Abstract
Shigella spp. are Gram-negative bacterial pathogens that infect human colonic epithelia and cause bacterial dysentery. These bacteria express multiple copies of a syringe-like protein complex, the Type Three Secretion apparatus (T3SA), which is instrumental in the etiology of the disease. The T3SA triggers the plasma membrane (PM) engulfment of the bacteria by host cells during the initial entry process. It then enables bacteria to escape the resulting phagocytic-like vacuole. Freed bacteria form actin comets to move in the cytoplasm, which provokes bacterial collision with the inner leaflet of the PM. This phenomenon culminates in T3SA-dependent secondary uptake and vacuolar rupture in neighboring cells in a process akin to what is observed during entry and named cell-to-cell spread. The activity of the T3SA of Shigella flexneri was recently demonstrated to display an on/off regulation during the infection. While the T3SA is active when bacteria are in contact with PM-derived compartments, it switches to an inactive state when bacteria are released within the cytosol. These observations indicate that effector proteins transiting through the T3SA are therefore translocated in a highly time and space constrained fashion, likely impacting on their cellular distribution. Herein, we present what is currently known about the composition, the assembly and the regulation of the T3SA activity and discuss the consequences of the on/off regulation of T3SA on Shigella effector properties and functions during the infection. Specific examples that will be developed include the role of effectors IcsB and VirA in the escape from LC3/ATG8-positive vacuoles formed during cell-to-cell spread and of IpaJ protease activity against N-miristoylated proteins. The conservation of a similar regulation of T3SA activity in other pathogens such as Salmonella or Enteropathogenic Escherichia coli will also be briefly discussed.
Highlights
Shigella spp. (e.g., S. flexneri, S. sonnei, S. dyssenteriae, and S. boydii) are gram negative enteropathogen bacteria that are closely related to commensal Escherichia coli
We describe the evidences indicating that Shigella T3SA activity oscillates depending on the adhesion of bacteria to the host plasma membrane (PM)
Using a conditional mutant ipaC allele that remained trapped in protrusions or in vacuoles that derived from it, or using the F-actin depolymerizing inhibitor jasplakinolide, which induced host cell retraction that causes random collisions between intracellular bacteria and the PM, we demonstrated that interactions of cytoplasmic bacteria with the PM compartments formed during cell-to-cell spread was critical for reactivation of T3SA
Summary
Shigella spp. (e.g., S. flexneri, S. sonnei, S. dyssenteriae, and S. boydii) are gram negative enteropathogen bacteria that are closely related to commensal Escherichia coli. Bacteria at permissive temperatures display at their surface inactive T3SA that can be switched to the active state upon contact with host cells, allowing almost instantaneous secretion of prestored translocators and effectors (Enninga et al, 2005). This study indicated that intracellular Shigella undergoes cyclical all-or-none activation of its T3SA depending on interactions with the PM during entry or cell-to-cell spreading steps of the infection cycle.
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