Epithelium intrinsic vitamin A signaling co-ordinates pathogen clearance in the gut via IL-18

AbstractIntestinal epithelial cells (IECs) are at the forefront of host-pathogen interactions, coordinating a cascade of immune responses to confer protection against pathogens. Here we show that IEC-intrinsic vitamin A signaling restricts pathogen invasion early in the infection and subsequently activates immune cells to promote pathogen clearance. Mice blocked for retinoic acid receptor (RAR) signaling selectively in IECs (stopΔIEC) showed significantly higher Salmonella burden in colonic tissues early in the infection associated with higher luminal and systemic loads of the pathogen at later stages. Higher susceptibility of stopΔIEC mice correlated with attenuated mucosal interferon gamma (IFNγ) production by underlying immune cells. We found that, at homeostasis, the intestinal epithelium of stopΔIEC mice produced significantly lower amounts of interleukin 18 (IL-18), a potent inducer of IFNγ. Regulation of IL-18 by vitamin A was also observed in a dietary model of vitamin A supplementation. IL-18 reconstitution in stopΔIEC mice restored resistance to Salmonella by promoting epithelial cell shedding to eliminate infected cells and limit pathogen invasion early in infection. Further, IL-18 augmented IFNγ production by underlying immune cells to restrict pathogen burden and systemic spread. Our work uncovers a critical role for vitamin A in coordinating a biphasic immune response to Salmonella infection by regulating IL-18 production by IECs.Author SummaryEpithelial cells line the intestinal lumen, forming a barrier between the body and dietary and microbial contents in the lumen. Apart from absorbing nutrients from diet, these epithelial cells help mediate a stable, symbiotic relationship between microbes in the gut and the immune cells. During infection, they help co-ordinate the immune response to counter the infection. How dietary micronutrients, such as vitamin A, inform epithelial cell function during infection is poorly understood. Using a model where epithelial cells in the gut cannot respond to vitamin A signals, we find that epithelial vitamin A signaling promotes resistance to Salmonella infection. We show that, vitamin A increases the production of a key cytokine, interleukin 18, by epithelial cells. IL-18 promotes shedding of infected epithelial cells to reduce the pathogen invasion while also inducing the production of interferon gamma by immune cells to mediate pathogen clearance. Thus, epithelial cells dynamically respond to dietary vitamin A to regulate interleukin 18 production and potentiate resistance to infection.

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TLR2-mediated innate immune priming boosts lung anti-viral immunity

European Respiratory Journal ◽

10.1183/13993003.01584-2020 ◽

2020 ◽

pp. 2001584

Author(s):

Jason Girkin ◽

Su-Ling Loo ◽

Camille Esneau ◽

Steven Maltby ◽

Francesca Mercuri ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Innate Immunity ◽

Viral Load ◽

Epithelial Cell ◽

Epithelial Cells ◽

Immune Cell ◽

Innate Immune ◽

Immune Priming ◽

Tlr2 Activation

Research questionAssessment of whether TLR2 activation boosts the innate immune response to rhinovirus infection, as a treatment strategy for virus-induced respiratory diseases.MethodsWe employed treatment with a novel TLR2 agonist (INNA-X) prior to rhinovirus infection in mice, and INNA-X treatment in differentiated human bronchial epithelial cells derived from asthmatic-donors. We assessed viral load, immune cell recruitment, cytokines, type I and III IFN production, as well as the lung tissue and epithelial cell immune transcriptome.ResultsWe show in vivo, that a single INNA-X treatment induced innate immune priming characterised by low-level IFN-λ, Fas ligand, chemokine expression and airway lymphocyte recruitment. Treatment 7-days before infection significantly reduced lung viral load, increased IFN-β/λ expression and inhibited neutrophilic inflammation. Corticosteroid treatment enhanced the anti-inflammatory effects of INNA-X. Treatment 1-day before infection increased expression of 190 lung tissue immune genes. This tissue gene expression signature was absent with INNA-X treatment 7-days before infection, suggesting an alternate mechanism, potentially via establishment of immune cell-mediated mucosal innate immunity. In vitro, INNA-X treatment induced a priming response defined by upregulated IFN-λ, chemokine and anti-microbial gene expression that preceded an accelerated response to infection enriched for NF-κB-regulated genes and reduced viral loads, even in epithelial cells derived from asthmatic donors with intrinsic delayed anti-viral immune response.ConclusionAirway epithelial cell TLR2 activation induces prolonged innate immune priming, defined by early NF-κB activation, IFN-λ expression and lymphocyte recruitment. This response enhanced anti-viral innate immunity and reduced virus-induced airway inflammation.

