Malaria infection starts with injection of Plasmodium sporozoites by an Anopheles mosquito into the skin of the mammalian host. How sporozoites locate and enter a blood vessel is a critical, but poorly understood process. Here, we examine sporozoite motility and their interaction with dermal blood vessels, using intravital microscopy in mice. Our data suggest that sporozoites exhibit two types of motility: In regions far from blood vessels, they exhibit ′avascular motility′, defined by high speed and less confinement, while in the vicinity of blood vessels their motility is more constrained. We find that curvature of sporozoite tracks engaging with vasculature optimizes contact with dermal capillaries. Imaging of sporozoites with mutations in key adhesive proteins highlight the importance of the sporozoite's gliding speed and its ability to modulate adhesive properties for successful exit from the inoculation site.
Animal experimentation: All animal work was conducted in accordance with the recommendations by the Johns Hopkins University Animal Care and Use Committee (IACUC), under the IACUC-approved protocol #M011H467.
- Urszula Krzych, Walter Reed Army Institute of Research, United States
© 2015, Hopp et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
eLife has published papers on many tropical diseases, including malaria, Ebola, leishmaniases, Dengue and African sleeping sickness.
Tafenoquine is a newly licensed antimalarial drug for the radical cure of Plasmodium vivax malaria. The mechanism of action and optimal dosing are uncertain. We pooled individual data from 1102 patients and 72 healthy volunteers studied in the pre-registration trials. We show that tafenoquine dose is the primary determinant of efficacy. Under an Emax model, we estimate the currently recommended 300 mg dose in a 60 kg adult (5 mg/kg) results in 70% of the maximal obtainable hypnozoiticidal effect. Increasing the dose to 7.5 mg/kg (i.e. 450 mg) would result in 90% reduction in the risk of P. vivax recurrence. After adjustment for dose, the tafenoquine terminal elimination half-life, and day 7 methaemoglobin concentration, but not the parent compound exposure, were also associated with recurrence. These results suggest that the production of oxidative metabolites is central to tafenoquine’s hypnozoiticidal efficacy. Clinical trials of higher tafenoquine doses are needed to characterise their efficacy, safety and tolerability.