Invasive mice and rodent malaria in Africa: dissecting a natural parasite host shift involving two very well studied laboratory models – MICETRAL

Emerging diseases are often the product of a host shift, that is the sudden colonization of a new host species by few parasites that are subsequently able to establish a new and viable population. A host shift incorporates several steps : (1) a contact between a donor and a recipient host species; (2) the transmission of the parasite between host species; (3) the adaptation of the parasite to overcome the biological barriers of the new host and finally (4) the evolution of the parasite and the host in response to the selective pressures they impose on each other. In our project, we will dissect these steps in the system involving, in Gabon, the house mouse and some rodent malaria agents. In this country, the house mouse is invasive and has captured these new pathogens.
More specifically, we will: (1) Task 1 - carry out an important sampling and mapping of native and invasive rodent species across sylvatic and village environments in Gabon to identify the areas of species overlap that may lead to opportunities for host shift, and molecularly screen all individuals in order to compare the prevalence and diversity of rodent malaria parasites across the different host species and environments. (2) Task 2 - identify the vectors that were likely involved in the host transfer by performing an entomological survey (transversal and longitudinal) in different sites where both native infected hosts and infected house mice are present. (3) Task 3 - Analyse the adaptation of Plasmodium to the house mouse, both genetically and phenotypically. For that, we will: (i) sequence the entire genome of several populations of rodent malaria agents circulating in their natural hosts and compare them to the genome of populations of parasites living in house mice. We will use the tools of comparative genomics and population genomics to identify candidate regions of the genomes that potentially participated in the adaptation of these parasites to mice (e.g. genome scans of positive selection and divergent selection). (ii) Compare the evolution of the genome of the parasites isolated from invasive mice in Gabon with the evolution of the genome of a bank of isolates of the same parasites that have been serially passaged through mice since their collection in the 60/70’s and search for patterns of convergent evolution to determine if artificial passage on the same host species may have led to similar genetic adaptations as the one observed in natura. We will finally carry out a phenotypic characterization of the different rodent malaria species found in the field using experimental infections in the laboratory. For this purpose, we will compare the within host dynamics and virulence of parasite populations isolated from wild rats and house mice in their native and foreign hosts in a 2 by 2 cross-transplant design. Transmission potential will be established by feeding vectors on the infected hosts and quantifying Plasmodium prevalence/intensity in the mosquito. (4) Task 4 - Determine if mice have evolved resistance or tolerance in response to these new infections by challenging mice from infected and uninfected populations and describe the impacts of infection on host health (anaemia, loss weight, survival…) during the course of infection. We will compare immune responses and their immunopathological effects, using both physiological and immunogenomic assays. We will also analyse the genome of mice from naturally-infected and un-infected populations to detect signatures of selection associated with Plasmodium selection pressure.
This host-parasite system, involving two very well-known laboratory models (mouse and rodent malaria), offers a unique opportunity to dissect in details the causes and consequences of a host shift.