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.

The effect of diet and time after bacterial infection on fecundity, resistance, and tolerance in Drosophila melanogaster

“…; Lough et al. ). Indeed, L. lactis‐ infected flies showed reduced survival at 168 HPI, suggesting that the bacteria or the host immune system damages the host later in the infection.…”

“…Disease tolerance tended to improve in mice that survived the initial acute infection phase, which was characterized by pathogen proliferation, and increased resistance in survivors (Lough et al. ). Our study examines tolerance at two timepoints across a range of pathogen densities, where tolerance does indeed change at each timepoint in question.…”

“…The importance of examining host responses at different timepoints after infection was underlined by a recent study on individual infection trajectories in mice (Lough et al. ). Individual mice that survived an infection exhibited a typical and reproducible pattern in their trajectories.…”

Use of multi-trait and random regression models to identify genetic variation in tolerance to porcine reproductive and respiratory syndrome virus

“…difference in exposure and onset of infection, differences in the individual immune status, co-infections), which can severely bias tolerance estimates and mask the underlying genetic signal [16, 18]. For this reason, empirical evidence for genetic variation in host tolerance to infections stems primarily from challenge experiments in inbred lines of model species [2, 50, 51]. The PHGC challenge data constitute a unique data source for investigating the genetic basis and relative importance of host resistance and tolerance in outbred pigs’ responses to virus infections, since it provides the required measures of both pathogen load and performance for large sample sizes, without the confounding factors inherent to field data.…”

Inbreeding shapes tuberculosis progression in female adult badgers (Meles meles)

“…Furthermore, recent scientific advances have demonstrated that the genetic background of hosts is one of the main drivers of host disease outcomes after exposure to pathogens and is what determines the host tolerance or resistance to infection (e.g. Chapman & Hill, ; Lough, Kyriazakis, Bergmann, Lengeling, & Doeschl‐Wilson, ). Therefore, understanding how inbreeding shapes disease dynamics in wild populations is crucial when considering the design and implementation of management strategies to control infection and limit disease dispersion.…”