Polymeric Immunoglobulin Receptor in Intestinal Immune Defense against the Lumen-Dwelling Protozoan ParasiteGiardia

Abstract

The polymeric Ig receptor (pIgR) is conserved in mammals and has an avian homologue, suggesting evolutionarily important functions in vertebrates. It transports multimeric IgA and IgM across polarized epithelia and is highly expressed in the intestine, yet little direct evidence exists for its importance in defense against common enteric pathogens. In this study, we demonstrate that pIgR can play a critical role in intestinal defense against the lumen-dwelling protozoan parasite Giardia, a leading cause of diarrheal disease. The receptor was essential for the eradication of Giardia when high luminal IgA levels were required. Clearance of Giardia muris, in which IgA plays a dominant role, was severely compromised in pIgR-deficient mice despite significant fecal IgA output at 10% of normal levels. In contrast, eradication of the human strain Giardia lamblia GS/M, for which adaptive immunity is less IgA dependent in mice, was unaffected by pIgR deficiency, indicating that pIgR had no physiologic role when lower luminal IgA levels were sufficient for parasite elimination. Immune IgA was greatly increased in the serum of pIgR-deficient mice, conferred passive protection against Giardia, and recognized several conserved giardial Ags, including ornithine carbamoyltransferase, arginine deiminase, α-enolase, and α- and β-giardins, that are also detected in human giardiasis. Corroborative observations were made in mice lacking the J chain, which is required for pIgR-dependent transepithelial IgA transport. These results, together with prior data on pIgR-mediated immune neutralization of luminal cholera toxin, suggest that pIgR is essential in intestinal defense against pathogenic microbes with high-level and persistent luminal presence.

Release of metabolic enzymes by Giardia in response to interaction with intestinal epithelial cells

“…We have also recently shown that the host response towards Giardia of differentiated Caco-2 cells is partly mediated by soluble factor(s) [8]. The secreted proteins we identify here are immunodominant in human infections [29,36] and experimental mouse infections [13]. The targeting of secreted giardial proteins for immunoneutralization may thus represent a useful therapeutic strategy, aimed at treating or preventing Giardia infections.…”

“…In vitro interaction models for G. lamblia and intestinal cells are well established [7][8][9][10][11], as are rodent models [12][13][14] and this has increased the knowledge of the infection [15][16][17].…”

Upregulation effect of glycyrrhizin on secretory component expression in Caco-2 cells

“…Free SC can bind to several bacterial proteins, such as colonization factor antigen (Oliveira et al, 2001), Clostridium difficile toxin A (Dallas and Rolfe, 1998), and Streptococcus pneumoniae surface protein C (PspC) (Hammerschmidt et al, 2000). High expression of SC is considered to play an important role in limiting the inflammatory response (Davids et al, 2006;Giugliano et al, 1995;Dallas et al, 1998).…”

“…Fax: 8624-22703576. key defense against enteropathogenic Escherichia coli (Araújo et al, 2001), and can inhibit Salmonella typhimurium adhesion to HeLa cells (Bessler et al, 2006). Increasing evidence indicates that high SC expression is important in limiting the inflammatory response to bacterial and viral products, via the antiinflammatory function of SC (Davids et al, 2006;Giugliano et al, 1995;Dallas et al, 1998).…”

TNF-α Mediated Secretory Component is Positively Regulated by PI3K/AKT/MTOR in CACO-2 Cells

“…SC is a nonspecific scavenger of microorganisms and plays a key role in protecting and balancing the intestinal mucous membrane in limiting the inflammation process (1). SC is a key defense to bacteria (2-5) and parasites (6). Moreover, SC can play a critical role in the immune neutralization of the Cholera toxin (7).…”