Gaucher disease protects against tuberculosis

Proceedings of the National Academy of Sciences, vol. 120, pp. e2217673120

Abstract

Biallelic mutations in the glucocerebrosidase ( GBA1 ) gene cause Gaucher disease, characterized by lysosomal accumulation of glucosylceramide and glucosylsphingosine in macrophages. Gaucher and other lysosomal diseases occur with high frequency in Ashkenazi Jews. It has been proposed that the underlying mutations confer a selective advantage, in particular conferring protection against tuberculosis. Here, using a zebrafish Gaucher disease model, we find that the mutation GBA1 N370S, predominant among Ashkenazi Jews, increases resistance to tuberculosis through the microbicidal activity of glucosylsphingosine in macrophage lysosomes. Consistent with lysosomal accumulation occurring only in homozygotes, heterozygotes remain susceptible to tuberculosis. Thus, our findings reveal a mechanistic basis for protection against tuberculosis by GBA1 N370S and provide biological plausibility for its selection if the relatively mild deleterious effects in homozygotes were offset by significant protection against tuberculosis, a rampant killer of the young in Europe through the Middle Ages into the 19th century.

Authors 11

1. Jingwen Fan

   MRC Laboratory of Molecular Biology · University of Cambridge · Molecular Immunity Unit

   Affiliation as printed

   MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK

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

   Public Health

2. Victoria L. Hale

   MRC Laboratory of Molecular Biology

   Affiliation as printed

   MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK

   Public Health

3. Lindsey T. Lelieveld Aachen Department of Medical Biochemistry Leiden Institute of Chemistry

   Leiden University

   Affiliation as printed

   Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University 2333 CC, Leiden, The Netherlands

   Public Health

4. Laura J. Whitworth

   MRC Laboratory of Molecular Biology · University of Cambridge · Molecular Immunity Unit

   Affiliation as printed

   MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK

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

5. Elisabeth M. Busch‐Nentwich

   Queen Mary University of London · University of Cambridge · Molecular Immunity Unit

   Affiliation as printed

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

   School of Biological and Behavioral Sciences, Queen Mary University of London, London E1 4NS, UK

6. Mark A. Troll

   MRC Laboratory of Molecular Biology · University of Cambridge · Molecular Immunity Unit

   Affiliation as printed

   MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK

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

   Public Health

7. Paul H. Edelstein

   University of Cambridge · Molecular Immunity Unit · University of Pennsylvania

   Affiliation as printed

   Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104

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

   Public Health

8. Timothy Martin Cox

   University of Cambridge

   Affiliation as printed

   Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK

   Public Health

9. Francisco Jose Roca

   University of Cambridge · Instituto Murciano de Investigación Biosanitaria · Molecular Immunity Unit · Universidad de Murcia

   Affiliation as printed

   Biomedical Research Institute of Murcia Pascual Parrilla (IMIB-Arrixaca), Murcia 30120, Spain

   Department of Biochemistry and Molecular Biology B and Immunology, University of Murcia, Murcia 30120, Spain

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

   Public Health

10. Johannes M. F. G. Aerts Aachen Department of Medical Biochemistry Leiden Institute of Chemistry

    Leiden University

    Affiliation as printed

    Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University 2333 CC, Leiden, The Netherlands

    Public Health

11. Lalita Ramakrishnan corresponding

    MRC Laboratory of Molecular Biology · University of Cambridge · Molecular Immunity Unit

    Affiliation as printed

    MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK

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

    Public Health