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Reduced Frequencies and Heightened CD103 Expression among Virus-Induced CD8+T Cells in the Respiratory Tract Airways of Vitamin A-Deficient Mice

Clinical and Vaccine Immunology ◽

10.1128/cvi.05576-11 ◽

2012 ◽

Vol 19 (5) ◽

pp. 757-765 ◽

Cited By ~ 26

Author(s):

Rajeev Rudraraju ◽

Sherri L. Surman ◽

Bart G. Jones ◽

Robert Sealy ◽

David L. Woodland ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Epithelial Cells ◽

Vitamin A ◽

Respiratory Tract ◽

Vitamin A Deficiency ◽

Expression Patterns ◽

Lower Airway ◽

Upper Respiratory Tract

ABSTRACTVitamin A deficiency (VAD) has profound effects on immune responses in the gut, but its effect on other mucosal responses is less well understood. Sendai virus (SeV) is a candidate human parainfluenza virus type 1 (hPIV-1) vaccine and a candidate vaccine vector for other respiratory viruses. A single intranasal dose of SeV elicits a protective immune response against hPIV-1 within days after vaccination. To define the effect of VAD on acute responses toward SeV, we monitored both antibodies and CD8+T cells in mice. On day 10 following SeV infection, there was a trend toward lower antibody activities in the nasal washes of VAD mice than in those of controls, while bronchoalveolar lavage (BAL) fluid and serum antibodies were not reduced. In contrast, there was a dramatic reduction of immunodominant CD8+T cell frequencies in the lower respiratory tract (LRT) airways of VAD animals. These T cells also showed unusually high CD103 (the αE subunit of αEβ7) expression patterns. In both VAD and control mice, E-cadherin (the ligand for αEβ7) was better expressed among epithelial cells lining the upper respiratory tract (URT) than in LRT airways. The results support a working hypothesis that the high CD103 expression among T cell populations in VAD mice alters mechanisms of T cell cross talk with URT and LRT epithelial cells, thereby inhibiting T cell migration and egress into the lower airway. Our data emphasize that the consequences of VAD are not limited to gut-resident cells and characterize VAD influences on an immune response to a respiratory virus vaccine.

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Single-cell transcriptomics reveal the heterogeneity and dynamic of cancer stem-like cells during breast tumor progression

Cell Death and Disease ◽

10.1038/s41419-021-04261-y ◽

2021 ◽

Vol 12 (11) ◽

Author(s):

Guojuan Jiang ◽

Juchuanli Tu ◽

Lei Zhou ◽

Mengxue Dong ◽

Jue Fan ◽

...

Keyword(s):

