Elucidating Spatially-Resolved Changes in Host Signaling During Plasmodium Liver-Stage Infection.

Elizabeth K K Glennon,Alexis Kaushansky,Sophia M Reeder,Veronica I Primavera,Ling Wei,Tinotenda Tongogara

doi:10.3389/fcimb.2021.804186

Abstract

Upon transmission to the human host, Plasmodium sporozoites exit the skin, are taken up by the blood stream, and then travel to the liver where they infect and significantly modify a single hepatocyte. Low infection rates within the liver have made proteomic studies of infected hepatocytes challenging, particularly in vivo, and existing studies have been largely unable to consider how protein and phosphoprotein differences are altered at different spatial locations within the heterogeneous liver. Using digital spatial profiling, we characterized changes in host signaling during Plasmodium yoelii infection in vivo without disrupting the liver tissue. Moreover, we measured alterations in protein expression around infected hepatocytes and identified a subset of CD163+ Kupffer cells that migrate towards infected cells during infection. These data offer the first insight into the heterogeneous microenvironment that surrounds the infected hepatocyte and provide insights into how the parasite may alter its milieu to influence its survival and modulate immunity.

Highlights

Upon introduction to the human host by the bite of an infectious mosquito, Plasmodium parasites migrate to the liver where they invade a hepatocyte and proceed to develop and replicate
Digital Spatial Profiling (DSP) has primarily been used to study heterogeneity within the tumor microenvironment, which has been strongly linked to disease progression and treatment outcomes (Stewart et al, 2020; Wang et al, 2021)
By measuring changes in host proteins in concentric rings around infected hepatocytes and correlations between these proteins we identified an influx of

Summary

Introduction

Upon introduction to the human host by the bite of an infectious mosquito, Plasmodium parasites migrate to the liver where they invade a hepatocyte and proceed to develop and replicate. Once parasites complete their development within the liver, thousands of individual merozoites egress from the host hepatocyte and migrate to the bloodstream where they invade erythrocytes and initiate the symptomatic blood stage of infection. In addition to selecting particular hepatocytes for invasion, Plasmodium Liver-Stage Spatial Profiling parasites modify the host cell throughout their development within the liver, including cell size (Balasubramanian et al, 2019), microtubule and organelle organization (Vijayan et al, 2020), and signaling cascades (Kaushansky et al, 2013a; Glennon et al, 2019). Experiments with genetically attenuated parasites demonstrated that parasites that successfully invade but die before completing LS infection can induce immunity and reduce susceptibility to subsequent infection (Vaughan and Kappe, 2017)

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Conclusion