Following systemic infection, Salmonella spp. colonize the gall bladder from the liver. Bacteria can replicate extracellularly in the lumen or can actively invade the gall bladder epithelium in a Salmonella pathogenicity island 1 (sPI-1)-dependent manner (step 1). Although the bacteria can replicate inside the epithelial cells, in the Salmonella-containing vacuole (sCV), they do not translocate to the lamina propria and mucosa. This intracellular infection leads to a local inflammatory response (step 2) mediated by neutrophils (step 3), with subsequent tissue damage and epithelial sloughing (step 4). This could lead to the release of Salmonella spp. cells into the lumen for invasion of new epithelial cells. Based on data from REF. 41.

a | Electron micrograph of Salmonella enterica subsp. enterica serovar Typhi in a biofilm on the surface of a human gallstone. b | S. Typhi probably gains access to the gall bladder during the acute phase of infection and initially attaches to gallstone surfaces through a specific interaction between flagellin and cholesterol. This initial binding could be facilitated by outer-membrane protein C (ompC). Subsequent attachment of bacteria is aided by the presence of, but not motility mediated by, flagella^59,62. On cholesterol, biofilm formation is dependent on the presence of exopolysaccharide (green), probably including the o antigen capsule⁵⁵. Detachment of bacteria from the biofilm would allow entry into the intestine via bile, followed by shedding in the faeces and urine⁷⁰. c | A possible alternative strategy by which S. Typhi persists in the gall bladder is through invasion of gall bladder epithelial cells. In this model, invasive bacteria replicate intracellularly, and shedding could occur as a part of epithelial regeneration, wherein gall bladder epithelial cells containing S. Typhi would be extruded to the lumen, and released bacteria could infect new cells or be shed into the intestine via bile⁸².