Molecular and Cellular Mechanisms of Shigella flexneri Dissemination

Abstract

The intracellular pathogen Shigella flexneri is the causative agent of bacillary dysentery in humans. The disease is characterized by bacterial invasion of intestinal cells, dissemination within the colonic epithelium through direct spread from cell to cell, and massive inflammation of the intestinal mucosa. Here, we review the mechanisms supporting S. flexneri dissemination. The dissemination process primarily relies on actin assembly at the bacterial pole, which propels the pathogen throughout the cytosol of primary infected cells. Polar actin assembly is supported by polar expression of the bacterial autotransporter family member IcsA, which recruits the N-WASP/ARP2/3 actin assembly machinery. As motile bacteria encounter cell-cell contacts, they form plasma membrane protrusions that project into adjacent cells. In addition to the ARP2/3-dependent actin assembly machinery, protrusion formation relies on formins and myosins. The resolution of protrusions into vacuoles occurs through the collapse of the protrusion neck, leading to the formation of an intermediate membrane-bound compartment termed vacuole-like protrusions (VLPs). VLP formation requires tyrosine kinase and phosphoinositide signaling in protrusions, which relies on the integrity of the bacterial type 3 secretion system (T3SS). The T3SS is also required for escaping double membrane vacuoles through the activity of the T3SS translocases IpaB and IpaC, and the effector proteins VirA and IcsB. Numerous factors supporting envelope biogenesis contribute to IcsA exposure and maintenance at the bacterial pole, including LPS synthesis, membrane proteases, and periplasmic chaperones. Although less characterized, the assembly and function of the T3SS in the context of bacterial dissemination also relies on factors supporting envelope biogenesis. Finally, the dissemination process requires the adaptation of the pathogen to various cellular compartments through transcriptional and post-transcriptional mechanisms.

Invasion of epithelial cells are correlated with secretion of Biosurfactant via the type 3 secretion system (SST3) ofShigella flexneri

“…Many mechanisms have been demonstrated how S. flexneri can disseminate inside epithelial cells [68, 69], helping to escape autophagy phenomenon [70] and to spread inside host cell [71] by using a specific domain of IcsB that interacts with cholesterol [27]. In this work we showed that S. flexneri , S. boydii and S. sonnei can spread using swarming phenomenon.…”

The Actomyosin Network and Cellular Motility: A S100A4 Regulatory View into the Process

“…Mutations in cytoplasmic actin have been related to autosomal dominant hearing loss [144]. Mutation or molecular mechanisms that result in changes of activity of actin-binding proteins, such as the nucleating facilitating protein complex Arp2/3 have been linked, albeit indirectly, to bacillary dysentery, as their functions are high jacked by the Shigella bacterial strains to disseminate in the colonic epithelium [145]. Involvement of the Arp2/3 complex and their regulator WASp have also been shown to lead to immunodeficiency and reduced platelet numbers, as the loss of WASp expression leads to the Wiskott-Aldrich syndrome [146].…”

Therapeutic lipid-coated hybrid nanoparticles against bacterial infections

“…Once in the cytosol, Listeria monocytogenes will induce the polymerization of host actin laments and the force generated by actin polymerization allow them to move into neighbouring cells resulting in a productive infection. 128 Similar routes to infection is adopted by Shigella exneri, 129,130 Salmonella enterica, 131 and Mycobacterium tuberculosis. 132 Thus, while professional phagocytes not only serve to eradicate intracellular pathogens, ironically it also provides a reservoir of latent infection representing a signicant barrier to antibiotic treatment.…”