Identifying the genetic mechanisms facilitating host range and virulence of a viral pathogen that threatens European amphibian biodiversity

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Amphibians are experiencing catastrophic declines, caused by the emergence of infectious diseases. In Europe, the causative agent is predominantly viral (ranavirus), and our work has shown that emergence of ranavirus in amphibian communities can result in at least three different patterns: the mortality and population decline can be host-specific, it can affect the whole host community or infections can be asymptomatic, co-occurring in areas where lethal infections are common. From analysis of viral isolates we have determined that this variation correlates with viral phylogeney: in Spain, a genetic lineage responsible for amphibian community mortality and decline co-circulates with a genetically distinct asymptomatic lineage; in the UK, a third lineage is associated with death and decline of a single host species (common frogs - infection of other host species is rare and does not lead to significant mortality or decline in spill-over hosts).Here we propose to take advantage of this novel system to ascertain what genetic factors are responsible for these differences in host range and virulence. Our approach is three-pronged: first, we will sequence 130 ranavirus genomes to catalogue genetic variation amongst the European lineages and identify candidate loci. We will also take a more bottom-up phylogenetic approach, identifying any genetic variants that map with differences in host species in a global panel of ranavirus genomes. Second, we carry out controlled infection experiments to verify the different host range and virulence of different viral isolates in three animal models (two anurans and one caudate chosen to encompass the host range we have observed in Spain). Third, we will generate viral knockouts, targeting candidate regions we have identified in the first two objectives, and test hypotheses regarding gene function using recombinants and wild type virus in our animal models.Our results will be a crucial contribution to our understanding of why ranaviruses are such lethal pathogens in some circumstances. Ranavirus emergence is on the increase across Europe, and is emerging as a novel threat to amphibian and reptile biodiversity in Latin America and Madagascar, two amphibian and reptile biodiversity hotspots. Our research will more widely inform the epidemiological community as to what genetic factors may be important for viruses to exploit novel hosts. Given that most emerging infections are viral and emergence arises through host jumps, we expect our findings to be of broad interest to this community.