltage-gated potassium channel (BK channel) on bladder umbrella urothelial cells is increased by lipopolysaccharide (LPS). It is hypothesized that this channel’s activity is important in the urothelial innate immune response during urinary tract infection (UTI). We performed in vivo studies using female C57BL/6 mice whose bladders were inoculated with LPS (150 μl of 1 mg/ml) or uropathogenic Escherichia coli (UPEC, UTI89), without and with intravesical BK inhibitor iberiotoxin (IBTX, 1 μM). Inflammatory biomarkers (chemokines and cytokines) were measured in urine specimens collected 2 h after inoculation using a 32-multiplex ELISA. Of these 32 biomarkers, 19 and 15 were significantly elevated 2 h after LPS and UPEC exposure, respectively. IBTX significantly abrogated the elevations of 15 out of 19 biomarkers after LPS inoculation and 12 out of 15 biomarkers after UPEC inoculation. In a separate experiment, qPCR for IL-6, interferon-γ-induced protein 10 (CXCL10), and macrophage inflammatory protein 2 (CXCL2) in urothelium paralleled the changes measured in urine of these same biomarkers, supporting that urinary changes in biomarker levels reflected urothelial expression changes. These in vivo data demonstrated that BK channel activity is crucial in the urothelial host innate immune response, as measured by changes in urinary biomarkers, in UTI pathogenesis.

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