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

Abstract

Live attenuated Shigella vaccines elicit protective immune responses, but involve a potential risk of inducing a strong inflammatory reaction. The bacterial invasiveness that is crucial for Ag delivery causes inflammatory destruction of infected epithelial cells and proinflammatory cell death of infected macrophages. In this study, the noninvasive Shigella mutant ΔipaB was equipped with Yersinia invasin protein, which has been shown to mediate bacterial invasion and targeting to M cells located in follicle-associated epithelium. Invasin-expressing ΔipaB (ΔipaB/inv) was internalized into epithelial cells and retained in the intraphagosomal space. ΔipaB/inv did not induce necrotic cell death of infected macrophages nor cause symptomatic damage after intranasal vaccination of mice. ΔipaB/inv was safer and more effective than the conventional live vaccine, ΔvirG. Infection by ΔipaB/inv caused polymorphonuclear neutrophil infiltration in the lung, but did not induce production of large amounts of proinflammatory cytokines. We concluded that the low experimental morbidity and high vaccine efficacy of ΔipaB/inv are primarily based on high protective immune responses, which may be enhanced by the polymorphonuclear neutrophil infiltration unaccompanied by tissue injury.

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

“…The Shigella Δ ipaB /Inv strain has a compromised T3SS secretion, though it is internalized due to the expression of the Yersinia invasin protein (Isberg et al , 1987). Once inside cells, this mutant is unable to escape the internalization vacuole and does not replicate (Suzuki et al , 2006). Interestingly, we observed that primary infection with this mutant strain did not compromise re‐infection, which was comparable to that observed in mock‐treated cells (Figs 6B and C, and EV4A).…”

Type III Secretion Systems and Disease

“…A noninvasive Shigella strain with a mutation in ipaB was complemented with inv, an invasin gene of Yersinia (⌬ipaB inv strain). This rendered the ⌬ipaB inv strain invasion competent and immunogenic, yet it remained confined to the phagosome and did not induce clinically evident pathology in an animal model (140). As a result, it provides a very attractive alternative to virG mutant vaccine strains as well as a generally interesting paradigm for developing vaccines against intracellular pathogens.…”

“…To address the residual pathology associated with virG mutant strains while still eliciting an immune response protective against an intracellular pathogen, an alternative strategy was developed by Suzuki et al (140). A noninvasive Shigella strain with a mutation in ipaB was complemented with inv, an invasin gene of Yersinia (⌬ipaB inv strain).…”

Th17 Cells Are the Dominant T Cell Subtype Primed by Shigella flexneri Mediating Protective Immunity

“…This model is the only available animal model in rodents to study both innate and adaptive immune responses to Shigella infection, and therefore, has been largely used so far (6)(7)(8)(9)(10)(11). Induction of the inflammatory process requires fully invasive Shigella, carrying the virulence plasmid encoding the virulence effectors mandatory for the invasive/proinflammatory phenotype.…”