Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation

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

doi:10.1016/j.xgen.2023.100290

Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation

Cell Genom. 2023 Apr 4;3(5):100290. doi: 10.1016/j.xgen.2023.100290. eCollection 2023 May 10.

Authors

Kyle D Gibbs¹, Liuyang Wang¹, Zhuo Yang², Caroline E Anderson¹, Jeffrey S Bourgeois^{1

3}, Yanlu Cao¹, Margaret R Gaggioli¹, Martin Biel², Rosa Puertollano⁴, Cheng-Chang Chen^{5

6}, Dennis C Ko^{1

3

7}

Affiliations

¹ Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA.
² Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany.
³ University Program in Genetics and Genomics, Duke University, Durham, NC 27710, USA.
⁴ Cell and Developmental Biology Center, National Heart, Lung, & Blood Institute, NIH, Bethesda, MD 20892, USA.
⁵ Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
⁶ Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
⁷ Division of Infectious Diseases, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA.

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.

Keywords: GWAS; Hi-HOST; MgtA; PhoPQ; RNA-seq; SPI-2; THP-1; eQTL; lymphoblastoid cell line; rs10873679.

Grants and funding

R01 AI118903/AI/NIAID NIH HHS/United States