Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation
Cell Genomics
Authors: Kyle D. Gibbs, Liuyang Wang, Zhuo Yang, Caroline E. Anderson, Jeffrey S. Bourgeois, Yanlu Cao, Margaret R. Gaggioli, Martin Biel, Rosa Puertollano, Cheng-Chang Chen, Dennis C. Ko
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.
COA
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