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Related Experiment Video

Updated: Aug 11, 2025

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Gaucher disease protects against tuberculosis.

Jingwen Fan1,2, Victoria L Hale2, Lindsey T Lelieveld3

  • 1Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK.

Proceedings of the National Academy of Sciences of the United States of America
|February 6, 2023
PubMed
Summary

The Gaucher disease mutation GBA1 N370S enhances tuberculosis resistance in zebrafish by increasing microbicidal activity. This explains its prevalence in Ashkenazi Jews, as heterozygotes are susceptible, but homozygotes gain protection.

Keywords:
Gaucher diseaselysosomal glucosylsphingosinemacrophagestuberculosis resistancezebrafish

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Area of Science:

  • Genetics
  • Immunology
  • Microbiology

Background:

  • Gaucher disease results from GBA1 gene mutations, causing lysosomal storage. This disease and related lysosomal disorders are prevalent in Ashkenazi Jews.
  • A proposed hypothesis suggests GBA1 mutations offer a selective advantage, specifically protection against tuberculosis.

Purpose of the Study:

  • To investigate the protective mechanism of the GBA1 N370S mutation against tuberculosis using a zebrafish model.
  • To explore the role of glucosylsphingosine in macrophage lysosomes in conferring resistance.

Main Methods:

  • Utilized a zebrafish model of Gaucher disease.
  • Analyzed the impact of the GBA1 N370S mutation on tuberculosis resistance.
  • Examined the microbicidal activity of glucosylsphingosine in macrophage lysosomes.

Main Results:

  • The GBA1 N370S mutation significantly increased resistance to tuberculosis in the zebrafish model.
  • Glucosylsphingosine within macrophage lysosomes demonstrated microbicidal activity against tuberculosis.
  • Heterozygotes for the mutation remained susceptible to tuberculosis, unlike homozygotes.

Conclusions:

  • The study reveals a mechanistic basis for tuberculosis protection conferred by the GBA1 N370S mutation.
  • The findings provide biological plausibility for the selection of GBA1 N370S due to protection against tuberculosis, a historical major cause of mortality.