scholarly journals Type III interferon signaling restricts enterovirus 71 infection of goblet cells

2019 ◽  
Vol 5 (3) ◽  
pp. eaau4255 ◽  
Author(s):  
Charles Good ◽  
Alexandra I. Wells ◽  
Carolyn B. Coyne
Keyword(s):  
Goblet Cell ◽  
Intestinal Epithelium ◽  
Cell Function ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Goblet Cells ◽  
Neurological Complications ◽  
Ev71 Infection ◽  
Apical Surface ◽  
Type Iii

Recent worldwide outbreaks of enterovirus 71 (EV71) have caused major epidemics of hand, foot, and mouth disease with severe neurological complications, including acute flaccid paralysis. EV71 is transmitted by the enteral route, but little is known about the mechanisms it uses to cross the human gastrointestinal tract. Using primary human intestinal epithelial monolayers, we show that EV71 infects the epithelium from the apical surface, where it preferentially infects goblet cells. We found that EV71 infection did not alter epithelial barrier function but did reduce the expression of goblet cell–derived mucins, suggesting that it alters goblet cell function. We also show that the intestinal epithelium responds to EV71 infection through the selective induction of type III interferons (IFNs), which restrict EV71 replication. Collectively, these findings define the early events associated with EV71 infections of the human intestinal epithelium and show that host IFN signaling controls replication in an IFN-specific manner.

scholarly journals Type III interferon signaling restricts Enterovirus 71 infection of goblet cells

2018 ◽  
Author(s):  
Charles Good ◽  
Alexandra I. Wells ◽  
Carolyn B. Coyne
Keyword(s):  
Goblet Cell ◽  
Intestinal Epithelium ◽  
Cell Function ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Goblet Cells ◽  
Neurological Complications ◽  
Ev71 Infection ◽  
Apical Surface ◽  
Type Iii

AbstractRecent worldwide outbreaks of enterovirus (EV71) have caused major epidemics of hand, foot, and mouth disease (HFMD) with severe neurological complications, including acute flaccid paralysis. EV71 is transmitted by the enteral route, but very little is known about the mechanisms it utilizes to cross the human gastrointestinal (GI) tract. Using primary human intestinal epithelial monolayers, we show that EV71 infects the GI epithelium from the apical surface, where it preferentially infects goblet cells. Unlike echovirus 11 (E11), an enterovirus that infects enterocytes, EV71 infection did not alter epithelial barrier function, but did reduce the expression of a goblet cell-derived mucin, suggesting it alters goblet cell function. We also show that the intestinal epithelium responds to EV71 infection through the selective induction of type III IFNs, which potently restrict EV71 replication. Collectively, these findings define the early events associated with EV71 infections of the human intestinal epithelium and show that host IFN signaling controls replication in an IFN-specific manner.

scholarly journals Antiviral Efficacy of Flavonoids against Enterovirus 71 Infection in Vitro and in Newborn Mice

Viruses ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 625 ◽  
Author(s):  
Wenwen Dai ◽  
Jinpeng Bi ◽  
Fang Li ◽  
Shuai Wang ◽  
Xinyu Huang ◽  
...  
Keyword(s):  
Protective Efficacy ◽  
Lethal Dose ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Neurological Complications ◽  
Ev71 Infection ◽  
Newborn Mice ◽  
Reported Data

Enterovirus 71 (EV71) infection is known to cause hand, foot, and mouth disease (HFMD), which is associated with neurological complications; however, there is currently no effective treatment for this infection. Flavonoids are a large group of naturally occurring compounds with multiple bioactivities, and the inhibitory effects of several flavonoids against EV71 have been studied in cell cultures; however, to date, there are no reported data on their effects in animal models. In this study, we confirmed the in vitro activities of eight flavonoids against EV71 infection, based on the inhibition of cytopathic effects. Moreover, these flavonoids were found to reduce viral genomic RNA replication and protein synthesis. We further demonstrated the protective efficacy of these flavonoids in newborn mice challenged with a lethal dose of EV71. Apigenin, luteolin, kaempferol, formononetin, and penduletin conferred survival protection of 88.89%, 91.67%, 88.89%, 75%, and 66.67%, respectively, from the lethal EV71 challenge. In addition, isorhamnetin provided the highest mice survival protection of 100% at a dose of 10 mg/kg. This study, to the best of our knowledge, is the first to evaluate the in vivo anti-EV7l activities of multiple flavonoids, and we accordingly identified flavonoids as potential leading compounds for anti-EV71 drug development.

