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Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation

Kyle D Gibbs1, Liuyang Wang1, Zhuo Yang2

  • 1Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA.

Cell Genomics
|May 25, 2023
PubMed

Insights

Human genetic diversity impacts host-pathogen interactions. A study shows mucolipin-2 (MCOLN2) restricts Salmonella Typhi by limiting magnesium, revealing a key nutritional immunity mechanism.

Area of Science:

  • Immunology
  • Genetics
  • Microbiology

Background:

  • Host-pathogen interactions are influenced by human genetic diversity.
  • Salmonella enterica serovar Typhi (S. Typhi) causes typhoid fever and is restricted to humans.
  • Nutritional immunity is a host defense mechanism that limits pathogen replication by controlling nutrient availability or introducing toxic metabolites.

Purpose of the Study:

  • To investigate the genetic factors influencing intracellular replication of S. Typhi.
  • To identify host cell mechanisms contributing to resistance against S. Typhi infection.
  • To elucidate the role of divalent cation channels in host defense against bacterial pathogens.

Main Methods:

  • Conducted a cellular genome-wide association study (GWAS) using nearly a thousand worldwide human cell lines to assess intracellular S. Typhi replication.
  • Performed intracellular S. Typhi transcriptomics and manipulated magnesium availability.
  • Measured Mg2+ currents directly using patch-clamping of the endolysosomal membrane.

Main Results:

  • Demonstrated that mucolipin-2 (MCOLN2 or TRPML2) restricts intracellular S. Typhi replication.
  • Identified magnesium deprivation as the mechanism by which MCOLN2 restricts S. Typhi.
  • Showed that Mg2+ currents conducted through MCOLN2 limit S. Typhi growth within endolysosomes.

Conclusions:

  • Magnesium limitation is a critical component of nutritional immunity against S. Typhi.
  • MCOLN2 plays a significant role in host resistance to S. Typhi by controlling magnesium levels.
  • Human genetic variations in MCOLN2 may contribute to variable host resistance against typhoid fever.
Keywords:
GWASHi-HOSTMgtAPhoPQRNA-seqSPI-2THP-1eQTLlymphoblastoid cell liners10873679

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