Salmonella Transiently Reside in Luminal Neutrophils in the Inflamed Gut

Abstract

Background Enteric pathogens need to grow efficiently in the gut lumen in order to cause disease and ensure transmission. The interior of the gut forms a complex environment comprising the mucosal surface area and the inner gut lumen with epithelial cell debris and food particles. Recruitment of neutrophils to the intestinal lumen is a hallmark of non-typhoidal Salmonella enterica infections in humans. Here, we analyzed the interaction of gut luminal neutrophils with S. enterica serovar Typhimurium ( S. Tm) in a mouse colitis model. Results Upon S. Tm wt infection, neutrophils transmigrate across the mucosa into the intestinal lumen. We detected a majority of pathogens associated with luminal neutrophils 20 hours after infection. Neutrophils are viable and actively engulf S. Tm, as demonstrated by live microscopy. Using S. Tm mutant strains defective in tissue invasion we show that pathogens are mostly taken up in the gut lumen at the epithelial barrier by luminal neutrophils. In these luminal neutrophils, S. Tm induces expression of genes typically required for its intracellular lifestyle such as siderophore production iroBCDE and the Salmonella pathogenicity island 2 encoded type three secretion system (TTSS-2). This shows that S. Tm at least transiently survives and responds to engulfment by gut luminal neutrophils. Gentamicin protection experiments suggest that the life-span of luminal neutrophils is limited and that S . Tm is subsequently released into the gut lumen. This “fast cycling” through the intracellular compartment of gut luminal neutrophils would explain the high fraction of TTSS-2 and iroBCDE expressing intra- and extracellular bacteria in the lumen of the infected gut. Conclusion In conclusion, live neutrophils recruited during acute S. Tm colitis engulf pathogens in the gut lumen and may thus actively engage in shaping the environment of pathogens and commensals in the inflamed gut.

Motile invaded neutrophils in the small intestine ofToxoplasma gondii-infected mice reveal a potential mechanism for parasite spread

“…Both Salmonella and Listeria can use myeloid cells to spread between host tissues, in some cases through active stimulation of cell motility (57)(58)(59). In addition, Salmonella infection stimulates the transepithelial migration of DCs and neutrophils into the gut lumen, and it has been proposed that CD18 + cells transport Salmonella from the intestinal lumen to the bloodstream (14,57,58,60). Using an in vivo model of oral T. gondii infection, we extend these findings by directly visualizing the migration and transepithelial passage of parasite-containing neutrophils and demonstrating that these cells can establish infection in new hosts.…”

“…Nevertheless, we have limited understanding of how and in which cells infection is established in the intestine, the extent to which the parasite replicates and spreads within the intestine, and how these factors contribute to the development of pathology (2, 4-9). The ability to label living parasites fluorescently and track them in the tissues of infected hosts provides an important tool for investigating these questions (10)(11)(12)(13)(14).Starting in the small intestine, T. gondii must travel long distances and surmount a variety of biological barriers to establish chronic infection in the brain. These barriers include the mucus, the intestinal epithelium, and the blood-brain barrier (7,15).…”

“…Nevertheless, we have limited understanding of how and in which cells infection is established in the intestine, the extent to which the parasite replicates and spreads within the intestine, and how these factors contribute to the development of pathology (2,(4)(5)(6)(7)(8)(9). The ability to label living parasites fluorescently and track them in the tissues of infected hosts provides an important tool for investigating these questions (10)(11)(12)(13)(14).…”

“…However, such techniques rarely have been applied to the intestine, particularly in the context of infection (14,(24)(25)(26)(27)(28). Here we used a physiologically relevant oral infection model in conjunction with two-photon microscopy to reveal that neutrophils in the lumen of the small intestine are motile reservoirs of live T. gondii.…”

Liver Abscesses as Pseudotumoral Lesions

“…Rearrangements of the actin cytoskeleton are brought about by elements of the bacterial type III protein secretion system, a virulence complex which activates the regulatory proteins, Cdc42 and Rac, to produce membrane ruffles that engulf the bacteria, while the pathogenicity island 2/SPI2 translocates effectors that promote intracellular survival and growth, associated with focal actin polymerization around the Salmonella-containing vacuole of the host cell (Guiney and Lesnick 2005). Salmonellae can also be taken up by host cells through macropinocytosis and phagocytosis, e.g., by luminal neutrophils in the inflamed gut during early infection (Loetscher et al 2012). Replicating bacteria within host cells can counteract the autophagy pathway and evade elimination via the induction of aggresome-like induced structures through the action of a translocated virulence protein, deubiquitinase (Thomas et al 2012).…”