scholarly journals Indoles from the commensal microbiota act via the AHR and IL-10 to tune the cellular composition of the colonic epithelium during aging

2020 ◽  
Vol 117 (35) ◽  
pp. 21519-21526 ◽  
Author(s):  
Domonica N. Powell ◽  
Alyson Swimm ◽  
Robert Sonowal ◽  
Alexis Bretin ◽  
Andrew T. Gewirtz ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Goblet Cell ◽  
Intestinal Epithelium ◽  
Dynamic Structure ◽  
Goblet Cells ◽  
Type I ◽  
Cellular Composition ◽  
Type I Ifn ◽  
Commensal Microbiota ◽  
Goblet Cell Differentiation

The intestinal epithelium is a highly dynamic structure that rejuvenates in response to acute stressors and can undergo alterations in cellular composition as animals age. The microbiota, acting via secreted factors related to indole, appear to regulate the sensitivity of the epithelium to stressors and promote epithelial repair via IL-22 and type I IFN signaling. As animals age, the cellular composition of the intestinal epithelium changes, resulting in a decreased proportion of goblet cells in the colon. We show that colonization of young or geriatric mice with bacteria that secrete indoles and various derivatives or administration of the indole derivative indole-3 aldehyde increases proliferation of epithelial cells and promotes goblet cell differentiation, reversing an effect of aging. To induce goblet cell differentiation, indole acts via the xenobiotic aryl hydrocarbon receptor to increase expression of the cytokine IL-10. However, the effects of indoles on goblet cells do not depend on type I IFN or on IL-22 signaling, pathways responsible for protection against acute stressors. Thus, indoles derived from the commensal microbiota regulate intestinal homeostasis, especially during aging, via mechanisms distinct from those used during responses to acute stressors. Indoles may have utility as an intervention to limit the decline of barrier integrity and the resulting systemic inflammation that occurs with aging.

scholarly journals Modulation of Conjunctival Goblet Cell Function by Inflammatory Cytokines

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
L. Contreras-Ruiz ◽  
A. Ghosh-Mitra ◽  
M. A. Shatos ◽  
D. A. Dartt ◽  
S. Masli
Keyword(s):  
Sjögren’S Syndrome ◽  
Inflammatory Cytokines ◽  
Goblet Cell ◽  
Ocular Surface ◽  
Cell Function ◽  
Sjögren's Syndrome ◽  
Goblet Cells ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Sjögren‘S Syndrome

Ocular surface inflammation associated with Sjögren’s syndrome is characterized by a loss of secretory function and alteration in numbers of mucin secreting goblet cells. Such changes are a prominent feature of ocular surface inflammatory diseases and are attributed to inflammation; however, the exact effect of the inflammatory cytokines on conjunctival goblet cell function remains largely unknown. In this study, we developed a primary culture of mouse goblet cells from conjunctival tissue and evaluated the effects on their function by inflammatory cytokines detected in the conjunctiva of mouse model of Sjögren’s syndrome (Thrombospondin-1 deficient mice). We found that apoptosis of goblet cells was primarily induced by TNF-αand IFN-γ. These two cytokines also inhibited mucin secretion by goblet cells in response to cholinergic stimulation, whereas IL-6 enhanced such secretion. No changes in secretory response were detected in the presence of IL-13 or IL-17. Goblet cells proliferated to varying degrees in response to all the tested cytokines with the greatest response to IL-13 followed by IL-6. Our results therefore reveal that inflammatory cytokines expressed in the conjunctiva during an ocular surface disease directly disrupt conjunctival goblet cell functions, compromising the protective function of tears, thereby contributing to ocular surface damage.

