Shifting focus from resistance to disease tolerance

Parasites have been proposed to modulate the fitness of hybridizing hosts in part based on observations in the European house mouse hybrid zone (HMHZ), a tension zone in which hybrids show reduced fitness. We here review evidence (1) for parasite load differences in hybrid versus parental mice and (2) for health and fitness effects of parasites promoting or preventing introgression and hybridization. The question of relative resistance or susceptibility of hybrids to parasites in the HMHZ has long been controversial. Recent field studies found hybrids to be more resistant than mice from parental subspecies against infections with pinworms and protozoans (Eimeria spp.). We argue that the field studies underlying the contradictory impression of hybrid susceptibility have limitations in sample size, statistical analysis and scope, focusing only on macroparasites. We suggest that weighted evidence from field studies indicate hybrid resistance. Health is a fitness component through which resistance can modulate overall fitness. Resistance, however, should not be extrapolated directly to a fitness effect, as the relationship between resistance and health can be modulated by tolerance. In our own recent work, we found that the relationship between health and resistance (tolerance) differs between infections with the related species E. falciformis and E. ferrisi. Health and tolerance need to be assessed directly and the choice of parasite has made this difficult in previous experimental studies of house mice. We discuss how experimental Eimeria spp. infections in hybrid house mice can address resistance, health and tolerance in conjunction

DNA-based quantification and counting of transmission stages provides different but complementary parasite load estimates: an example from rodent coccidia (Eimeria)

Background: Counting parasite transmission stages in faeces is the classical measurement to quantify “parasite load”. DNA-based quantifications of parasite intensities from faecal samples are relatively novel and often validated against such counts. When microscopic and molecular quantifications do not correlate, it is unclear whether oocyst counts or DNA-based intensity better reflects biologically meaningful concepts. Here, we investigate this issue using the example of Eimeria ferrisi (Coccidia), an intracellular parasite of house mice (Mus musculus). Methods: We performed an infection experiment of house mice with E. ferrisi, in which the intensity of infection correlates with increased health impact on the host, measured as temporary weight loss during infection. We recorded the number of parasite transmissive stages (oocysts) per gram of faeces (OPG) and, as a DNA-based measurement, the number of Eimeria genome copies per gram of faeces for 10 days post-infection (dpi). We assessed weight loss relative to the day of experimental infection as a proxy of host health and evaluated whether DNA or oocyst counts are better predictors of host health. Results: Absolute quantification of Eimeria DNA and oocyst counts showed similar but slightly diverging temporal patterns during 10 dpi. We detected Eimeria DNA earlier than the first appearance of oocysts in faeces. Additionally, Eimeria OPGs within each dpi did not explain parasite DNA intensity. Early dpi were characterized by high DNA intensity with low oocyst counts, while late infections showed the opposite pattern. The intensity of Eimeria DNA was consistently a stronger predictor of either maximal weight loss (1 value per animal during the infection course) or weight loss on each day during the experiment when controlling for between-dpi and between-individual variance. Conclusions: Eimeria ferrisi oocyst counts correlate weakly with parasite intensity assessed through DNA quantification. DNA is likely partially derived from life-cycle stages other than transmissive oocysts. DNA-based intensities predict health outcomes of infection for the host more robustly than counts of transmissive stages. We conclude that DNA-based quantifications should not necessarily require validation against counts of transmissive stages. Instead, DNA-based load estimates should be evaluated as complementary sources of information with potential specific biological relevance for each host-parasite system

Intensity of infection with intracellular Eimeria spp. and pinworms is reduced in hybrid mice compared to parental subspecies

