Gaucher Disease Protects Against Tuberculosis
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract Biallelic mutations in the glucocerebrosidase ( GBA1 ) gene cause Gaucher disease, characterized by lysosomal accumulation of glucosylceramide and glucosylsphingosine in macrophages. This 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 19 th century. Significance Statement Gaucher disease is a recessively inherited disorder in which the lipids glucosylceramide and glucosylsphingosine accumulate in lysosomes of macrophages. Macrophages are the first immune cells to engulf infecting bacteria and we find that glucosylsphingosine increases their ability to kill Mycobacterium tuberculosis that causes tuberculosis. Gaucher disease due to a particular mutation is frequent in Ashkenazi Jews. Since from the middle ages they were often confined to areas of high tuberculosis prevalence, it has been proposed that the mutation prevailed because heterozygotes, who do not accumulate lipids nor manifest Gaucher disease, were protected. Our findings raise the possibility that selection operated on homozygotes manifesting mild forms of Gaucher disease who were protected against tuberculosis which would often have been fatal.
Authors 11
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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 0AW, UK
MRC Laboratory of Molecular Biology, Cambridge CB 0QH, UK
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MRC Laboratory of Molecular Biology
Affiliation as printed
MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK
MRC Laboratory of Molecular Biology, Cambridge CB 0QH, UK
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Affiliation as printed
Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands
Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, 2 CC Leiden, The Netherlands
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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 0AW, UK
MRC Laboratory of Molecular Biology, Cambridge CB 0QH, UK
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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 0AW, UK
School of Biological and Behavioral Sciences, Queen Mary University of London, London E1 4NS, England, UK
School of Biological and Behavioral Sciences, Queen Mary University of London, London E1 NS, England, UK
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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 0AW, UK
MRC Laboratory of Molecular Biology, Cambridge CB 0QH, UK
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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, Pennsylvania
Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0AW, UK
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Affiliation as printed
Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK
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University of Cambridge · Instituto Murciano de Investigación Biosanitaria · Molecular Immunity Unit · Universidad de Murcia
Affiliation as printed
Department of Biochemistry and Molecular Biology B and Immunology, Biomedical Research Institute of Murcia (IMIB-Arrixaca), University of Murcia, Murcia, Spain
Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0AW, UK
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Affiliation as printed
Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, 2333 CC Leiden, The Netherlands
Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, 2 CC Leiden, The Netherlands
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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 0AW, UK
MRC Laboratory of Molecular Biology, Cambridge CB 0QH, UK
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