scholarly journals Increased Frequency of Circulating Follicular Helper T Cells in Children with Hand, Foot, and Mouth Disease Caused by Enterovirus 71 Infection

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Jianping Wu ◽  
David Cui ◽  
Xianzhi Yang ◽  
Jianzhou Lou ◽  
Jie Lin ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Serum Levels ◽  
Mouth Disease ◽  
Ev71 Infection ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Foot And Mouth

Enterovirus 71 (EV71) is a major causative agent of hand, foot, and mouth disease (HFMD) in children. The role of T follicular helper (TFH) cells in EV71-infected children remains unclear in regulating humoral immunity. The frequency of circulating ICOShigh/PD-1highCXCR5+CD4+TFH cells in the children with mild and severe EV71 infection and healthy controls (HC) was detected by flow cytometry, respectively. IL-21 and IL-6 mRNA expression and their serum levels, Bcl-6 mRNA expression, and specific neutralizing antibodies against EV71 (NAb-EV71) were measured. In the acute stage of patients with EV71 infection, increased frequencies of circulating TFH cells with ICOShighand PD-1highexpression in the mild and severe patients were observed, and the positive correlations among the frequencies of circulating TFH cells and the serum levels of IL-21, IL-6, and NAb-EV71 titres were detected, respectively. Moreover, the expressions of IL-6 and IL-21 mRNA in PBMCs from patients were also significantly higher than those of HC. However, further analysis did not reveal any significant differences between mild and severe patients. These data indicate a role of TFH cells and associated cytokines in modulating the humoral response during the pathogenesis of EV71 infection.

scholarly journals Study the current scenario of hand foot mouth disease an Indian prospective

2020 ◽  
Vol 7 (7) ◽  
pp. 1558
Author(s):  
Ravi Sahota ◽  
Navpreet Kaur ◽  
Gurpal Singh ◽  
Nisha Upadhyay
Keyword(s):  
Communicable Disease ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Neurological Complications ◽  
Mouth Disease ◽  
Human Enterovirus ◽  
Cross Sectional ◽  
Timely Initiation ◽  
Human Enterovirus 71 ◽  
Hand Foot Mouth Disease

Background: The hand-foot-mouth disease (HFMD) is an acute communicable disease, mostly affecting children under 5 years of age and caused by human enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16). The usual incubation period is 3 to 7 days. Early symptoms are likely to be fever often followed by a sore throat followed by loss of appetite and general malaise. Aim and objectives was to study the trend of hand foot and mouth disease in a private hospital in Uttarakhand over 5 successive years.Methods: This cross-sectional study was carried among 297 cases of HFMD newborn screened at pediatrics department of Sahota Super-specialty hospital, Kashipur, Uttarakhand during year 2015 to 2019 after ethical clearance of institutional ethical committee. Diagnosis is coded with ICD-10. SPSS version 20 was used to calculate frequencies and percentiles.Results: Almost 29 cases of HMFD were picked in 2015, 32 cases in 2016, 43 cases in 2017, 81 cases in 2018, 112 in 2019. Fever observed in 86% cases. Neurological complications were observed in 9 (3%) cases, pneumonitis in 14 (4.7%) cases, cardiomyopathy observed in 3 (<1%) case. One death was reported.Conclusions: It is vital to screen patients with HFMD for these abnormal clinical presentations, allowing timely initiation of appropriate interventions to reduce the mortality. Increased awareness about vaccination in a developing nation like India and vaccination program at the grass root levels have eradicated certain lethal diseases.

