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bioRxiv · 10.1101/2022.05.08.491078

Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation

Gibbs, K. D.·Wang, L.·Anderson, C. E.·Bourgeois, J. S.·Cao, Y.·Gaggioli, M. R.·Puertollano, R.·Ko, D. C.
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Abstract

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. One-Sentence SummaryHuman immune cells genetically vary in their ability to use magnesium deprivation to restrict growth of the typhoid fever bacterium.

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Gibbs, K. D., Wang, L., Anderson, C. E., Bourgeois, J. S., Cao, Y., Gaggioli, M. R., Puertollano, R., Ko, D. C.. 2022-05-08. Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation. https://doi.org/10.1101/2022.05.08.491078

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