Longitudinal analysis of Plasmodium sporozoite motility in the dermis reveals component of blood vessel recognition

Abstract

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. In this study, 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.

DOI: http://dx.doi.org/10.7554/eLife.07789.001

eLife digest

Malaria remains a devastating disease in many parts of the world. Malaria parasites enter the host via the skin, where they are deposited by infected mosquitoes as they look for blood. The parasites must exit the skin to reach the liver, where they multiply and ultimately infect red blood cells, where they cause the symptoms of the disease. In the skin, the parasites must move to find blood vessels that they enter to travel via the blood circulation to the liver. Only about 10–20% of parasites make it out of the skin, making this a bottleneck for the parasite.

Scientists have been working to develop vaccines that would protect people against malaria. One way these could work would be to stop malaria parasites from leaving the skin and entering the blood vessels. But to do that, more needs to be learnt about how the parasites move in the skin and enter the blood vessels.

Hopp et al., using a mouse model of malaria, created malaria parasites that produce a fluorescent protein that allows the parasites to be tracked after they have been injected into the skin of a mouse's ear. This revealed that the parasites have two ways of moving. After first being injected, the parasites move quickly and freely. The parasites slow down when they come close to a blood vessel and move on or around the vessel for some time before entering it. During this stage of movement, the parasites tend to move in paths that follow the curvature of the blood vessels, which may improve how well they make contact with the blood vessel surface and may enable them to find the areas of the vessels best suited for entry.

Next, Hopp et al. investigated how two parasite mutants move through mouse skin. Both mutants had previously been found to be less likely than wild-type parasites to exit the inoculation site. Hopp et al. found that one of the mutants moves slowly after being injected and so explores a smaller tissue volume than normal and encounters fewer blood vessels. The second mutant parasite spends more time than normal moving on the surface of the blood vessels, but finds it difficult to enter them.

Continuing this work will allow us to learn more about the interactions between the parasite and the blood vessels, which in turn could reveal key events that could be targeted by a vaccine. Furthermore, the significant amount of time that the parasites spend moving and looking for blood vessels in the skin could be a good time to target them with antibodies and prevent malaria infection.

DOI: http://dx.doi.org/10.7554/eLife.07789.002