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...

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Bibliographic Details
Published inbioRxiv
Main Authors Gibbs, Kyle D, Wang, Liuyang, Anderson, Caroline E, Bourgeois, Jeffrey S, Cao, Yanlu, Gaggioli, Margart R, Puertollano, Rosa, Ko, Dennis C
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 08.05.2022
Subjects
Cell lines
Genetic diversity
Genome-wide association studies
Genomes
Host-pathogen interactions
Intracellular
Magnesium
Nutrients
Pathogens
Replication
Salmonella
Transcriptomics
Typhoid
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Summary: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 Mg2+ limitation as a key component of nutritional immunity against S. Typhi. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://doi.org/10.7924/r4x92bd76
DOI:10.1101/2022.05.08.491078