Chapter 19 : Signal Transduction in the Intestinal Mucosa

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This chapter considers the remarkable signal transduction networks that have evolved between intestinal microbes and their host in trying to maintain the balance of health and disease. Resident bacteria serve a central line of resistance to colonization by exogenous microbes and thus assist in preventing the potential invasion of the intestinal mucosa by an incoming pathogen. A number of enteric pathogens and some opportunistic commensal bacteria possess the means to provoke NF-κB activation and, subsequently, intestinal inflammation. Innate epithelial defense mechanisms provide a rapid response whereby microbial pathogens in the host are quickly detected and signals are generated that activate mucosal antimicrobial defense mechanisms. The intimate interaction between enteropathogenic (EPEC) and the intestinal epithelium causes the induction of phosphate fluxes within the host cells, as well as the activation of protein kinase C (PKC), phospholipase C, and NF-κB. Chloride secretion in the intestinal mucosa involves the collaborative effort of several transporters. The current paradigm postulates that intestinal epithelial cells respond to serovar Typhimurium by the polarized release of distinct proinflammatory chemoattractants, which sequentially orchestrate neutrophil movement across the intestinal epithelium. Speculatively, microorganisms intimately associated with the intestinal mucosa may have evolved such mechanisms to dampen the host proinflammatory and immune responses without provoking apoptotic death. A more complete understanding of the signal transduction cascades that exist between the intestinal bacteria and the human host in the intestinal mucosa may uncover new insights into human diseases and reveal novel approaches to treating them.

Citation: McCormick B. 2005. Signal Transduction in the Intestinal Mucosa, p 265-282. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch19

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Bacterial Proteins
Bacterial Pathogenesis
Type III Secretion System Proteins
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Figure 1

Activation of the NF-κB pathway can be induced by a variety of bacterial constituents. In unstimulated cells, NF-κB is sequestered in the cytoplasm by IκB. Bacterial components such as LPS selectively bind to TLR4, while components of the peptidoglycan selectively interact with intracytoplasmic Nods (Nod1 or Nod2) to initiate signaling that sets in motion a series of enzymatic modifications of IκB, such as phosphorylation, ubiquitination, and degradation. Loss of IκB allows NF-κB to translocate to the nucleus, bind to the promoters of many proinflammatory effector genes, and activate the proinflammatory program. Many of these cellular events are also caused by bacterial effector proteins, which are delivered into the intestinal cells (by type III secretion systems) and directly modulate the activities of host cell proteins (e.g., SopB from serovar Typhimurium). Perturbation of any of these enzymatic steps (such as with YopJ from ) could inhibit the entire pathway.

Citation: McCormick B. 2005. Signal Transduction in the Intestinal Mucosa, p 265-282. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch19
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Figure 2

Intestinal bacteria have evolved different strategies to induce chloride secretion and regulate the tight-junction complex. Cholera toxin binds to the ganglioside receptor, GM1, and enters epithelial cells as an AB5 complex by retrograde trafficking through the Golgi and endoplasmic reticulum (ER). Dissociation and cleavage of the A subunit results in the A1 peptide- mediated ADP-ribosylation of Gsα. This results in sustained activation of adenylate cyclase and elevation of the cAMP concentration, which in turn increase electrogenic chloride secretion. Through a different pathway, TDH of V. parahemolyticus elevates the intracellular Ca2+ concentration, resulting in the activation of CaCC. Phosphorylated inositol derivatives are also involved in regulating Ca2+-mediated chloride secretion and have stimulatory or inhibitory effects. As shown here, the S. enterica serovar Typhimurium intracellular SopB protein affects inositol phosphate signaling events. One such event is the transient increase in the concentration of Ins(1,4,5,6)P4 (IP4), which antagonizes the closure of chloride channels, influencing net electrolyte transport and hence fluid secretion. Infection of epithelial cells also results in the production of PGs such as PGE2; this elevates cAMP levels, which can lead to further Cl− secretion. The epithelial tight junction is a macromolecular structure consisting of both transmembrane-spanning proteins, such as occludin, and a number of claudin isoforms. This complex provides a barrier to the paracellular space, preventing free access of bacteria or their products to the underlying compartment. Pathogens, however, have developed strategies to disrupt the tight-junction barrier. S. flexneri, for example, can modulate the function of the tight-junction components in a manner which allows passage of the organism through the paracellular space, which is particularly relevant for the ability of Shigella to infect the colon.

Citation: McCormick B. 2005. Signal Transduction in the Intestinal Mucosa, p 265-282. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch19
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Figure 3

(A) Model of proposed events affecting -induced PMN transmigration across the intestinal epithelium. evokes a potent inflammatory response in the host, the hallmark of which is the migration of PMN across the intestinal mucosa. This process includes extravasation of circulating PMN from the microvasculature, passage of PMN across the lamina propria, and paracellular movement of PMN across the epithelium. PMN recruitment is coordinated by the release of proinflammatory cytokines, among which are IL-8 and PEEC. By an unknown mechanism, invasion also causes the transcellular transport of flagellin to the basolateral membrane domain, where it promotes the release of IL-8 by interacting with TLR-5 and activates the NF-κB pathway. Concurrently, the type III secretion product, SipA, is necessary and sufficient for induction of PMN transmigration across model intestinal epithelia in a PKC-dependent manner, which leads to the apical secretion of PEEC. (B) Model of serovar Typhimurium-induced signaling in epithelial cells by the secreted protein SipA. Interaction of SipA with the apical domain of polarized epithelial cells leads to activation of ARF6 (GTPARF6) at the apical membrane, most probably through the mammalian guanine exchange factor ARNO. This leads to an increase in PLD activity and local production of phosphatidic acid (PA), which is metabolized to DAG by phosphatidic acid phosphohydrolase (PAP). Generation of DAG recruits PKC to the apical membrane. Activation of PKC at this site (PKC*) is necessary for the apical release of the chemokine PEEC and subsequent basolateral-to-apical PMN transepithelial migration.

Citation: McCormick B. 2005. Signal Transduction in the Intestinal Mucosa, p 265-282. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch19
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