Tracing Personalized Health Curves during Infections

Department of Microbiology and Immunology, Stanford University, Stanford, CA, United States of America.
PLoS Biology (Impact Factor: 11.77). 09/2011; 9(9):e1001158. DOI: 10.1371/journal.pbio.1001158
Source: PubMed

ABSTRACT It is difficult to describe host-microbe interactions in a manner that deals well with both pathogens and mutualists. Perhaps a way can be found using an ecological definition of tolerance, where tolerance is defined as the dose response curve of health versus parasite load. To plot tolerance, individual infections are summarized by reporting the maximum parasite load and the minimum health for a population of infected individuals and the slope of the resulting curve defines the tolerance of the population. We can borrow this method of plotting health versus microbe load in a population and make it apply to individuals; instead of plotting just one point that summarizes an infection in an individual, we can plot the values at many time points over the course of an infection for one individual. This produces curves that trace the course of an infection through phase space rather than over a more typical timeline. These curves highlight relationships like recovery and point out bifurcations that are difficult to visualize with standard plotting techniques. Only nine archetypical curves are needed to describe most pathogenic and mutualistic host-microbe interactions. The technique holds promise as both a qualitative and quantitative approach to dissect host-microbe interactions of all kinds.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hosts are likely to respond to parasitic infections by a combination of resistance (expulsion of pathogens) and tolerance (active mitigation of pathology). Of these strategies, the basis of tolerance in animal hosts is relatively poorly understood, with especially little known about how tolerance is manifested in natural populations. We monitored a natural population of field voles using longitudinal and cross-sectional sampling modes and taking measurements on body condition, infection, immune gene expression, and survival. Using analyses stratified by life history stage, we demonstrate a pattern of tolerance to macroparasites in mature compared to immature males. In comparison to immature males, mature males resisted infection less and instead increased investment in body condition in response to accumulating burdens, but at the expense of reduced reproductive effort. We identified expression of the transcription factor Gata3 (a mediator of Th2 immunity) as an immunological biomarker of this tolerance response. Time series data for individual animals suggested that macroparasite infections gave rise to increased expression of Gata3, which gave rise to improved body condition and enhanced survival as hosts aged. These findings provide a clear and unexpected insight into tolerance responses (and their life history sequelae) in a natural vertebrate population. The demonstration that such responses (potentially promoting parasite transmission) can move from resistance to tolerance through the course of an individual's lifetime emphasises the need to incorporate them into our understanding of the dynamics and risk of infection in the natural environment. Moreover, the identification of Gata3 as a marker of tolerance to macroparasites raises important new questions regarding the role of Th2 immunity and the mechanistic nature of the tolerance response itself. A more manipulative, experimental approach is likely to be valuable in elaborating this further.
    PLoS Biology 07/2014; 12(7):e1001901. DOI:10.1371/journal.pbio.1001901 · 12.69 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hosts may mitigate the impact of parasites by two broad strategies: resistance, which limits parasite burden, and tolerance, which limits the fitness or health cost of increasing parasite burden. The degree and causes of variation in both resistance and tolerance are expected to influence host-parasite evolutionary and epidemiological dynamics and inform disease management, yet very little empirical work has addressed tolerance in wild vertebrates. Here, we applied random regression models to longitudinal data from an unmanaged population of Soay sheep to estimate individual tolerance, defined as the rate of decline in body weight with increasing burden of highly prevalent gastrointestinal nematode parasites. On average, individuals lost weight as parasite burden increased, but whereas some lost weight slowly as burden increased (exhibiting high tolerance), other individuals lost weight significantly more rapidly (exhibiting low tolerance). We then investigated associations between tolerance and fitness using selection gradients that accounted for selection on correlated traits, including body weight. We found evidence for positive phenotypic selection on tolerance: on average, individuals who lost weight more slowly with increasing parasite burden had higher lifetime breeding success. This variation did not have an additive genetic basis. These results reveal that selection on tolerance operates under natural conditions. They also support theoretical predictions for the erosion of additive genetic variance of traits under strong directional selection and fixation of genes conferring tolerance. Our findings provide the first evidence of selection on individual tolerance of infection in animals and suggest practical applications in animal and human disease management in the face of highly prevalent parasites.
    PLoS Biology 07/2014; 12(7):e1001917. DOI:10.1371/journal.pbio.1001917 · 11.77 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nitric oxide (NO) and carbon monoxide (CO) are gasotransmitters that suppress the development of severe forms of malaria associated with Plasmodium infection. Here, we addressed the mechanism underlying their protective effect against experimental cerebral malaria (ECM), a severe form of malaria that develops in Plasmodium-infected mice, which resembles, in many aspects, human cerebral malaria (CM). NO suppresses the pathogenesis of ECM via a mechanism involving (1) the transcription factor nuclear factor erythroid 2-related factor 2 (NRF-2), (2) induction of heme oxygenase-1 (HO-1), and (3) CO production via heme catabolism by HO-1. The protection afforded by NO is associated with inhibition of CD4(+) T helper (TH) and CD8(+) cytotoxic (TC) T cell activation in response to Plasmodium infection via a mechanism involving HO-1 and CO. The protective effect of NO and CO is not associated with modulation of host pathogen load, suggesting that these gasotransmitters establish a crosstalk-conferring disease tolerance to Plasmodium infection.

Preview (2 Sources)

Available from