3.8 Article

A New Method Based on the von Mises-Fisher Distribution Shows that a Minority of Liver-Localized CD8 T Cells Display Hard-To-Detect Attraction to Plasmodium-Infected Hepatocytes

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FRONTIERS IN BIOINFORMATICS
卷 1, 期 -, 页码 -

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FRONTIERS MEDIA SA
DOI: 10.3389/fbinf.2021.770448

关键词

CD8 T cell; malaria; biased movement; simulated movement; cell movement model; attracted movement

资金

  1. This work was supported by NIH grant (No. R01 GM118553) to VG. [R01 GM118553]
  2. NIH

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Malaria is a deadly disease caused by Plasmodium parasites, and understanding how CD8 T cells search for the parasites in the liver can improve the efficacy of future vaccines. This study found that the search process for malaria liver stages is random, with only a small fraction of T cells displaying attraction to the parasites. The speed and turning angles of T cell movement correlated with attraction, suggesting a potential mechanism to enhance vaccine effectiveness.
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.

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