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Emergence of host-adapted Salmonella Enteritidis through rapid evolution in an immunocompromised host

Nature Microbiology volume 1, Article number: 15023 (2016) Cite this article

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Abstract

Host adaptation is a key factor contributing to the emergence of new bacterial, viral and parasitic pathogens. Many pathogens are considered promiscuous because they cause disease across a range of host species, while others are host-adapted, infecting particular hosts1. Host adaptation can potentially progress to host restriction, where the pathogen is strictly limited to a single host species and is frequently associated with more severe symptoms. Host-adapted and host-restricted bacterial clades evolve from within a broader host-promiscuous species and sometimes target different niches within their specialist hosts, such as adapting from a mucosal to a systemic lifestyle. Genome degradation, marked by gene inactivation and deletion, is a key feature of host adaptation, although the triggers initiating genome degradation are not well understood. Here, we show that a chronic systemic non-typhoidal Salmonella infection in an immunocompromised human patient resulted in genome degradation targeting genes that are expendable for a systemic lifestyle. We present a genome-based investigation of a recurrent blood-borne Salmonella enterica serotype Enteritidis (S. Enteritidis) infection covering 15 years in an interleukin-12 β1 receptor-deficient individual that developed into an asymptomatic chronic infection. The infecting S. Enteritidis harboured a mutation in the mismatch repair gene mutS that accelerated the genomic mutation rate. Phylogenetic analysis and phenotyping of multiple patient isolates provides evidence for a remarkable level of within-host evolution that parallels genome changes present in successful host-restricted bacterial pathogens but never before observed on this timescale. Our analysis identifies common pathways of host adaptation and demonstrates the role that immunocompromised individuals can play in this process.

Host adaptation is central to pathogen evolution and is a founding element in the emergence of many classical and emerging diseases such as typhoid, whooping cough and bubonic plague. For example, typhoid fever is caused by the human-restricted genetic clades Salmonella Typhi and S. Paratyphi A, which evolved independently within the broadly promiscuous Salmonella enterica species. Genome analysis of host-restricted pathogens has linked host adaptation with both gene acquisition and genome degradation2,3. Loss of coding capacity by pseudogene formation or deletion is thought to proceed through a combination of neutral or mildly deleterious mutations becoming fixed in the population during evolutionary bottlenecks and positive selection for the loss of function of genes no longer required or disadvantageous in the new host or environmental niche3–5. S. enterica is a diverse species that harbours both host-promiscuous and host-adapted clades. S. enterica serovars such as Typhimurium and Enteritidis are predominantly associated with gastroenteritis, a disease normally self-limiting to the intestine. However, bacteraemia can occur even with non-typhoidal serovars, and this is frequently associated with malnutrition, human immunodeficiency virus infection, or primary immune deficiencies such as mutations in interleukins (IL)-12 and -23 and their receptors6–8.

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Figure 1: Phylogeny of S. Enteritidis gastroenteritis isolates and blood isolates from the IL-12 β1 receptor-deficient patient.
Figure 2: Patient isolates have acquired a large number of pseudogenes.
Figure 3: Colonization of the murine host and interaction with epithelial-like cells by patient isolates.

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Acknowledgements

The authors thank D. Harris, G. Langridge and the Pathogen Informatics team for help with sequencing and bioinformatics and the Sanger Institute Research Support Facility for help with the animal studies. This work was funded by the Wellcome Trust through core funding for the Sanger Institute Pathogen Variation Group.

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Author notes

  1. Gordon Dougan and Robert A. Kingsley: These authors contributed equally to this work.

Authors and Affiliations

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

    Elizabeth J. Klemm, James Hadfield, Jessica L. Forbester, Simon R. Harris, Christine Hale, Thomas Wileman, Simon Clare, Leanne Kane, David Goulding, Thomas D. Otto, Sally Kay, Julian Parkhill, Calman A. MacLennan, Gordon Dougan & Robert A. Kingsley

  2. Department of Infectious Diseases, Cambridge University Hospitals, CB2 0QQ, Cambridge, UK

    Effrossyni Gkrania-Klotsas & Andrew Carmichael

  3. Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, CB2 0QQ, Cambridge, UK

    Effrossyni Gkrania-Klotsas

  4. School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, B15 2TT, Birmingham, UK

    Jennifer N. Heath & Calman A. MacLennan

  5. Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, CB2 0QQ, Cambridge, UK

    Rainer Doffinger & Dinakantha Kumararatne

  6. Clinical Microbiology and Public Health Laboratory, Addenbrooke's Hospital, CB2 0QQ, Cambridge, UK

    Fiona J. Cooke

  7. Department of Medicine, University of Cambridge, CB2 0SP, Cambridge, UK

    Andrew M. L. Lever & Gordon Dougan

  8. The Institute of Food Research, Norwich Research Park, Norwich, NR4 7UA, Norfolk, UK

    Robert A. Kingsley

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Contributions

R.A.K. and G.D. designed the study. E.J.K., D.K., R.D., A.C., A.M.L.L., J.H., R.A.K., E.G.K., J.H., J.F., S.C., L.K., S.K., D.G., T.W., C.H. and F.J.C. collected the data. E.J.K., R.A.K., T.D.O., J.F., J.P., S.H. and C.M. analysed the data. E.J.K., R.A.K., G.D., E.G.K. and J.P. wrote the manuscript.

Corresponding author

Correspondence to Robert A. Kingsley.

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The authors declare no competing financial interests.

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Supplementary Figures 1–10, Tables I–V, Discussion and References (PDF 3741 kb)

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Klemm, E., Gkrania-Klotsas, E., Hadfield, J. et al. Emergence of host-adapted Salmonella Enteritidis through rapid evolution in an immunocompromised host. Nat Microbiol 1, 15023 (2016). https://doi.org/10.1038/nmicrobiol.2015.23

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