Impairment of the intestinal barrier is evident in untreated but absent in suppressively treated HIV-infected patients

Epple, Hans-Joerg; Schneider, Thomas; Troeger, Hanno; Kunkel, Désirée; Allers, Kristina; Moos, Verena; Amasheh, Maren; Loddenkemper, Christoph; Fromm, Michael; Zeitz, Martin; Schulzke, Joerg D.

doi:10.1136/gut.2008.150425

Cited by 144 publications

(152 citation statements)

References 65 publications

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“…Microbial translocation across the intestinal and possibly genital mucosa is considered to be the most likely reason for increased immune activation and inflammation during HIV-1 infection (9, 59). Activated T cells in the intestinal mucosa have been cited as the source of proinflammatory cytokines that breach the mucosal barrier in the gut (9,60,61). Our results show that HIV-1 gp120 directly induces an inflammatory response in GECs and provides an alternative explanation of a direct mechanism of barrier disruption and microbial translocation early after exposure to HIV (7).…”

Section: Discussionmentioning

confidence: 69%

HIV-1 gp120 Induces TLR2- and TLR4-Mediated Innate Immune Activation in Human Female Genital Epithelium

Nazli

Kafka

Ferreira

et al. 2013

The Journal of Immunology

117

115

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Although women constitute half of all HIV-1–infected people worldwide (UNAIDS World AIDS Day Report, 2011), the earliest events in the female reproductive tract (FRT) during heterosexual HIV-1 transmission are poorly understood. Recently, we demonstrated that HIV-1 could directly impair the mucosal epithelial barrier in the FRT. This suggested that the HIV-1 envelope glycoprotein gp120 was being recognized by a membrane receptor on genital epithelial cells, leading to innate immune activation. In this study, we report that pattern-recognition receptors TLR2 and -4 bind to HIV-1 gp120 and trigger proinflammatory cytokine production via activation of NF-κB. The gp120–TLR interaction also required the presence of heparan sulfate (HS). Bead-binding assays showed that gp120 can bind to HS, TLR2, and TLR4, and studies in transfected HEK293 cells demonstrated that HS and TLR2 and -4 were necessary to mediate downstream signaling. Exposure to seminal plasma from HIV-1–infected and uninfected men with gp120 added to it induced a significant proinflammatory cytokine response from genital epithelial cells and disruption of tight junctions, indicating a role for gp120 in mucosal barrier disruption during HIV-1 heterosexual transmission. These studies provide, for the first time to our knowledge, a possible mechanism by which HIV-1 gp120 could directly initiate innate immune activation in the FRT during heterosexual transmission.

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Section: Discussionmentioning

confidence: 69%

HIV-1 gp120 Induces TLR2- and TLR4-Mediated Innate Immune Activation in Human Female Genital Epithelium

Nazli

Kafka

Ferreira

et al. 2013

The Journal of Immunology

117

115

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“…To ensure the purity of microdissected ectocervical epithelia, mRNA level of cytokeratin 13 was measured, which is mainly expressed in epithelial cells and less expressed in submucosa. 29,30 CT values in real-time PCR measurement of cytokeratin was 10-fold less in epithelial regions compared with subepithelial region, which indicated that the epithelial cells were enriched at least by 1,000-fold in the microdissected epithelia compared with subepithelial regions (data not shown). Therefore, the epithelial cells seem to be the main source of observed chemokine expression in our study.…”

Section: Cytokine Gene Expression In Epithelial Cells Following Hiv Ementioning

confidence: 99%

“…ectocervical tissues. 29 In addition, exposure to HIV has shown to induce production of TNF-a, IL-6, IL-8, MCP-1 in T84 intestinal epithelial cell lines and TNF-a, IL-6, MCP-1, IL-10, IL1b in primary endometrial epithelial cells. 10 We examined chemokine and cytokine levels in the epithelial cells of the tissues exposed to HIV since it may facilitate the establishment of local HIV infection after HIV crosses the epithelial barrier.…”

Section: Cytokine Gene Expression In Epithelial Cells Following Hiv Ementioning

confidence: 99%

HIV Exposure to the Epithelia in Ectocervical and Colon Tissues Induces Inflammatory Cytokines Without Tight Junction Disruption

