Shigella flexneriinfection: pathogenesis and vaccine development

Abstract

Shigella flexneri is a gram-negative bacterium which causes the most communicable of bacterial dysenteries, shigellosis. Shigellosis causes 1.1 million deaths and over 164 million cases each year, with the majority of cases occurring in the children of developing nations. The pathogenesis of S. flexneri is based on the bacteria's ability to invade and replicate within the colonic epithelium, which results in severe inflammation and epithelial destruction. The molecular mechanisms used by S. flexneri to cross the epithelial barrier, evade the host's immune response and enter epithelial cells have been studied extensively in both in vitro and in vivo models. Consequently, numerous virulence factors essential to bacterial invasion, intercellular spread and the induction of inflammation have been identified in S. flexneri. The inflammation produced by the host has been implicated in both the destruction of the colonic epithelium and in controlling and containing the Shigella infection. The host's humoral response to S. flexneri also appears to be important in protecting the host, whilst the role of the cellular immune response remains unclear. The host's immune response to shigellosis is serotype-specific and protective against reinfection by the same serotype, making vaccination a possibility. Since the 1940s vaccines for S. flexneri have been developed with little success, however, the growing understanding of S. flexneri's pathogenesis and the host's immune response is assisting in the generation of more refined vaccine strategies. Current research encompasses a variety of vaccine types, which despite disparity in their efficacy and safety in humans represent promising progress in S. flexneri vaccine development.

High Vaccine Efficacy against Shigellosis of Recombinant Noninvasive Shigella Mutant That Expresses Yersinia Invasin

“…Several strategies have been reported to improve the efficacy of invasive Shigella vaccines and to prevent strong inflammatory reaction (12). These attenuated invasive Shigella vaccines have also served as a vector for foreign Ag delivery to the mucosal immune system (61), because the early entry of invasive Shigella occurs via M cells in rabbit ligated intestinal loop model of Shigella infection (3,4).…”

“…In recent years, a number of attenuated Shigella strains have been constructed and evaluated as candidates for use in vaccines (12)(13)(14). These strains have been classified into two groups on the basis of the function of the mutated gene: 1) strains in which one or two genes in the metabolism have been inactivated, such as thyA, aroA, and aroD (15)(16)(17), and 2) strains harboring mutation of virG (icsA), a gene essential for cell-to-cell spreading, in addition to one of above gene mutations (18 -24).…”

“…SC502 is safe in humans at low doses, but causes symptoms such as diarrhea and fever at high doses (14). Mutations in chromosome or virulence plasmid have been introduced to generate noninvasive live vaccine strains, but a high bacterial dose and long period of vaccination are needed to achieve protective immunity (12).…”

“…However, because Shigella invasion is mainly associated with the ability of the bacteria to induce strong inflammatory reaction, it is very difficult to maintain a balance between invasiveness, inflammation, and immunogenicity (12,28). After Shigella invade epithelial cells, the bacteria escape from the phagosome and are released into the cytoplasm, where they activate IL-8 production via the Nod1-NF-B pathway (29).…”

Mutational analysis of the major periplasmic loops of Shigella flexneri Wzy: identification of the residues affecting O antigen modal chain length control, and Wzz-dependent polymerization activity

“…Oag is the serotype determinant and also the protective antigen of the bacteria (Jennison & Verma, 2004;Stagg et al, 2009;Sun et al, 2013). On the basis of the composition of Oag, S. flexneri can be divided into 17 serotypes (Sun et al, 2013).…”