Genetic diversity in animal immune systems is usually beneficial. In hybrid recombinants, this is less clear, as the immune system could also be impacted by genetic conflicts. In the European house mouse hybrid zone, the long‐standing impression that hybrid mice are more highly parasitized and less fit than parentals persists despite the findings of recent studies. Working across a novel transect, we assessed infections by intracellular protozoans, Eimeria spp., and infections by extracellular macroparasites, pinworms. For Eimeria, we found lower intensities in hybrid hosts than in parental mice but no evidence of lowered probability of infection or increased mortality in the centre of the hybrid zone. This means ecological factors are very unlikely to be responsible for the reduced load of infected hybrids. Focusing on parasite intensity (load in infected hosts), we also corroborated reduced pinworm loads reported for hybrid mice in previous studies. We conclude that intensity of diverse parasites, including the previously unstudied Eimeria, is reduced in hybrid mice compared to parental subspecies. We suggest caution in extrapolating this to differences in hybrid host fitness in the absence of, for example, evidence for a link between parasitemia and health.Peer Reviewe

alicebalard/parasiteLoad: Used in article Balard et al.

Parasite load / parasite prevalence across HZ. Adapted from S. Baird

Resistenz und Toleranz gegenüber Eimeria in der europäischen Hausmaus-Hybridzone

Genetic diversity in animal hybrids can affect each physiological system differently. If reproduction usually suffers from breakdown of coadapted complexes, resistance to parasite could benefit from the novelty brought by recombination. The question of hybrid relative resistance or susceptibility to parasites in the European house mouse hybrid zone has been discussed for the past thirty years, leading to contradictory conclusions on relative hybrid fitness. But drawing conclusions on hybrid host fitness in relation to parasites requires first to investigate the link between resistance and host health. Resistance (the host’s capacity to reduce parasite burden) and tolerance (the host’s capacity to reduce impact on host health of a given parasite burden) manifest two different lines of immune defences. Trade-offs arise, as resistance limits infection load and thereby the scope of possible tolerance, and both resistance and tolerance can be costly in terms of resource allocation. During this PhD project, we assessed infections by intracellular protozoans, Eimeria spp., using field sampling and laboratory infection of wild and wild-derived mice from a hybrid zone between \textit{Mus musculus domesticus} and \textit{Mus musculus musculus}. We asked (1) whether hybrid mice are more or less resistant than their parents and (2) how resistance and tolerance are correlated, this correlation potentially differing between Eimeria species. We found lower intensities in hybrid hosts than in parental mice and no evidence of lowered probability of infection or increased mortality in the centre of the hybrid zone. This challenges the longstanding impression that hybrid mice are more highly parasitised than parentals. Upon experimental infection, we found a trade-off between resistance and tolerance in E. falciformis, but not in E. ferrisi. Building on previous research showing that resistance and tolerance should be studied jointly, our results show that assumptions on coupling of the two can not be transferred across even closely related parasite taxa. We showed that the impact of parasitism on hybrid fitness is a complex matter that needs to be investigated for each parasite beyond the measurement of hybrid vigour on resistance, taking into account possible trade-offs between resistance and tolerance

The Social Inclusion of Older People in France : Social Participation, Loneliness and Giving

International audienceThe social exclusion of older people challenges the notion of ag-ing well, both from a scientific and a political perspective. In this con-text, the responses brought to this issue through public policies may vary depending on the diverse scientific theories they are built upon. In France, the first political response to the social exclusion of older people has been the social inclusion policies of the 1960s. In later years, the growing medicalization of old-age policies contributed to relegating this issue to the background, until it resurfaced in the early 2000s with the abnormally high death toll of the 2003 heat wave. The notion of loneliness then replaced social exclusion, highlighting a lack of social cohesion where older people are concerned. The fight against isolation and loneliness became a national cause and was handed over to local stakeholders.This paper analyzes the design and implementation of projects and initiatives targeting older people, and discusses a survey of old-er people examining feelings of loneliness and/or uselessness. We will begin with a brief overview of theories on successful aging, to show how the question of social exclusion eventually came to the forefront. We will then examine the evolution of this notion in French old-age policies. Finally, we will present the findings of the VIEU project, offering avenues of reflection to consider social inclusion from a new perspectiv

