Progress and pitfalls in Shigella vaccine research

Abstract

Renewed awareness of the substantial morbidity and mortality that Shigella infection causes among young children in developing countries, combined with technological innovations in vaccinology, has led to the development of novel vaccine strategies in the past 5 years. Along with advancement of classic vaccines in clinical trials and new sophisticated measurements of immunological responses, much new data has been produced, lending promise to the potential for production of safe and effective Shigella vaccines. Herein, we review the latest progress in Shigella vaccine development within the framework of persistent obstacles.

Figure 1

Figure 1A. Live Shigella mucosal priming. (1) From the intestinal lumen, Shigella crosses the intestinal epithelial barrier through the M cells, possibly by a receptor-mediated uptake , and it is endocytosed by macrophages and dendritic cells in the subepithelial region of the M cell pocket. Conceivably, the organism could also be sampled from the lumen by DC residing between epithelial cells through their extended dendrites. (2) The bacteria escape the phagocytic vacuole and induce apoptosis of the infected cells. As a result, live organisms are released and invade epithelial cells from the basolateral side, spreading from cell to cell throughout the mucosal epithelial layer. (3) Infected epithelial cells in turn secrete IL-8 and other chemotactic factors that will recruit polymorphonuclear (PMN) lymphocytes. Activated macrophages and PMN secrete a cascade of pro-inflammatory molecules (e.g., IL-18, IL-1β, TNF-α, IL-6, IFN-γ) further attracting phagocytic cells, which would ultimately kill and clear the organism. This initial inflammatory response sets the stage for adaptive immunological priming. (4) Apoptotic infected macrophages, neutrophils and other antigenic material released from infected cells may be taken up by DC, allowing for presentation and cross-presentation of bacterial antigens to T cells. These antigen-loaded DC are transported to adjacent interfollicular T cell zones of mucosal lymphoid follicles or regional lymph nodes where they stimulate naïve T cells. Stimulated T cells in turn proliferate vigorously and differentiate into effector and memory T cells. This process leads to the activation of CD4⁺ Th2 cells, which support the production of antibodies, and Th1 cells, that will facilitate and expand inflammatory responses. Being an intracellular pathogen, Shigella is also expected to activate cytotoxic CD8⁺ T cells (CTL) that could eventually kill infected cells (e.g., intraepithelial -IEL- CTL) and secrete IFN-γ and other cytokines to further enhance Th1 CMI. B and T cells primed by mucosal pathogens acquire homing receptor molecules that will allow them to migrate to mucosal effector sites. Figure 1B. Immunological effector mechanisms. A. Innate immunity. Shigella infection triggers an inflammatory response in the intestinal epithelium with recruitment of PMN, macrophages and NK cells, which will capture and kill the organism. These activated phagocytic cells release pro-inflammatory cytokines, which in turn contribute to the recruitment of B and T cells. B. Adaptive immunity. (1) IgA produced by mucosal ASC are secreted through the epithelial cells. IgG, produced by local IgG ASC or present in circulation can diffuse into the intestinal lumen or be actively transported through the FcRn receptor. Both antibodies could block the organisms abrogating cell attachment. (2) Antibodies could also block the bacteria that have breached the intestinal epithelial barrier preventing further cell invasion. IgG can mediate bacterial killing through opsonophagocytosis or lysis in the presence of complement. (3) Th1 cells could limit bacterial dissemination through induction of IEL with cytotoxic capacity. (4) Th2 cells provide support for production of antibodies and contribute to B cell differentiation and induction of B_M cells. B memory cells can reactivate and mount a quick anamnestic response upon antigen exposure. Although the presence of antibodies against the O-polysaccharide and Shigella Ipas appear to be critical for protection, the contribution of other immunological effectors is likely necessary to clear an infection. Abbreviations: PMN: polymorphonuclear lymphocytes; DC: dendritic cells; CTL: cytotoxic T cells (CTL); B_M: B memory cells; FcRn: Fc-γ (IgG) neonatal intestinal receptor; IEL: intraepithelial lymphocytes; NK: natural killer. Black arrows indicate soluble protein mediators (e.g cytokines); blue arrows indicate changes in cell phenotype; grey arrows depict cytokines and molecular mediators that drive cell proliferation and differentiation in the lymph nodes.