Sankapal

Gupta

Ratner

et al. 2016

AIDS Research and Human Retroviruses

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Epithelial cells in human cervical and colonic mucosa do not express HIV receptor. However, HIV transmission occurs across the unbreached epithelia by an unknown mechanism. In this study, the effect of HIV exposure on tight junction (TJ) and cytokine production in ectocervical and colon mucosal epithelia in tissue biopsies was investigated in an organ culture model. After HIV exposure, the distribution patterns and quantities of epithelial TJ and adherens proteins were evaluated by immunofluorescence staining followed by confocal microscopy. Cytokine mRNA in the mucosal epithelia was also evaluated by real-time reverse transcription-polymerase chain reaction (RT-PCR). HIV transmission was evaluated by measuring p24 production in culture supernatant. Our results showed there were no significant changes in the distribution and quantities of epithelial TJ/adherens junction (AJ) proteins after exposure to HIV. However, higher levels of CXCL10 and CXCL11 mRNA expression were detected in HIV-exposed ectocervical epithelia. In case of colon mucosa, higher levels of CXCL10 and IL-6 mRNA expression were detected in HIV-exposed colon mucosa. Our study suggests that HIV induces cytokine production in epithelial cells, which may facilitate HIV transmission by recruiting HIV target cells in the submucosal region. Furthermore, HIV transmission may not occur through epithelial TJ/AJ disruption.

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“…7,37 However, Y. enterocolitica did not induce apoptosis but epithelial necrosis, indicated by an increase in LDH release. Y. enterocolitica-derived cytotoxicity has already been investigated in different tissues.…”

Section: Necrosis and Apoptosis Induction By Y Enterocoliticamentioning

confidence: 99%

“…Infection of mice with Y. enterocolitica O8 resulted in a decrease of epithelial resistance as measured by impedance spectroscopy, but showed unaltered Na þ -glucose co-transport or electrogenic Cl À secretion. 6 During the last two decades several enteric pathogens were described to disturb the intestinal barrier in different ways, including induction of local cell damage, eg by apoptosis, necrosis or focal leaks, [7][8][9] stimulation of fluid and electrolyte secretion, activation of inflammatory cascades, as well as disruption of the tight junction (TJ) of epithelial cells. 10 TJs are known as key determinants of barrier function.…”

mentioning

confidence: 99%

Yersinia enterocolitica induces epithelial barrier dysfunction through regional tight junction changes in colonic HT-29/B6 cell monolayers

Hering

Richter

Krug

et al. 2011

Laboratory Investigation

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Yersinia enterocolitica is a common cause of acute gastroenteritis. This study aimed to clarify the mechanisms leading to barrier dysfunction and diarrhea. Exposure of human colonic HT-29/B6 cells to Y. enterocolitica resulted in a decrease in transepithelial resistance from 404 ± 23 to 163 ± 21 O cm 2 (Po0.001) in parallel with an increase in mannitol (182 Da) and fluorescein (332 Da) permeability, whereas short circuit current did not change. This effect was time dependent, required the presence of living bacteria, could not be triggered by bacterial supernatants and was not due to Yersinia outer proteins. Concomitantly, Y. enterocolitica induced necrosis as indicated by an increase in lactate dehydrogenase-release, whereas epithelial apoptosis was not upregulated. Local changes in conductivity were detected by conductance scanning, indicating 'leaky regions' within the epithelium that were visualized by biotinylation and confocal microscopy. In these regions, claudin-3 and -4 and, especially claudin-8, were redistributed off the tight junction (TJ) into the cytoplasm. In addition, the expression of claudin-2, -3, -8, -10 and ZO-1 was diminished as quantified by immunoblotting. Moreover, we found claudin-8 to be regulated by the c-Jun N-terminal kinase, the inhibition of which attenuated the Y. enterocolitica-induced decrease in transepithelial resistance and restored claudin-8 protein level. In conclusion, barrier dysfunction in Y. enterocolitica infection is due to circumscribed epithelial TJ protein changes and necrotic cell loss, as a consequence of which leak flux diarrhea and antigen-uptake provoking extraintestinal arthritis may be triggered.

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Impairment of the intestinal barrier is evident in untreated but absent in suppressively treated HIV-infected patients

Cited by 144 publications

References 65 publications

HIV-1 gp120 Induces TLR2- and TLR4-Mediated Innate Immune Activation in Human Female Genital Epithelium

HIV-1 gp120 Induces TLR2- and TLR4-Mediated Innate Immune Activation in Human Female Genital Epithelium

HIV Exposure to the Epithelia in Ectocervical and Colon Tissues Induces Inflammatory Cytokines Without Tight Junction Disruption

Yersinia enterocolitica induces epithelial barrier dysfunction through regional tight junction changes in colonic HT-29/B6 cell monolayers

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