Breast Cancer ◽

Epithelial Cell ◽

Epithelial Cells ◽

Tumor Progression ◽

Single Cell ◽

Immune Cells ◽

Breast Tumor ◽

Immune Cell ◽

Cell Lineage ◽

Breast Tumor Progression

AbstractBreast cancer stem-like cells (BCSCs) play vital roles in tumorigenesis and progression. However, the origin and dynamic changes of BCSCs are still to be elucidated. Using the breast cancer mouse model MMTV-PyMT, we constructed a single-cell atlas of 31,778 cells from four distinct stages of tumor progression (hyperplasia, adenoma/MIN, early carcinoma and late carcinoma), during which malignant transition occurs. We identified that the precise cell type of ERlow epithelial cell lineage gave rise to the tumors, and the differentiation of ERhigh epithelial cell lineage was blocked. Furthermore, we discovered a specific signature with a continuum of gene expression profiles along the tumor progression and significantly correlated with clinical outcomes, and we also found a stem-like cell cluster existed among ERlow epithelial cells. Further clustering on this stem-like cluster showed several sub-clusters indicating heterogeneity of stem-like epithelial cells. Moreover, we distinguished normal and cancer stem-like cells in this stem-like epithelial cell cluster and profiled the molecular portraits from normal stem-like cell to cancer stem-like cells during the malignant transition. Finally, we found the diverse immune cell infiltration displayed immunosuppressive characteristics along tumor progression. We also found the specific expression pattern of cytokines and their corresponding cytokine receptors in BCSCs and immune cells, suggesting the possible cross-talk between BCSCs and the immune cells. These data provide a useful resource for illuminating BCSC heterogeneity and the immune cell remodeling during breast tumor progression, and shed new light on transcriptomic dynamics during the progression at the single-cell level.

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Effects of vitamin A on growth and differentiation of human tracheobronchial epithelial cell cultures in serum-free medium

Journal of Cell Science ◽

10.1242/jcs.93.1.133 ◽

1989 ◽

Vol 93 (1) ◽

pp. 133-142

Author(s):

D.P. Chopra ◽

M.M. Klinger ◽

J.K. Sullivan

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

Vitamin A ◽

Cell Cultures ◽

Cell Multiplication ◽

Serum Free Medium ◽

Free Medium ◽

Plasma Membrane Vesicles ◽

Serum Free ◽

Epithelial Cell Cultures

Differentiating epithelial cell cultures from human tracheobronchial epithelium have been propagated in serum-free medium. The major objective of this study was to examine the trophic effects of vitamin A on cell multiplication and morphology of the tracheal cell cultures. The cellular responses were analyzed in terms of growth kinetics, morphological and ultrastructural alterations and secretion of glycoconjugates. Cell cultures in control medium exhibited characteristics of epithelial cells including microvilli on cell surfaces, desmosomes between cells, and numerous secretory vesicles in the cytoplasm. Vitamin A at 10(−6) M and 10(−7) M inhibited cell replication and enhanced the secretion of [3H]glucosamine-labeled glycoconjugates. Further, vitamin A increased the production of plasma membrane vesicles and acquisition by the cells of a highly secretory ultrastructure. This in vitro model of human epithelial cells will be important in the investigation of various aspects of growth and differentiation.

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Basic Immunology

Tutorial Topics in Infection for the Combined Infection Training Programme ◽

10.1093/oso/9780198801740.003.0012 ◽

2019 ◽

Author(s):

Jonathan Lambourne ◽

Ruaridh Buchanan

Keyword(s):

Immune Response ◽

Immune System ◽

Epithelial Cells ◽

Immune Cells ◽

Innate Immune System ◽

Adaptive Immune System ◽

Lymphoid Organs ◽

Innate Immune ◽

Adaptive Immune ◽

Pathogen Entry

There are four major components of the immune system. These include: 1. mechanical barriers to pathogen entry. 2. the innate immune system. 3. the adaptive immune system. 4. the lymphoid organs. Mechanical barriers include skin and mucous membranes and tight junctions between epithelial cells prevent pathogen entry. Breaches can be iatrogenic, for example, IV lines, surgical wounds, and mucositis, and are a large source of healthcare- associated infections. The innate immune system provides the first internal line of defence, as well as initiating and shaping the adaptive immune response. The innate system comprises a range of responses: phagocytosis by neutrophils and macrophages (guided in part by the adaptive immune system), the complement cascade, and the release of antimicrobial peptides by epithelial cells (e.g. defensins, cathelicidin). The adaptive immune system includes both humoral (antibody- mediated) and cell-mediated responses. It is capable of greater diversity and specificity than the innate immune system, and can develop memory to pathogens and provide increased protection on re-exposure. Immune cells are divided into myeloid cells (neutrophils, eosinophils, basophils, mast cells, and monocytes/macrophages) and lymphoid cells (B, T, and NK cells). These all originate in the bone marrow from pluripotent haematopoietic stem cells. The lymphoid organs include the spleen, the lymph nodes, and mucosal-associated lymphoid tissues—which respond to antigens in the blood, tissues, and epithelial surfaces respectively. The three main ‘professional’ phagocytes are macrophages, dendritic cells, and neutrophils. They are similar with respect to how they recognize pathogens, but differ in their principal location and effector functions. Phagocytes express an array of Pattern Recognition Receptors (PRRs) e.g. Toll-like receptors and lectins (proteins that bind carbohydrates). PRRs recognize Pathogen- Associated Molecular Patterns (PAMPs)— elements which are conserved across species, such as cell-surface glycoproteins and nucleic acid sequences. Though limited in number, PRRs have evolved to recognize a huge array of pathogens. Binding of PRRs to PAMPs enhances phagocytosis. Macrophages are tissue-resident phagocytes, initiating and co-ordinating the local immune response. The cytokines and chemokines they produce cause vasodilation and alter the expression of endothelial cell adhesion factors, recruiting circulating immune cells.

