What sets S. Typhi apart from the many mediocre strains of Salmonella? S. Typhi is virulent, equipped with the offensive and defensive weapons that pacify it’s host. It can cross the gut epithelium with impunity and then fend off the hostile forces that await: antibodies, neutrophils, macrophages, dendritic cells, T and B lymphocytes, and dreaded complement. It moves through M cells or enterocytes by allowing itself to be engulfed into a phagosome, then releasing effector molecules that prevent the vacuole from fusing with a lethal lysosome. By sheltering in a macrophage, the microbe both evades counterattacks and is carried throughout the host by the circulating macrophage: Invasion by Evasion.

Salmonella Typhi is weaponized with Salmonella Pacification Islands, contiguous collections of genes that are dropped as a module onto the Salmonella chromosome. With the 25 genes of SPI1, Salmonella enters epithelial cells by deploying a type-3 protein secretion system to shoot effector proteins into host cells, producing ruffling membranes through which it burrows in. SPI2, with about 15 genes, enables Salmonella to defilade and proliferate within a macrophage.

From defense to offense: within a host cell, S. Typhi releases Typhoid Toxin, a powerful exotoxin that preferentially attacks the target’s immune system and the central nervous system. An SPI containing 5 genes provides the firepower.