Table 1.

Multi-scale ecological and evolutionary drivers of Plasmodium knowlesi.

Adapted from Estrada-Pena et al. [7]

Scale and description	Drivers	Gaps in knowledge
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