Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation
Journal
Cell Genomics
Date Issued
2023
Author(s)
Gibbs, Kyle D.
Wang, Liuyang
Yang, Zhuo
Anderson, Caroline E.
Bourgeois, Jeffrey S.
Cao, Yanlu
Gaggioli, Margaret R.
Biel, Martin
Puertollano, Rosa
Ko, Dennis C.
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 defense during bacterial infection is nutritional immunity: host cells attempt to restrict bacterial replication by denying bacteria access to key nutrients or supplying toxic metabolites. 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 availability-demonstrates that the divalent cation channel mucolipin-2 (MCOLN2 or TRPML2) restricts S. Typhi intracellular replication through magnesium deprivation. Mg2+ currents, conducted through MCOLN2 and out of endolysosomes, were measured directly using patch-clamping of the endolysosomal membrane. Our results reveal Mg2+ limitation as a key component of nutritional immunity against S. Typhi and as a source of variable host resistance.
Type
journal article