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Tight Junctions - The Link Between HIV-Associated Intestinal Barrier Dysfunction and Loss of Immune Homeostasis

Chung, Charlotte Yuk-Yan
http://rave.ohiolink.edu/etdc/view?acc_num=case1417822947

Abstract Details

2015, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
Systemic inflammation in the HIV-infected patient plays a crucial role in the pathogenesis of CD4+ T cell depletion, and is recently postulated to also drive the development of non-AIDS related morbidities, including cardiovascular, liver, and kidney diseases, in patients on suppressive antiretroviral therapy (ART) who are largely healthy otherwise. Systemic inflammation results from elevated circulating levels of microbial products, which, in untreated HIV infection and other disease processes, was shown to originate from the gut, secondary to increased intestinal permeability. Indeed, HIV drastically disrupts the intestinal mucosal immune and structural barrier. Recent efforts have characterized the mechanisms causing intestinal epithelial dysfunction in untreated HIV infection. Persistently increased intestinal permeability in ART-treated HIV-infected patients points to a similar origin for circulating microbial products in this population; however, a mechanism for the intestinal epithelial dysfunction involved is lacking. We analyzed intestinal biopsy tissues for changes in the epithelium on the cellular and molecular levels, and demonstrated the first direct molecular evidence of intestinal epithelial dysregulation in the suppressive ART-treated HIV-infected population. The colonic epithelium was grossly intact, but progressive transcriptional downregulation of TJ components was observed along the proximal-to-distal colon. Our results highlight the importance of TJ dysregulation in HIV-associated intestinal epithelial barrier breakdown. How HIV-mediated intestinal mucosal dysfunction contributes to epithelial TJ dysregulation is currently unknown. To investigate the modulatory effects of immune cells on intestinal epithelial permeability, I developed an in vitro intestinal epithelium – immune cell co-culture system. Caco-2 cell, a human colorectal adenocarcinoma cell line, monolayer showed biphasic permeability perturbations, evaluated using transepithelial resistance and paracellular inulin flux, when co-cultured with activated T cells on the basolateral side of the monolayer. Early strengthening of the barrier was accompanied by a transient increase in claudin-2 and a sustained increase in claudin-4 protein levels. Prolonged T cell contact resulted in weakening of the epithelial barrier. Our results reveal that activated T cells both protect and disrupt the intestinal epithelium via modulating intestinal TJ protein levels. We propose that HIV-associated loss of intestinal mucosal immune homeostasis impacts activated T cell-induced intestinal epithelial TJ regulation, thereby promoting intestinal barrier dysfunction.
Alan Levine, PhD (Advisor)
Derek Taylor, PhD (Committee Chair)
Noa Noy, PhD (Committee Member)
Alex Huang, MD PhD (Committee Member)
Donald Anthony, MD PhD (Committee Member)
237 p.
Cellular Biology; Immunology; Pharmacology; Virology
tight junction; HIV; paracellular permeability; systemic inflammation; immune activation; intestinal epithelial cells; microbial translocation; ART-treated; intestinal barrier dysfunction; transepithelial resistance; IEC - T cell interaction

Recommended Citations

Citations

  • Chung, C. Y.-Y. (2015). Tight Junctions - The Link Between HIV-Associated Intestinal Barrier Dysfunction and Loss of Immune Homeostasis [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1417822947

    APA Style (7th edition)

  • Chung, Charlotte. Tight Junctions - The Link Between HIV-Associated Intestinal Barrier Dysfunction and Loss of Immune Homeostasis. 2015. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1417822947.

    MLA Style (8th edition)

  • Chung, Charlotte. "Tight Junctions - The Link Between HIV-Associated Intestinal Barrier Dysfunction and Loss of Immune Homeostasis." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1417822947

    Chicago Manual of Style (17th edition)

case1417822947
239
© 2015, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.