Table 1 Multi-scale ecological and evolutionary drivers of Plasmodium knowlesi.

Continental: global spread and dispersal of pathogen

Earth history

Phylogenetic links between P. knowlesi and other related taxa, shared life-history traits

Regional/biogeographic: broad climatic variation or geographical boundaries restrict P. knowlesi to SE Asia

Barriers to dispersal; natural distribution of hosts and vectors and biodiversity patterns

Distribution of the hosts and vectors of the parasite and the enabling and limiting factors for this distribution

Local landscape: fine-scale distribution of species within the habitat

Interaction between parasite, host, and vector within a rapidly changing habitat

Changing forest cover and land use and the effects on the distribution of vectors and hosts of P. knowlesi and parasite transmission rate

Individual: limiting and facilitating factors of transmission to humans

Individual health, behaviour, interaction with the vector and host, level of detection and treatment

Severity of infection in Malaysian Borneo versus the rest of SE Asia; asymptomatic carriage of the parasite within communities; degree of human to human transmission

Cellular: disease pathways

Infection route, immunological status, previous exposure

P. knowlesi multiplication in human blood; methods for accurate diagnosis

Molecular: human resistance to the disease; different genotypes of the parasite

Human host resistance or susceptibility; different P. knowlesi genotypes have varying disease severity and host preferences

Genetic factors influencing disease severity, genetic factors influencing choice of hosts and vectors, erythrocyte invasion pathways