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Mucosal interactions with enteropathogenic bacteria
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Nadine Cerf-Bensussan, Pamela Schnupf, Valérie Gaboriau-Routhiau, Philippe J. Sansonetti
Among the six secretion systems currently described in bacteria, three systems (type III, IV, and VI) allow penetration of host-cell membranes and intracytosol injection of effectors. The best characterized are type III systems (T3SS), which are evolutionarily related to the flagellar system and are well conserved across a variety of taxa (in contrast to the effector proteins that are generally specific to each pathogen and govern their adaptation to their host). T3SS are formed of 20–30 proteins, the assembly of which is tightly regulated. Following assembly of a basal body into the inner and outer bacterial membranes, early substrates including the needle subunit and the needle-length control protein are targeted across this apparatus and assemble to form the extracellular needle (Figure 25.5). Tip proteins are then secreted and assembled at the tip of the needle, but further secretion remains blocked until host-cell contact. Upon host-bacterium contact, a second switch triggers the secretion of translocators that form a pore into the host-cell membrane. Bacterial effector proteins are then translocated into the host-cell cytosol. The mechanism activating this second switch has been deciphered for Shigella flexneri. In the anaerobic intestinal environment, Shigella is primed for invasion and expresses extended needles, which may help establish contact with the intestinal epithelium. These processes are tightly regulated. For example, a transcriptional regulator of anaerobic metabolism (called fumarate and nitrate reduction) represses effector secretion. This repressor is inactivated in the presence of oxygen. Because of the numerous capillaries underlying the epithelium, the luminal zone immediately adjacent to epithelial cells contains sufficient oxygen to inactivate fumarate and nitrate reduction. Thus, when Shigella comes close to the epithelial surface, the anaerobic block of secretion is reverted, allowing secretion of Ipa effectors into epithelial cells and host invasion. Whether this mechanism can be generalized to other T3SS-expressing enteropathogens remains to be defined, but the presence of fumarate and nitrate reduction boxes upstream of genes required for T3SS functions in Yersinia spp. and serovars of Salmonella enteritidis suggests that indeed this is likely to be the case.
Mechanisms of bacillary dysentery: lessons learnt from infant rabbits
Published in Gut Microbes, 2020
Seminal studies conducted in non-human primates have revealed that S. flexneri is an intracellular pathogen that resides in epithelial cells in the colon.7 Tissue culture systems have been developed very early on to model S. flexneri intracellular invasion.8 The development of in vitro tissue culture systems was instrumental in our understanding of the molecular determinants supporting S. flexneri intracellular invasion. This led to the discovery that S. flexneri invasion relies on the presence of “the invasion plasmid”9 that harbors the 37kb “entry region”10 encoding the type-3 secretion system (T3SS). Bacterial effector proteins, which are delivered into targeted host cells by the T3SS, manipulate various cellular processes. Modulation of the actin cytoskeleton by effector proteins leads to the uptake of the bacteria by non-phagocytic cells, such as epithelial cells, into primary vacuoles (Figure 1(a)).11 Escape from primary vacuoles grants the pathogen access to the host cell cytosol (Figure 1(a)). Cytosolic bacteria express a virulence factor, IcsA,12,13 involved in the recruitment of the host cell actin assembly machinery at the bacterial pole (Figure 1(a)).14,15 Actin polymerization propels the pathogen throughout the cytosol of infected cells, and mediates the formation of membrane protrusions that project into adjacent cells at cell-cell contacts (Figure 1(a)).16-19 The formed protrusions resolve into secondary vacuoles, from which the pathogen escapes, thereby gaining access to the cytosol of adjacent cells and achieving cell-to-cell spread (Figure 1(a)).20 As bacteria grow exponentially and spread from cell to cell, single invasion events lead to the formation of infection foci harboring numerous-infected cells within a few hours (Figure 1(b), WT). This is in contrast with the spreading-defective ΔicsA mutant that is fully invasive but does not spread from cell to cell and remains confined to primarily infected cells (Figure 1(b), ΔicsA).
The YrbE phospholipid transporter of Salmonella enterica serovar Typhi regulates the expression of flagellin and influences motility, adhesion and induction of epithelial inflammatory responses
Published in Gut Microbes, 2020
Smriti Verma, Rachel A. Prescott, Laura Ingano, Kourtney P. Nickerson, Emily Hill, Christina S. Faherty, Alessio Fasano, Stefania Senger, Bobby J. Cherayil
Since S. Typhi infection occurs following the ingestion of contaminated food or water, the early steps in pathogenesis involve adhesion to and invasion of the intestinal epithelium, particularly the follicle-associated epithelium overlying Peyer’s patches in the ileum.6,7 Because S. Typhi infects only humans, much of what we know about Salmonella–host interactions has been learnt from the study of S. Typhimurium, a broad host range serovar that infects a variety of animals, including laboratory mice.8 Although there are important differences between S. Typhi and S. Typhimurium with respect to genomic structure, host range, virulence factors and disease outcomes, the general mechanisms involved in infection are similar in the two pathogens.6,7,9–11 Following ingestion and transit through the proximal gut, Salmonella moves from the intestinal lumen to the epithelium using flagella-mediated motility and then adheres loosely to the epithelial cells by means of a variety of surface adhesins.12–16 Insertion of the Salmonella pathogenicity island 1 (SPI1)-encoded type III secretion system (TTSS) into the apical membrane of the epithelial cell follows, resulting in firm adhesion or docking.16,17 A number of bacterial effector proteins are then injected through the syringe-like SPI1 TTSS into the epithelial cytoplasm, leading to actin polymerization-mediated protrusions of the plasma membrane that ultimately engulf the bacteria within a membrane-bound vacuole.18 The bacteria are then translocated across the epithelium into the lamina propria and, in the case of S. Typhi, are disseminated to systemic tissues.19S. Typhimurium infection in humans is usually confined to the gastrointestinal tract, where it causes an acute inflammatory response that is responsible for the associated diarrhea, vomiting and abdominal pain.1,11 This response is attenuated by various mechanisms during S. Typhi infection, which may facilitate systemic spread of the pathogen and help to explain the relatively minor intestinal symptoms of typhoid.1