Chapter 10 : Upregulation of Innate Defense Mechanisms by Enteric Infections

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This chapter examines the role of the intestinal epithelium in innate immune defense against enteric microbial pathogens. It focuses on in vitro and in vivo model systems that can be used to define epithelial cell innate immune defense mechanisms that are activated in response to microbial infection and a spectrum of intestinal epithelial innate defense mechanisms that can be activated by microbial pathogens that use different strategies to interact with the host. Interactions between enteric microbial pathogens and intestinal epithelial cells involve, by definition, two major players: the pathogen and the host epithelial cell. Invasive and noninvasive pathogens can activate epithelial cell signaling cascades that are essential for the development of innate defense. This involves a number of sophisticated evolutionary coevolved strategies on the part of the microbes and the host epithelial cells that are the targets of infection. Relevant to the activation of innate mucosal defense by intestinal epithelial cells, some of the members of one family of pattern-recognition receptors (PRR), the Toll-like receptors (TLR), are expressed by intestinal epithelial cells. Antimicrobial peptides and proteins are highly conserved in evolution and appear to play an important role in intestinal epithelial cell innate defense. Intestinal epithelial cells are an integral component of innate mucosal defense. In this role, they can produce antimicrobial peptides, chemokines, cytokines, nitric oxide (NO), and eicosanoids and express receptors for cytokines and pathogen-associated molecular patterns (PAMP), each of which can play a role in epithelial cell innate defense mechanisms.

Citation: Kagnoff M. 2003. Upregulation of Innate Defense Mechanisms by Enteric Infections, p 155-174. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch10
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Human intestinal xenograft model. Human fetal intestine (small intestine or colon) is transplanted subcutaneously onto the backs of SCID adult mice and allowed to mature for 10 or more weeks. The mature xenograft contains a fully regenerated intestinal mucosa lined by an epithelium that is of human origin, and the lumen is sterile as assessed by the absence of 16S rRNA. Early epithelial cell signaling events in the xenografts in response to microbial infection can be studied in mice infected intraluminally with human enteric pathogens ( ). In another approach, mice can be injected with human recombinant cytokines known to act on human intestinal epithelial cells to study intestinal epithelial cell signaling events and responses to human mediators in an in vivo model that has an intact human intestinal epithelium ( ). Tissue responses can be studied using histological and molecular approaches. Tissues can also be removed and studied ex vivo (e.g., in modified Ussing chambers).

Citation: Kagnoff M. 2003. Upregulation of Innate Defense Mechanisms by Enteric Infections, p 155-174. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch10
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Image of FIGURE 2

Immunohistochemical detection of LL-37/hCAP18 in the epithelium of normal human colon and small intestine. Biopsy specimens from normal human colon (A and B) and proximal human small intestine (C and D) were examined for LL-37/hCAP18 using indirect immunoperoxidase staining. In normal colon, LL37/hCAP18 is expressed mainly by the surface epithelium and adjacent epithelium in the upper crypts (A). There is little or no expression of LL37/hCAP18 in the villus or crypt epithelium in proximal small intestine (C), although in some specimens staining is seen in duodenal Brunner's glands (not shown).

Citation: Kagnoff M. 2003. Upregulation of Innate Defense Mechanisms by Enteric Infections, p 155-174. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch10
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Image of FIGURE 3

DC may sample luminal microbes. In this model, epithelial cells are proposed to produce CCL20 (MIP3α) that can chemoattract DC, a key cell type required for antigen presentation to T cells. DC subsequently send out dendrites that cross the epithelial layer and extend into the intestinal lumen where they can sample luminal bacteria. The passage of dendrites across the epithelium is thought to involve an unsealing and resealing of epithelial cell tight junctions and involves interactions between proteins expressed by DC and intestinal epithelial cells (e.g., occludin, claudin-1, JAM) ( ).

Citation: Kagnoff M. 2003. Upregulation of Innate Defense Mechanisms by Enteric Infections, p 155-174. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch10
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Image of FIGURE 4

Epithelial cells produce mediators and express receptors important in innate and adaptive mucosal immunity.

Citation: Kagnoff M. 2003. Upregulation of Innate Defense Mechanisms by Enteric Infections, p 155-174. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch10
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