Exploitation of Mammalian Host Cell Function by Shigella spp.

Larean D. Brandon; Marcia B. Goldberg

doi:10.1128/9781555818111.ch12

Chapter 12 : Exploitation of Mammalian Host Cell Function by Shigella spp.

Authors: Larean D. Brandon¹, Marcia B. Goldberg¹

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Affiliations: 1: Infectious Disease Division, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114

Content Type: Monograph

Publication Year: 2000

Category: Bacterial Pathogenesis

Book DOI: 10.1128/9781555818111

Chapter DOI: 10.1128/9781555818111.ch12

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Abstract:

Shigella species are the causative agents of shigellosis (a form of bacillary dysentery) and lead to an estimated 1.1 million deaths per annum, most notably in developing world countries where nutrition and hygiene are suboptimal. The pathogenicity of Shigella depends upon a complex series of molecular events that are mediated by factors expressed on the large 220-kilobase virulence plasmid. This chapter describes the detailed molecular events involved in these interactions of shigellae with the host cell. Shigellae invade human colonic epithelial cells. The initial step in the pathogenesis of shigellosis most likely involves specific interactions of the organism, with the mucin associated with the apical surface of colonic epithelial cells. In vitro studies demonstrate that shigellae are unable to enter polarized colonic epithelial cells at the apical pole, but rather can enter only at the basolateral surfaces. Entry of Shigella at the basolateral face of colonic epithelial cells involves a complex set of molecular reactions. The SSRRASS phosphorylation consensus sequence in IcsA contains the site for processing by the IcsP (SopA) outer membrane protease. Genetic and biochemical studies demonstrate that IcsA is an autotransported protein and therefore can be included in the family of proteins that use the Type IV secretion pathway. VirF (a protein expressed on the virulence plasmid) is the global regulator of the virulence genes on the large 220-kb plasmid. Most of the genes known to be regulated by VirF have been discussed in the chapter.

Citation: Brandon L, Goldberg M. 2000. Exploitation of Mammalian Host Cell Function by Shigella spp., p 175-187. In Brogden K, Roth J, Stanton T, Bolin C, Minion F, Wannemuehler M (ed), Virulence Mechanisms of Bacterial Pathogens, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818111.ch12

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Exploitation of Mammalian Host Cell Function by Shigella spp.

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FIGURE 1

Simplified schematic of the pathogenesis of shigellosis. Shigellae (black ovals) are initially taken up by M cells (cell A) and transcytosed to the basolateral face of the epithelial cells, where they are engulfed by macrophages (cell B). The bacteria release factors that promote apoptosis of the macrophages (thereby releasing the bacteria) and that promote the release of interleukin 1-β. This release promotes an inflammatory response that induces the transmigration of PMNs (cell C) between the epithelial cells to the apical face of the epithelial cell layer. The inflammatory response destroys the integrity of the tight junctions (black rectangles), thus enhancing uptake of the bacteria. Once the bacteria reach the basolateral face of the epithelial cells they are endocytosed and rapidly escape the endocytic vesicle (steps 1 and 2). They are subsequently released into the host cell cytoplasm where they divide ( 3 ), recruit actin filaments ( 4 ), and invade adjacent epithelial cells via actin-mediated motility ( 5 ). In the new host cell, the bacteria are found associated with double-membrane vesicles, from which they rapidly escape ( 6 and 7 ).

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FIGURE 1

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FIGURE 2

Proposed mechanism of targeting of IcsA to the bacterial old pole. Following translation, the targeting domain of IcsA (star) recognizes a polar target (hexagon) associated with the cytoplasmic membrane at the old pole. IcsA is then translocated across the cytoplasmic membrane at the pole and its carboxyterminal β domain is inserted into the outer membrane, such that the aminoterminal α domain is exposed on the bacterial surface. Following insertion into the outer membrane, IcsA diffuses laterally in the membrane. IcsP cleaves IcsA from all surfaces of the bacteria at a rate that is slower than the rate at which IcsA is inserted at the pole, such that a polar cap of IcsA is maintained.

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FIGURE 2

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FIGURE 3

Model of IcsA-mediated actin assembly. The amino-terminal glycine-rich repeat domain of IcsA (shaded bar) binds the verprolin (V) domain of N-WASP (open bar). This binding leads to unmasking of carboxy- terminal domains of N-WASP, thereby allowing binding of the Arp2/ 3 complex to the N-WASP acidic domain (A) and G-actin (Ag) to the N-WASP verprolin (V) domain. In the presence of the Arp2/3 complex actin is nucleated, with the Arp2/3 complex capping the pointed end of the actin nucleus. G-actin (Ag) is rapidly polymerized onto the uncapped barbed end. Subsequently, N-WASP and the growing actin filament are released from IcsA and crosslinked into the actin tail. Af, filamentous actin.

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FIGURE 3

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FIGURE 4

Model for modulating the expression of virulence genes. VirF is the global regulator of genes found on the virulence plasmid. The chromosomally encoded CpxA/CpxR two-component regulatory proteins regulate VirF. VirF activates the transcription of icsA and virB. The latter's gene product activates the transcription of the mxi-spa locus and the ipa operon. The chromosomally encoded H-NS protein is an antagonistic regulatory factor that represses the expression of virB at 30°C, but which is released from the virB promoter at 37°C.

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FIGURE 4

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