Exosomes represent a subtype of extracellular vesicle that is released through retrograde transport and fusion of multivesicular bodies with the plasma membrane. Although no perfect methodologies currently exist for the high-throughput, unbiased isolation of pure plasma exosomes, investigation of exosome-enriched plasma fractions of extracellular vesicles can confer a glimpse into the endocytic pathway on a systems level.
Researchers at the Chinese Academy of Sciences conducted high-coverage lipidomics with an emphasis on sterols and oxysterols, and proteomic analyses of exosome-enriched extracellular vesicles (EVs hereafter) from patients at different temporal stages of COVID-19, including the presymptomatic, hyperinflammatory, resolution and convalescent phases. This study highlights dysregulated raft lipid metabolism that underlies changes in EV lipid membrane anisotropy that alter the exosomal localization of presenilin-1 (PS-1) in the hyperinflammatory phase. The researchers also show in vitro that EVs from different temporal phases trigger distinct metabolic and transcriptional responses in recipient cells, including in alveolar epithelial cells, which denote the primary site of infection, and liver hepatocytes, which represent a distal secondary site. In comparison to the hyperinflammatory phase, EVs from the resolution phase induce opposing effects on eukaryotic translation and Notch signalling. These results provide insights into cellular lipid metabolism and inter-tissue crosstalk at different stages of COVID-19 and are a resource to increase our understanding of metabolic dysregulation in COVID-19.
Investigating the EV composition along the temporal course of COVID-19
a, The temporal trajectory of COVID-19 is generally divided into four stages in survivors, which includes the presymptomatic (S1), hyperinflammatory (S2), resolution (S3) and convalescent (S4) phases. The first half of the trajectory (that is, SARS-CoV-2 RNA positive) is largely virus driven, characterized by immunosuppression and the response of the host to the invading pathogen, whereas the second half comprises mainly host-driven metabolism to resolve the hyperinflammation and restore physiological homeostasis. Exosome-enriched EVs were isolated from fasting plasma, and high-coverage analyses of exosomal lipidome with a focus on sterols and oxysterols were conducted. b, The particle size distribution of isolated EVs. n = 4 independent experiments. c, Particle sizes of isolated EVs analysed by nanoscale flow cytometry. Representative plot from n = 4 independent experiments.