Abstract
Malaria is a disease caused by Plasmodium parasites, resulting in over 200 million infections and 400,000 deaths every year. A critical step of malaria infection is when sporozoites, injected by mosquitoes, travel to the liver and form liver stages. Malaria vaccine candidates which induce large numbers of malaria-specific CD8 T cells in mice are able to eliminate all liver stages, preventing fulminant malaria. However, how CD8 T cells find all parasites in 48 h of the liver stage lifespan is not well understood. Using intravital microscopy of murine livers, we generated unique data on T cell search for malaria liver stages within a few hours after infection. To detect attraction of T cells to an infection site, we used the von Mises-Fisher distribution in 3D, similar to the 2D von Mises distribution previously used in ecology. Our results suggest that the vast majority (70–95%) of malaria-specific and non-specific liver-localized CD8 T cells did not display attraction towards the infection site, suggesting that the search for malaria liver stages occurs randomly. However, a small fraction (15–20%) displayed weak but detectable attraction towards parasites which already had been surrounded by several T cells. We found that speeds and turning angles correlated with attraction, suggesting that understanding mechanisms that determine the speed of T cell movement in the liver may improve the efficacy of future T cell-based vaccines. Stochastic simulations suggest that a small movement bias towards the parasite dramatically reduces the number of CD8 T cells needed to eliminate all malaria liver stages, but to detect such attraction by individual cells requires data from long imaging experiments which are not currently feasible. Importantly, as far as we know this is the first demonstration of how activated/memory CD8 T cells might search for the pathogen in nonlymphoid tissues a few hours after infection. We have also established a framework for how attraction of individual T cells towards a location in 3D can be rigorously evaluated.
Highlights
Malaria is a disease caused by parasites of the genus Plasmodium that kills over 400,000 people every year (WHO, 2018)
Additional analysis based on the meandering index and turning angles for T cells showed that all cells tend to turn (Supplementary Figure S11) suggesting an active search for an infection
We focused on detecting if T cells are attracted to the site of infection, and our tests did not compare Plasmodiumspecific cells with control T cells because those results could be biased if both malaria-specific T cells and T cells with irrelevant specificity may be attracted to the infection site
Summary
Malaria is a disease caused by parasites of the genus Plasmodium that kills over 400,000 people every year (WHO, 2018). The liver stage of malaria infection is asymptomatic. Intravital imaging experiments showed that soon after infection, activated Plasmodium-specific CD8 T cells and CD8 T cells of irrelevant specificity cluster around Plasmodiuminfected hepatocytes (Cockburn et al, 2013; Kelemen et al, 2019). Mathematical modeling-based analysis of the T cell clustering data suggested that the formation of the clusters is best explained by a model in which the first T cell finds the liver stage randomly and the attraction of other T cells (including T cells with irrelevant specificity) to the parasite increases with the number of T cells per cluster (Kelemen et al, 2019). While an earlier study suggested that there may be attraction of distant T cells to the clustered liver stage (Kelemen et al, 2014), it remains unclear if attraction to the liver stage occurs prior to the formation of T cell clusters around parasites, as well as if attraction is exhibited by all or just a subset of cells
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