Evolution of virulence in immune-compromised hosts and the adaptation of emerging viruses

Projektinformationen

EvolVir

ID Finanzhilfevereinbarung: 701591

DOI

10.3030/701591

Projekt abgeschlossen

EK-Unterschriftsdatum 4 April 2016

Startdatum 1 Juli 2017

Enddatum 30 Juni 2019

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 195 454,80

EU-Beitrag

€ 195 454,80

Koordiniert durch

THE UNIVERSITY OF EDINBURGH
United Kingdom

Periodic Reporting for period 1 - EvolVir (Evolution of virulence in immune-compromised hosts and the adaptation of emerging viruses)

Berichtszeitraum: 2017-07-01 bis 2019-06-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Variation in resistance to infection is widespread in natural populations, and it is common to find not only extremely resistant individuals, but also individuals who are extremely susceptible to infection. Individuals that are inherently more susceptible to disease may arise due to specific genetic background, or due to other physiological aspects such as sex, age, nutrition levels or prior infection history.
In host-pathogen systems, theory predicts that host resistance mechanisms impose strong selection on pathogens, which in turn evolve counter-defences to avoid those mechanisms. While pathogen mediated selection is thought to drive genetic variation in host resistance levels, host immunity is also a strong evolutionary force shaping patterns of pathogen virulence. Some theory predicts that highest host resistance will favour the evolution of increased pathogen virulence.
The aim of this project was to test the role of immune-compromised hosts on the evolution of pathogen virulence, and to dissect the mechanisms that underpin pathogen evolution and transmission in hosts with variable immune responses. Using model fruit flies, I explored the effect of variable host resistance mechanisms on 1) the evolutionary trajectories of pathogens and 2) their spreading capacities. Drosophila offers unique tools and methods to address the effect of host immune-competence as both immune response and gene expression can be easily manipulated and measured. Rearing Drosophila in the laboratory is easy and cost efficient, making fruit flies the ideal host model to measure the impact of single gene mutants on the evolution of pathogens.
With this project, we measured in a first set of experiments to what extent host immune-competence may influence the evolution of virulence (phenotype) when passaged on hosts with different immune competences (here males vs. females), to test whether immune-compromised hosts and extreme sex ratio drive pathogen adaptation and if adaptation results in the evolution of more virulent pathogens. In a second set of experiment, we tracked the shedding of pathogen agents from hosts with impaired immune and repair system in epithelial gut cells, as a proxy for disease resistance and transmission of food-borne pathogens.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

In many eukaryote species, females often demonstrate higher resistance to pathogen than males. During this project period, we evolved Drosophila C virus (DCV) in two fly populations with extreme sex ratio showing different levels of resistance to the pathogen: on one hand a population composed of female flies only, and on the other hand male flies only. To understand the impact of this sexual dimorphism on the virus adaptation, we evolved the virus for 10 generations of passages from flies to flies. While very quickly (after 3 generations) we observed an accumulation of pathogen load in flies, we found after 10 generations an increase of virulence of the virus stock evolved in female flies, as measured by survival experiment of infected male and female flies. Interestingly, this result was particularly consistent across the 10 independent replicates performed for this study.

In addition to the study of pathogen evolution, we also investigated the effect of a specific mechanism of disease resistance, namely the gut epithelial damage repair system, on the transmission capacity of pathogens. Using mutant fly lines that were either unable to repair gut epithelial cells damaged during infections, or deficient in triggering an immune response within damaged cells, we measured pathogen shedding and pathogen load in infected mutants. We found that some mutations in gut damage repair genes impact the defecation rate of flies and may alter the proportion of flies shedding pathogen in their environment.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Our virus evolution experiments showed the potential rapid adaptation of a pathogen in host with small variation in immune mechanisms (males vs. females), with a response observed after only 10 generations of experimental passages. This work also illustrates the impact of immune sexual dimorphism can have on pathogen adaptation and how altered sex ratio in host populations can drive evolutionary changes to their microbes. Our results represent a possible case of rapid adaptation and more work is necessary to understand the underlying mechanisms of evolution in our experimental viral populations.

The impact of gut damage repair mechanisms on the defecation rate and the proportion of pathogen shedding hosts may have strong implication for the dissemination of diseases in population showing cases of inflammatory bowel syndromes. These findings opened new ideas towards the control of pathogen infection using the under-studied mechanism of pathogen expulsion from the gut, genetically manipulated in our experimental flies. In addition, we hoped that our work will stimulate the development of new strategies for the control of food-borne pathogens, or the transmission of beneficial gut microbes, by manipulating the defecation rate of their hosts.

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