#13: Respiratory and Intestinal Epithelial Cells Exhibit Differential Susceptibility and Innate Immune Responses to Contemporary EV-D68 Isolates

Abstract Background Enterovirus D68 (EV-D68) has been implicated in outbreaks of severe respiratory illness and associated with acute flaccid myelitis (AFM), a disease which causes paralysis in previously healthy patients, mostly children. AFM peaked in even numbered years, at least 2014–2018. While 2020 was expected to be a peak AFM year, few cases were seen, likely due to non-specific social distancing measures due to SARS-CoV-2. EV-D68 is primarily described as a respiratory pathogen, in contrast to ‘classic’ enteroviruses that are spread via the fecal-oral route. However, similar to other enteroviruses, EV-D68 has been detected in wastewater, suggesting it might also have an enteric route of transmission. Methods We used a panel of EV-D68 isolates, including a historic isolate from 2009 and multiple contemporary isolates from AFM peak years to define dynamics of viral replication and host response to infection. We performed comparative studies in primary human bronchial epithelial cells grown at an air-liquid interface and in primary human stem-cell derived intestinal enteroids. These human primary cell-based models more accurately reflect the cells targeted by EV-D68 in vivo. We defined growth characteristics, temperature sensitivity, infection polarity, and acid sensitivity in these parallel models. We used unbiased Luminex-based multianalyte profiling and bulk RNA-sequencing to define the innate immune response in each model. Results Conclusions Our findings suggest that a subset of contemporary isolates of EV-D68 have the potential to target both the human airway and gastrointestinal tracts as a potential route of infection, identifying a previously unrecognized potential route of infection as well as defining, for the first time, the innate immune response to infection in multiple relevant primary epithelial models. These findings are highly significant and are the first to characterize the viral replication and host innate immune response to a diverse panel of historic and contemporary EV-D68 isolates in both the respiratory and intestinal tracts.

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Innate immune response in CF airway epithelia: hyperinflammatory?

AJP Cell Physiology ◽

10.1152/ajpcell.00605.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. C218-C230 ◽

Cited By ~ 123

Author(s):

Terry E. Machen

Keyword(s):

Immune Response ◽

Epithelial Cells ◽

Innate Immune Response ◽

Cellular Signaling ◽

Basolateral Membrane ◽

Airway Epithelial Cells ◽

Innate Immune ◽

Airway Epithelial ◽

Airway Epithelia ◽

Intracellular Ca

The lack of functional cystic fibrosis (CF) transmembrane conductance regulator (CFTR) in the apical membranes of CF airway epithelial cells abolishes cAMP-stimulated anion transport, and bacteria, eventually including Pseudomonas aeruginosa, bind to and accumulate in the mucus. Flagellin released from P. aeruginosa triggers airway epithelial Toll-like receptor 5 and subsequent NF-κB signaling and production and release of proinflammatory cytokines that recruit neutrophils to the infected region. This response has been termed hyperinflammatory because so many neutrophils accumulate; a response that damages CF lung tissue. We first review the contradictory data both for and against the idea that epithelial cells exhibit larger-than-normal proinflammatory signaling in CF compared with non-CF cells and then review proposals that might explain how reduced CFTR function could activate such proinflammatory signaling. It is concluded that apparent exaggerated innate immune response of CF airway epithelial cells may have resulted not from direct effects of CFTR on cellular signaling or inflammatory mediator production but from indirect effects resulting from the absence of CFTRs apical membrane channel function. Thus, loss of Cl−, HCO3−, and glutathione secretion may lead to reduced volume and increased acidification and oxidation of the airway surface liquid. These changes concentrate proinflammatory mediators, reduce mucociliary clearance of bacteria and subsequently activate cellular signaling. Loss of apical CFTR will also hyperpolarize basolateral membrane potentials, potentially leading to increases in cytosolic [Ca2+], intracellular Ca2+, and NF-κB signaling. This hyperinflammatory effect of CF on intracellular Ca2+and NF-κB signaling would be most prominently expressed during exposure to both P. aeruginosa and also endocrine, paracrine, or nervous agonists that activate Ca2+signaling in the airway epithelia.

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Innate Immune Response to Viral Infections in Primary Bronchial Epithelial Cells is Modified by the Atopic Status of Asthmatic Patients

Allergy Asthma and Immunology Research ◽

10.4168/aair.2018.10.2.144 ◽

2018 ◽

Vol 10 (2) ◽

pp. 144 ◽

Cited By ~ 12

Author(s):

Sylwia Moskwa ◽

Wojciech Piotrowski ◽

Jerzy Marczak ◽

Małgorzata Pawełczyk ◽

Anna Lewandowska-Polak ◽

...

Keyword(s):

Immune Response ◽

Epithelial Cells ◽

Innate Immune Response ◽

Viral Infections ◽

Bronchial Epithelial Cells ◽

Innate Immune ◽

Bronchial Epithelial ◽

Asthmatic Patients ◽

Atopic Status ◽

Primary Bronchial Epithelial Cells

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Global gene expression patterns and induction of innate immune response in human laryngeal epithelial cells in response toAcinetobacter baumanniiouter membrane protein A

FEMS Immunology & Medical Microbiology ◽

10.1111/j.1574-695x.2008.00446.x ◽

2008 ◽

Vol 54 (1) ◽

pp. 45-52 ◽

Cited By ~ 18

Author(s):

Soon Ae Kim ◽

Sung Min Yoo ◽

Sung Hee Hyun ◽

Chul Hee Choi ◽

So Young Yang ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Epithelial Cells ◽

Membrane Protein ◽

Innate Immune Response ◽

Expression Patterns ◽

Protein A ◽

Global Gene Expression ◽

Innate Immune ◽

Gene Expression Patterns

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

Infection and Immunity ◽

10.1128/iai.00045-20 ◽

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.

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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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