Cytoskeleton of intestinal goblet cells: role of actin filaments in baseline secretion

1990 ◽  
Vol 259 (6) ◽  
pp. G991-G997 ◽  
Author(s):  
M. G. Oliver ◽  
R. D. Specian
Keyword(s):  
Plasma Membrane ◽  
Goblet Cell ◽  
Actin Filaments ◽  
Cellular Response ◽  
Apical Cell ◽  
Goblet Cells ◽  
Apical Plasma Membrane ◽  
Apical Surface ◽  
Cytochemical Localization

Although microtubules appear necessary to maintain mucin granule transport in intestinal goblet cells, the role of microfilaments in mucus secretion is unknown. To determine the functional significance of microfilaments in goblet cell secretion, fluorescent cytochemistry of microfilaments and autoradiographic studies on granule movement were performed on rabbit intestinal goblet cells, with and without the actin depolymerizing agents, cytochalasin D (cyto D), and dihydro-cytochalasin B (dihydro B). In normal goblet cells, cytochemical localization of F-actin with NBD-phallacidin demonstrated their restriction to the apical surface of the goblet cell. Visualization of the goblet cell apical surface by electron microscopy revealed the presence of a thin layer of cytoplasm overlying the granule mass. Treatment with cyto D and dihydro B eliminated NBD-phallacidin staining of the apical cell surface. Quantitative analysis of baseline granule translocation demonstrated that treatment with cyto D and dihydro B resulted in dramatic acceleration of granule movement through goblet cells. This cellular response results from an increase in baseline secretion and facilitation of secretion of newly synthesized mucins, not stimulation of an accelerated secretory event. These data imply that actin filaments fulfill a barrier function in baseline secretion by hindering granule access to the plasma membrane; once the granule contacts the plasma membrane, exocytosis occurs. Secretion is balanced by the translocation of subjacent granules. In contrast, an accelerated secretory event is not triggered by plasma membrane access alone; this event requires a regulatory signal. We hypothesize that, unlike accelerated secretion, baseline secretion is constitutive, with exocytosis limited solely by the physical constraint of secretory granule access to the apical plasma membrane.

scholarly journals Clinical Spectrum of an Outbreak of Enterovirus 71 (EV71) Infection in Southern Taiwan: Emphasis on the Neurological Complications

1999 ◽  
Vol 45 (4, Part 2 of 2) ◽  
pp. 167A-167A
Author(s):  
Ching-C Liu ◽  
Shih-M Wang ◽  
Hui-W Tseng ◽  
Jen-R Wang ◽  
Chao-C Huang ◽  
...  
Keyword(s):  
Enterovirus 71 ◽  
Neurological Complications ◽  
Clinical Spectrum ◽  
Ev71 Infection ◽  
Southern Taiwan

scholarly journals Bifidobacterium dentiumFortifies the Intestinal Mucus Layer via Autophagy and Calcium Signaling Pathways

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Melinda A. Engevik ◽  
Berkley Luk ◽  
Alexandra L. Chang-Graham ◽  
Anne Hall ◽  
Beatrice Herrmann ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Signaling Pathways ◽  
Goblet Cell ◽  
Cell Function ◽  
Goblet Cells ◽  
Mucus Layer ◽  
Content Type ◽  
Intestinal Mucus ◽  
Intestinal Mucus Layer