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Role of Platelets in Detection and Regulation of Infection

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314645 ◽

2020 ◽

Author(s):

Irina Portier ◽

Robert A. Campbell

Keyword(s):

Immune Response ◽

Infectious Diseases ◽

Platelet Activation ◽

Immune Cells ◽

Antimicrobial Proteins ◽

Pathogen Clearance

Platelets are classically known as essential mediators of hemostasis and thrombosis. However, in recent years, platelets have gained recognition for their inflammatory functions, which modulate the immune response during infectious diseases. Platelets contain various immunoreceptors that enable them to act as sentinels to recognize intravascular pathogens. Upon activation, platelets directly limit pathogen growth through the release of AMPs (antimicrobial proteins) and ensure pathogen clearance through activation of immune cells. However, aberrant platelet activation can lead to inflammation and thrombotic events.

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The Effect of Varying Levels of Dietary Vitamin A on Immune Response in the Chick

Poultry Science ◽

10.3382/ps.0730843 ◽

1994 ◽

Vol 73 (6) ◽

pp. 843-847 ◽

Cited By ~ 48

Author(s):

D. SKLAN ◽

D. MELAMED ◽

A. FRIEDMAN

Keyword(s):

Immune Response ◽

Vitamin A ◽

Dietary Vitamin

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Measles Virus Infects both Polarized Epithelial and Immune Cells by Using Distinctive Receptor-Binding Sites on Its Hemagglutinin

Journal of Virology ◽

10.1128/jvi.02691-07 ◽

2008 ◽

Vol 82 (9) ◽

pp. 4630-4637 ◽

Cited By ~ 79

Author(s):

Maino Tahara ◽

Makoto Takeda ◽

Yuta Shirogane ◽

Takao Hashiguchi ◽

Shinji Ohno ◽

...

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

Cell Lines ◽

Receptor Binding ◽

Immune Cells ◽

Binding Sites ◽

Measles Virus ◽

Apical Surface ◽

Attachment Protein ◽

Epithelial Cell Lines

ABSTRACT Measles is one of the most contagious human infectious diseases and remains a major cause of childhood morbidity and mortality worldwide. The signaling lymphocyte activation molecule (SLAM), also called CD150, is a cellular receptor for measles virus (MV), presumably accounting for its tropism for immune cells and its immunosuppressive properties. On the other hand, pathological studies have shown that MV also infects epithelial cells at a later stage of infection, although its mechanism has so far been unknown. In this study, we show that wild-type MV can infect and produce syncytia in human polarized epithelial cell lines independently of SLAM and CD46 (a receptor for the vaccine strains of MV). Progeny viral particles are released exclusively from the apical surface of these polarized epithelial cell lines. We have also identified amino acid residues on the MV attachment protein that are likely to interact with a putative receptor on epithelial cells. All of these residues have aromatic side chains and may form a receptor-binding pocket located in a different position from the putative SLAM- and CD46-binding sites on the MV attachment protein. Thus, our results indicate that MV has an intrinsic ability to infect both polarized epithelial and immune cells by using distinctive receptor-binding sites on the attachment protein corresponding to each of their respective receptors. The ability of MV to infect polarized epithelial cells and its exclusive release from the apical surface may facilitate its efficient transmission via aerosol droplets, resulting in its highly contagious nature.

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