Jejunal Brush Border Microvillous Alterations inGiardia muris-Infected Mice: Role of T Lymphocytes and Interleukin-6

Abstract

Intestinal colonization with the protozoan Giardia causes diffuse brush border microvillous alterations and disaccharidase deficiencies, which in turn are responsible for intestinal malabsorption and maldigestion. The role of T cells and/or cytokines in the pathogenesis of Giardia-induced microvillous injury remains unclear. The aim of this study was to assess the role of T cells and interleukin-6 (IL-6) in the brush border pathophysiology of acute murine giardiasis in vivo. Athymic nude (nu ؊ /nu ؊ ) CD-1 mice and isogenic immunocompetent (nu ؉ /nu ؉ ) CD-1 mice (4 weeks old) received an axenic Giardia muris trophozoite inoculum or vehicle (control) via orogastric gavage. Weight gain and food intake were assessed daily. On day 6, segments of jejunum were assessed for parasite load, brush border ultrastructure, IL-6 content, maltase and sucrase activities, villuscrypt architecture, and intraepithelial lymphocyte (IEL) infiltration. Despite similar parasitic loads on day 6, infected immunocompetent animals, but not infected nude mice, showed a diffuse loss of brush border microvillous surface area, which was correlated with a significant reduction in maltase and sucrase activities and a decrease in jejunal IL-6 concentration. In both athymic control and infected mice, jejunal brush border surface area and disaccharidases were high, but levels of tissue IL-6 were low and comparable to the concentration measured in immunocompetent infected animals. In both immunocompetent and nude mice, infection caused a small but significant increase in the numbers of IELs. These findings suggest that the enterocyte brush border injury and malfunction seen in giardiasis is, at least in part, mediated by thymus-derived T lymphocytes and that suppressed jejunal IL-6 does not necessarily accompany microvillous shortening.

Immunopathology of giardiasis: the role of lymphocytes in intestinal epithelial injury and malfunction

“…Intriguingly, this increase was reported in immunocompetent as well as in athymic animals infected with Giardia (Scott et al 2000), suggesting a role for extrathymic differentiation in this response. T-lymphocytes express the αβ T cell receptor (TCR) or the γδ TCR.…”

“…Conversely, in intestinal disorders such as celiac disease there is a striking increase in γδ IELs versus αβ Tcells (Kagnoff 1998). Results from studies in giardiasis reveal a much more subtle, but significant, increase in IELs than that commonly seen in celiac disease (Heyworth et al 1985, Oberhuber et al 1996, Scott et al 2000. More research is warranted to determine whether, unlike in celiac disease, the pathophysiology of giardiasis may be mediated by T-cells other than cytotoxic γδ IELs.…”

“…Sucrase activity is compared with the average activity measured in unmanipulated control tissues (solid line). Whole SMLN and CD8 + but not CD4 + T cells from infected animals significantly reduce brush border height, surface area, and disaccharidase activity; * P < 0.05 vs control, n = 8-12 per group (modified from Scott et al 2000).…”

“…Recent studies have shed new light on the mechanisms whereby host immune factors may lead to these abnormalities in giardiasis. First, in immuno-competent but not in T-cell deficient animals, acute giardiasis causes a diffuse loss of epithelial brush border surface area and decreases sucrase and maltase activities (Scott et al 2000). During the acute phase of the infection, epithelial abnormalities were not seen in the jejunum of Gupta et al 1973, Chawla 1975, Ducombe et al 1978, Gillon et al 1982, Faubert 1988, Belosevic et al 1989, 1992, Favennec et al 1991, Katelaris et al 1991, Cevallos et al 1995, Mohammed et al 1995, O'Handley et al 2001 athymic mice, despite comparable parasitic loads to those seen in immuno-competent animals, implying that the lack of microvillous injury could not be attributed to a reduction in trophozoite numbers.…”

SGLT-1-mediated glucose uptake protects human intestinal epithelial cells against Giardia duodenalis-induced apoptosis

“…Studies in human patients, in experimental animal models, or in cell culture systems, have established that the infection causes small intestinal structural and functional abnormalities. These may include apoptosis induced epithelial barrier defects, microvillous shortening, disaccharidase deficiencies, hypersecretion of chloride, as well as malabsorption of electrolytes and water associated with infiltration of intraepithelial lymphocytes ( [Belosevic et al, 1989], [Buret et al, 1992], [Scott et al, 2000], , [Scott et al, 2004], [Troeger et al, 2007] and [Panaro et al, 2007]). …”