Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation

Human genetic diversity can reveal critical factors in host-pathogen interactions. This is especially useful for human-restricted pathogens like Salmonella enterica serovar Typhi ( S . Typhi), the cause of Typhoid fever. One key dynamic during infection is competition for nutrients: host cells attempt to restrict intracellular replication by depriving bacteria of key nutrients or delivering toxic metabolites in a process called nutritional immunity. Here, a cellular genome-wide association study of intracellular replication by S . Typhi in nearly a thousand cell lines from around the world—and extensive follow-up using intracellular S . Typhi transcriptomics and manipulation of magnesium concentrations—demonstrates that the divalent cation channel mucolipin-2 (MCOLN2) restricts S . Typhi intracellular replication through magnesium deprivation. Our results reveal natural diversity in Mg 2+ limitation as a key component of nutritional immunity against S . Typhi. One-Sentence Summary Human immune cells genetically vary in their ability to use magnesium deprivation to restrict growth of the typhoid fever bacterium.