Health trajectories reveal the dynamic contributions of host genetic resistance and tolerance to infection outcome

Graham Lough, Ilias Kyriazakis, Silke Bergmann, Andreas Lengeling, Andrea B. Doeschl-Wilson*

*Corresponding author for this work

Research output: Contribution to journalArticle

20 Citations (Scopus)
6 Downloads (Pure)

Abstract

Resistance and tolerance are two alternative strategies hosts can adopt to survive infections. Both strategies may be genetically controlled. To date, the relative contribution of resistance and tolerance to infection outcome is poorly understood. Here, we use a bioluminescent Listeria monocytogenes (Lm) infection challenge model to study the genetic determination and dynamic contributions of host resistance and tolerance to listeriosis in four genetically diverse mouse strains. Using conventional statistical analyses, we detect significant genetic variation in both resistance and tolerance, but cannot capture the time-dependent relative importance of either host strategy. We overcome these limitations through the development of novel statistical tools to analyse individual infection trajectories portraying simultaneous changes in infection severity and health. Based on these tools, early expression of resistance followed by expression of tolerance emerge as important hallmarks for surviving Lm infections. Our trajectory analysis further reveals that survivors and non-survivors follow distinct infection paths (which are also genetically determined) and provides new survival thresholds as objective endpoints in infection experiments. Future studies may use trajectories as novel traits for mapping and identifying genes that control infection dynamics and outcome. A MATLAB script for user-friendly trajectory analysis is provided.

Original languageEnglish
Article number20152151
JournalProceedings of the Royal Society B: Biological Sciences
Volume282
Issue number1819
DOIs
Publication statusPublished - 18 Nov 2015

Keywords

  • Complex traits genetics
  • Host response strategies
  • Infection dynamics
  • Resistance
  • Tolerance
  • Trajectories

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Environmental Science(all)
  • Agricultural and Biological Sciences(all)

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