Innate Immune Defenses in the Intestinal Tract

Antimicrobial Lectins

Antimicrobial lectins represent a new family of inducible antimicrobial molecules with activity against Gram-positive bacteria. Identified in humans as hepatocarcinoma-intestine-pancreas/pancreatic-associated protein (HIP/PAP) and in mice under the name of RegIII, these small secreted C-type lectins consist of a carbohydrate recognition domain of around 16 kDa linked to an N-terminal signal peptide.^[35] Expression of these proteins is constitutive throughout the intestinal epithelium, principally by Paneth cells in the small intestine and endocrine cells in the colon.^[36,37,38] A recent study demonstrated that expression of one member of the RegIII family, RegIIIγ, is driven by bacterial-epithelial interactions.^[39**] At the time of weaning, characterized by profound changes in the intestinal microbiota composition, a significant increase in RegIIIγ mRNA levels occurred, which correlated with bacterial density along the duodenal-ileal axis.^[39**] Bacterial reconstitution of germ-free mice induced epithelial expression of RegIII.^[40] Moreover, HIP/PAP and RegIII protein expression was increased in response to mucosal damage and inflammatory stimuli.^[40]

The conserved carbohydrate binding motifs of HIP/PAP and RegIII have a strong binding affinity (K_d = 26 and 11 nM, respectively) to peptidoglycan exposed on the surface of Gram-positive bacteria, including Listeria innocua and Enterococcus faecalis.^[39**] The binding of HIP/PAP and RegIII proteins to peptidoglycan causes bacterial cell wall damage and cytoplasmic leakage, similar to that of cationic antimicrobial peptides.^[39**] In addition to their toxic activity, these lectins may have other biological functions in the intestine, as several studies have demonstrated that HIP/PAP is mitogenic and antiapoptotic for cells of the liver, pancreas and nervous system and promotes intestinal epithelial cell growth in vitro.^[35] Although the physiological relevance of these antimicrobial lectins in the intestine is poorly understood, these data suggest that they have an important role in innate defense against specific subsets of enteric bacteria.

Beyond direct antimicrobial activity, lectins may contribute indirectly to innate defense of the intestinal surface (Fig. 1). For example, intelectin-2 (also known as intestinal lactoferrin receptor) is a Ca²⁺-dependent, D-galactosyl-specific lectin produced principally in Paneth and goblet cells,^[41] although recent evidence suggests that enterocytes can also synthesize the protein.^[42*] Expression of intelectin-2 is normally limited to ileum, but in response to infection with the nematode Trichinella spiralis its expression is rapidly increased throughout the small intestine.^[43] A natural deletion of intelectin-2 impairs effective immune defense against enteric pathogens, such as T. spiralis.^[43] Intelectins are thought to confer mucosal protection through their ability to bind galactofuranosyl residues contained in carbohydrate chains of various microorganisms.^[44] Although intelectins lack agglutination properties,^[44] their deposition in the brush border membrane and preferential association with microvillar lipid rafts suggest that they shield against microbial infection by serving as decoy pathogen receptors or by protecting exposed epithelial binding sites^[42*] (Fig. 1). Additionally, it may help in stabilizing the brush border membrane through cross-linking of lipid and protein glycoconjugates.^[42*] Similar to intelectin, locally produced antiglycosyl antibodies of the immunoglobulin (Ig)G, IgM and IgA isotypes can function as major carbohydrate-binding proteins in the brush border membrane^[45,46*] and thereby protect against attachment of bacterial glycosyl-binding virulence factors such as cholera toxin B subunit^[45] (Fig. 1).^[42*,46*,47] The development of such antibodies during intestinal infections remains to be defined, but it appears likely that antiglycosyl antibodies serve a greater role in defending the intestinal epithelium than previously recognized.

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Figure 1.

Protection of cell surface carbohydrates in innate antimicrobial defense

Microvillar rafts, enriched in glycoproteins and glycolipids, provide a number of carbohydrate-binding sites for microbial adhesions [42,* 46,* 47]. Antimicrobial defense molecules, such as intelectins and antiglycosyl antibodies, bind to many of the same sites thereby preventing microbial attachment to the epithelial surface. IgG, immunoglobulin G.

Curr Opin Gastroenterol. 2007;23(2):115-120. © 2007  Lippincott Williams & Wilkins

Cite this: Innate Immune Defenses in the Intestinal Tract - Medscape - Mar 01, 2007.