Detection and quantification of house mouse Eimeria at the species level

Detection and quantification of coccidia in studies of wildlife can be challenging. Therefore, prevalence of coccidia is often not assessed at the parasite species level in non-livestock animals. Parasite species – specific prevalences are especially important when studying evolutionary questions in wild populations. We tested whether increased host population density increases prevalence of individual Eimeria species at the farm level, as predicted by epidemiological theory. We studied free-living commensal populations of the house mouse (Mus musculus) in Germany, and established a strategy to detect and quantify Eimeria infections. We show that a novel diagnostic primer targeting the apicoplast genome (Ap5) and coprological assessment after flotation provide complementary detection results increasing sensitivity. Genotyping PCRs confirm detection in a subset of samples and cross-validation of different PCR markers does not indicate bias towards a particular parasite species in genotyping. We were able to detect double infections and to determine the preferred niche of each parasite species along the distal-proximal axis of the intestine. Parasite genotyping from tissue samples provides additional indication for the absence of species bias in genotyping amplifications. Three Eimeria species were found infecting house mice at different prevalences: Eimeria ferrisi (16.7%; 95% CI 13.2–20.7), E. falciformis (4.2%; 95% CI 2.6–6.8) and E. vermiformis (1.9%; 95% CI 0.9–3.8). We also find that mice in dense populations are more likely to be infected with E. falciformis and E. ferrisi. We provide methods for the assessment of prevalences of coccidia at the species level in rodent systems. We show and discuss how such data can help to test hypotheses in ecology, evolution and epidemiology on a species level.Peer Reviewe

Coupling between tolerance and resistance for two related Eimeria parasite species

Resistance (host capacity to reduce parasite burden) and tolerance (host capacity to reduce impact on its health for a given parasite burden) manifest two different lines of defense. Tolerance can be independent from resistance, traded off against it, or the two can be positively correlated because of redundancy in underlying (immune) processes. We here tested whether this coupling between tolerance and resistance could differ upon infection with closely related parasite species. We tested this in experimental infections with two parasite species of the genus Eimeria. We measured proxies for resistance (the (inverse of) number of parasite transmission stages (oocysts) per gram of feces at the day of maximal shedding) and tolerance (the slope of maximum relative weight loss compared to day of infection on number of oocysts per gram of feces at the day of maximal shedding for each host strain) in four inbred mouse strains and four groups of F1 hybrids belonging to two mouse subspecies, Mus musculus domesticus and Mus musculus musculus. We found a negative correlation between resistance and tolerance against Eimeria falciformis, while the two are uncoupled against Eimeria ferrisi. We conclude that resistance and tolerance against the first parasite species might be traded off, but evolve more independently in different mouse genotypes against the latter. We argue that evolution of the host immune defenses can be studied largely irrespective of parasite isolates if resistance?tolerance coupling is absent or weak (E. ferrisi) but host?parasite coevolution is more likely observable and best studied in a system with negatively correlated tolerance and resistance (E. falciformis)

Generalist Eimeria species in rodents

Intracellular parasites of the genus Eimeria are described as tissue/host-specific. Phylogenetic classification of rodent Eimeria suggested that some species have a broader host range than previously assumed. We explore whether Eimeria spp. infecting house mice are misclassified by the most widely used molecular markers due to a lack of resolution, or whether, instead, these parasite species are indeed infecting multiple host species. With the commonly used markers (18S/COI), we recovered monophyletic clades of E. falciformis and E. vermiformis from Mus that included E. apionodes identified in other rodent host species (Apodemus spp., Myodes glareolus, and Microtus arvalis). A lack of internal resolution in these clades could suggest the existence of a species complex with a wide host range infecting murid and cricetid rodents. We question, however, the power of COI and 18S markers to provide adequate resolution for assessing host specificity. In addition to the rarely used marker ORF470 from the apicoplast genome, we present multilocus genotyping as an alternative approach. Phylogenetic analysis of 35 nuclear markers differentiated E. falciformis from house mice from isolates from Apodemus hosts. Isolates of E. vermiformis from Mus are still found in clusters interspersed with non-Mus isolates, even with this high-resolution data. In conclusion, we show that species-level resolution should not be assumed for COI and 18S markers in coccidia. Host–parasite cospeciation at shallow phylogenetic nodes, as well as contemporary coccidian host ranges more generally, is still open questions that need to be addressed using novel genetic markers with higher resolution.Peer Reviewe