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  • Review Article
  • Published:

Genetic susceptibility to invasive Salmonella disease

Nature Reviews Immunology volume 15, pages 452–463 (2015)Cite this article

Subjects

An Erratum to this article was published on 28 August 2015

This article has been updated

Key Points

  • Invasive Salmonella disease comprises enteric fever (caused by Salmonella enterica subsp. enterica serovar Typhi and S. enterica serovars Paratyphi A, B and C) and invasive non-typhoidal Salmonella (iNTS) disease (caused by NTS serovars, most notably S. enterica serovar Typhimurium and S. enterica serovar Enteritidis). Both diseases impose a substantial burden of morbidity and mortality globally, for which adequate control measures are lacking.

  • In this Review, we discuss data from population-based studies of enteric fever and primary immunodeficiencies resulting in susceptibility to iNTS disease. These studies are presented in the context of the well-defined mouse model of invasive Salmonella infection.

  • The study of primary immunodeficiencies, in part characterized by iNTS disease, has established the critical role of interferon-γ (IFNγ) production and IFNγ-induced effector mechanisms (in particular oxidative burst) in human immunity to NTS. These studies have helped to define the role of T helper 1 (TH1) cells in mediating the outcome of intracellular NTS infection, and have been complemented by more recent data describing the roles of TH17 lineage CD4+ T cells and neutrophils in human NTS immunity.

  • The recent publication of the first genome-wide association study of invasive Salmonella disease provides robust evidence for a host genetic determinant of enteric fever in human populations. Its identification of an MHC class II allele as a determinant of enteric fever susceptibility is in keeping with our broader understanding of immunity against Salmonella from the mouse model and human primary immunodeficiencies.

  • Our increasing understanding of the host genetic determinants of iNTS disease and enteric fever is improving our understanding of the immunobiology of invasive Salmonella infection and will inform the delivery of novel control strategies.

Abstract

Invasive Salmonella disease, in the form of enteric fever and invasive non-typhoidal Salmonella (iNTS) disease, causes substantial morbidity and mortality in children and adults in the developing world. The study of genetic variations in humans and mice that influence susceptibility of the host to Salmonella infection provides important insights into immunity to Salmonella. In this Review, we discuss data that have helped to elucidate the host genetic determinants of human enteric fever and iNTS disease, alongside data from the mouse model of Salmonella infection. Considered together, these studies provide a detailed picture of the immunobiology of human invasive Salmonella disease.

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Figure 1: The global distribution of invasive Salmonella disease.
Figure 2: TLR signalling in response to Salmonella PAMPs.
Figure 3: IL-12-dependent IFNγ-mediated immunity and IL-23 signalling in response to Salmonella infection.

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Change history

  • 28 August 2015

    In the original version of this article, the credit line in the legend of Figure 1 was incorrect and should read: “Copyright 2014 from 'Vaccines against invasive Salmonella disease: current status and future directions' by MacLennan, C. A., Martin, L. B. & Micoli, F. Reproduced by permission of Taylor & Francis LLC (http://www.tandfonline.com).”. This has now been corrected online.

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Acknowledgements

The authors thank P. Mastroeni and D. Holden for their comments on the manuscript.

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Authors and Affiliations

  1. Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, OX3 7BN, UK

    James J. Gilchrist & Adrian V. S. Hill

  2. Nuffield Department of Medicine, Jenner Institute, Old Road Campus Research Building, Roosevelt Drive, University of Oxford, Oxford, OX3 7DQ, UK

    Calman A. MacLennan & Adrian V. S. Hill

  3. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, Cambridge, UK

    Calman A. MacLennan

Authors
  1. James J. Gilchrist
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  2. Calman A. MacLennan
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  3. Adrian V. S. Hill
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Corresponding authors

Correspondence to James J. Gilchrist, Calman A. MacLennan or Adrian V. S. Hill.

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Competing interests

C.A.M. is the recipient of a clinical research fellowship from GlaxoSmithKline. J.J.G. and A.V.S.H. declare no competing interests.

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Supplementary information S1 (table)

Genetic variation resulting in invasive Salmonella susceptibility in humans and mice (PDF 356 kb)

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Glossary

Genome-wide association study

(GWAS). Hypothesis-free genetic association study that tests for associations between a trait of interest and variation at millions of single nucleotide polymorphisms across the genome.

Candidate gene studies

Genetic case-control studies in which the exposure of interest is variation at a genetic locus chosen according to a prior biological hypothesis.

Hypomorphic mutations

Mutations resulting in decreased function of the encoded protein.

Ectodermal dysplasia

A genetically and phenotypically heterogeneous group of congenital disorders characterized by abnormal hair and teeth, and reduced perspiration.

Hypermorphic mutations

Mutations that lead to increased function of the encoded protein.

Missense mutation

Mutation resulting in an amino acid change in the encoded protein product.

Nonsense mutation

Mutation resulting in a premature stop codon in the encoded transcript.

Inflammasome

Cytosolic multi-protein complex composed of an innate pattern-recognition receptor, an adaptor molecule and a pro-inflammatory effector caspase.

Pyroptosis

Pro-inflammatory programmed cell death, with cell lysis alongside pro-inflammatory cytokine release.

Autophagy

Cellular process targeting cytoplasmic contents, including cytoplasmic pathogens, for lysosomal degradation via the formation of double-membraned, intracellular autophagosomes.

Haematocrit

The proportion, by volume, of blood that is composed of red blood cells.

Siderophores

High-affinity iron-binding molecules that facilitate the sequestration of iron by microorganisms.

Hereditary haemochromatosis

Common autosomal recessive disorder characterized by iron overload and secondary organ dysfunction, most frequently caused by mutations in the HFE gene.

Severe combined immunodeficiency

A group of congenital immunodeficiencies defined by deficient T cell, B cell and/or natural killer cell lineages.

DiGeorge syndrome

Syndrome of hypoplastic thymus and parathyroid glands and congenital cardiac disease, caused by a 22q11.2 deletion.

Imputation

Statistical estimation of genotype information not directly assayed, by inference from surrounding genotype data and densely genotyped reference panels.

X-linked agammaglobulinaemia

Primary immunodeficiency secondary to mutations in Bruton's tyrosine kinase (BTK) resulting in defective B cell development with hypogammaglobulinaemia and reduced circulating B cells.

X-linked hyper IgM syndrome

Primary immunodeficiency secondary to mutations in the CD4+ T cell surface-expressed molecule CD40 ligand (CD40LG; also known as CD154), resulting in defective B cell activation and isotype switching.

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Gilchrist, J., MacLennan, C. & Hill, A. Genetic susceptibility to invasive Salmonella disease. Nat Rev Immunol 15, 452–463 (2015). https://doi.org/10.1038/nri3858

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