Host kinase regulation ofPlasmodium vivaxdormant and replicating liver stages

Abstract

AbstractUpon transmission to the liver,Plasmodium vivaxparasites form replicating schizonts, which continue to initiate blood-stage infection, or dormant hypnozoites that reactivate weeks to months after initial infection.P. vivaxphenotypes in the field vary significantly, including the ratio of schizonts to hypnozoites formed and the frequency and timing of relapse. Evidence suggests that both parasite genetics and environmental factors underly this heterogeneity. We previously demonstrated that data on the effect of a panel of kinase inhibitors with overlapping targets onPlasmodiumliver stage infection, in combination with a computational approach called kinase regression (KiR), can be used to uncover novel host regulators of infection. Here, we applied KiR to evaluate the extent to whichP. vivaxliver-stage parasites are susceptible to changes in host kinase activity. We identified a role for a subset of host kinases in regulating schizont and hypnozoite infection and schizont size and characterized overlap as well as variability in host phosphosignaling dependencies between parasite forms and across multiple patient isolates. Striking, our data point to variability in host dependencies acrossP. vivaxisolates, suggesting one possible origin of the heterogeneity observed acrossP. vivaxin the field.