title: Health trajectories reveal the dynamic contributions of host genetic resistance and tolerance to infection outcome.
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.
authors.affiliation: Genetics and Genomics Division, The Roslin Institute and R(D)SVS, University of Edinburgh, Edinburgh, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Lough
authors.affiliation: School of Agriculture, Food and Rural Development, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Ilias
authors.initials: I
authors.lastname: Kyriazakis
authors.affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Bergmann
authors.affiliation: Infection and Immunity Division, The Roslin Institute and R(D)SVS, University of Edinburgh, Edinburgh, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lengeling
authors.affiliation: Genetics and Genomics Division, The Roslin Institute and R(D)SVS, University of Edinburgh, Edinburgh, UK andrea.wilson@roslin.ed.ac.uk.
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Doeschl-Wilson
mesh_terms: D000818:Animals; D005260:Female; D014644:Genetic Variation; D007108:Immune Tolerance; D008089:Listeria monocytogenes / Q000502:physiology*; D008088:Listeriosis / Q000276:immunology / Q000382:microbiology / Q000662:veterinary*; D051379:Mice; D008815:Mice, Inbred Strains; D012376:Rodent Diseases / Q000276:immunology* / Q000382:microbiology
keywords: complex traits genetics; host response strategies; infection dynamics; resistance; tolerance; trajectories