ABSTRACTMuch remains unknown about how the intestinal microbiome interfaces with the protective intestinal mucus layer.Bifidobacteriumspecies colonize the intestinal mucus layer and can modulate mucus production by goblet cells. However, selectBifidobacteriumstrains can also degrade protective glycans on mucin proteins. We hypothesized that the human-derived speciesBifidobacterium dentiumwould increase intestinal mucus synthesis and expulsion, without extensive degradation of mucin glycans.In silicodata revealed thatB. dentiumlacked the enzymes necessary to extensively degrade mucin glycans. This finding was confirmed by demonstrating thatB. dentiumcould not use naive mucin glycans as primary carbon sourcesin vitro. To examineB. dentiummucus modulationin vivo, Swiss Webster germfree mice were monoassociated with live or heat-killedB. dentium. LiveB. dentium-monoassociated mice exhibited increased colonic expression of goblet cell markersKrüppel-like factor 4(Klf4),Trefoil factor 3(Tff3),Relm-β,Muc2, and several glycosyltransferases compared to both heat-killedB. dentiumand germfree counterparts. Likewise, liveB. dentium-monoassociated colon had increased acidic mucin-filled goblet cells, as denoted by Periodic Acid-Schiff-Alcian Blue (PAS-AB) staining and MUC2 immunostaining.In vitro,B. dentium-secreted products, including acetate, were able to increase MUC2 levels in T84 cells. We also identified thatB. dentium-secreted products, such as γ-aminobutyric acid (GABA), stimulated autophagy-mediated calcium signaling and MUC2 release. This work illustrates thatB. dentiumis capable of enhancing the intestinal mucus layer and goblet cell function via upregulation of gene expression and autophagy signaling pathways, with a net increase in mucin production.IMPORTANCEMicrobe-host interactions in the intestine occur along the mucus-covered epithelium. In the gastrointestinal tract, mucus is composed of glycan-covered proteins, or mucins, which are secreted by goblet cells to form a protective gel-like structure above the epithelium. Low levels of mucin or alterations in mucin glycans are associated with inflammation and colitis in mice and humans. Although current literature links microbes to the modulation of goblet cells and mucins, the molecular pathways involved are not yet fully understood. Using a combination of gnotobiotic mice and mucus-secreting cell lines, we have identified a human-derived microbe,Bifidobacterium dentium, which adheres to intestinal mucus and secretes metabolites that upregulate the major mucin MUC2 and modulate goblet cell function. Unlike otherBifidobacteriumspecies,B. dentiumdoes not extensively degrade mucin glycans and cannot grow on mucin alone. This work points to the potential of usingB. dentiumand similar mucin-friendly microbes as therapeutic agents for intestinal disorders with disruptions in the mucus barrier.

scholarly journals Investigation on Factors Associated with Severe Hand, Foot and Mouth Disease

2014 ◽  
Vol 3 (2) ◽  
pp. 82-91
Author(s):  
Gui-lin Yang ◽  
Ying-xia Liu ◽  
Mu-tong Fang ◽  
Yan-xia He ◽  
John Nunnari ◽  
...  
Keyword(s):  
Detection Rate ◽  
Multivariate Logistic Regression Analysis ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Ev71 Infection ◽  
Pathological Examination ◽  
Nasopharyngeal Swab ◽  
Neurogenic Pulmonary Edema ◽  
Factors Associated ◽  
Logistic Analysis

Abstract Objective To analyze the clinical and laboratory features of patients with mild and severe HFMD to identify early predictive or diagnostic markers for severe cases. Methods Samples of feces, nasopharyngeal-swab specimens, peripheral blood, serum and cerebral spinal fluid were collected. Postmortem pathological examination was conducted on 2 dead patients with complication due to neurogenic pulmonary edema. Reverse transcription-polymerase chain-reaction (RT-PCR), culture and isolation of enterovirus 71 (EV71) were performed to detect EV71 infection. Both univariate and multivariate logistic analysis were used to identify factors associated with severe cases. Results EV71 was mainly responsible for HFMD. In this study, 5 isolated EV71 strains belonged to C4 gene subtype. Compared with mild patients, EV71-RNA detection rate was higher and CoxA16 detection rate was lower among severe patients (P < 0.01). Inflammatory cell infiltration in the lung, cardiac and liver tissues were mild by postmortem pathological examination. It was found that body temperature, vomitting, limb tremor, neutrophil, blood glucose and EV71 infection were significantly related to the severe cases by univariate logistic analysis. However, after multivariate logistic regression analysis, only vomiting (OR 16.1, CI 2.3-110.5, P < 0.01) and limb tremor (OR 117.6, CI 13.8-1004.5, P < 0.01) were significantly and independently correlated with the severe cases. Conclusions EV71 was mainly responsible for HFMD, particularly for severe cases. Vomiting and limb tremor were predictive markers for severe cases.

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