Mass Spectrometry Identification of Biomarkers in Extracellular Vesicles From Plasmodium vivax Liver Hypnozoite Infections |
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| Affiliation: | 1. ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain;2. IGTP, Institute for Health Sciences Trias I Pujol, Barcelona, Spain;3. Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington, USA;4. Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand;5. Department of Laboratory Medicine and Pathology, and Department of Microbiology, University of Washington, Seattle, Washington, USA;6. MVRU, Mahidol Vivax Research Unit, Mahidol University, Bangkok, Thailand;7. Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain;8. Universitat Pompeu Fabra (UPF), Barcelona, Spain;9. Department of Pediatrics, University of Washington, Seattle, Washington, USA;10. ICREA, Catalan Institution for Research and Advanced Studies, Barcelona, Spain |
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| Abstract: | Latent liver stages termed hypnozoites cause relapsing Plasmodium vivax malaria infection and represent a major obstacle in the goal of malaria elimination. Hypnozoites are clinically undetectable, and presently, there are no biomarkers of this persistent parasite reservoir in the human liver. Here, we have identified parasite and human proteins associated with extracellular vesicles (EVs) secreted from in vivo infections exclusively containing hypnozoites. We used P. vivax-infected human liver-chimeric (huHEP) FRG KO mice treated with the schizonticidal experimental drug MMV048 as hypnozoite infection model. Immunofluorescence-based quantification of P. vivax liver forms showed that MMV048 removed schizonts from chimeric mice livers. Proteomic analysis of EVs derived from FRG huHEP mice showed that human EV cargo from infected FRG huHEP mice contain inflammation markers associated with active schizont replication and identified 66 P. vivax proteins. To identify hypnozoite-specific proteins associated with EVs, we mined the proteome data from MMV048-treated mice and performed an analysis involving intragroup and intergroup comparisons across all experimental conditions followed by a peptide compatibility analysis with predicted spectra to warrant robust identification. Only one protein fulfilled this stringent top-down selection, a putative filamin domain-containing protein. This study sets the stage to unveil biological features of human liver infections and identify biomarkers of hypnozoite infection associated with EVs. |
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| Keywords: | humanized mouse model hypnozoites extracellular vesicles proteomics biomarkers schizonticidal experimental drug MMV048 AEpS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0050" }," $$" :[{" #name" :" text" ," _" :" abundance estimated per sample D8" },{" #name" :" keyword" ," $" :{" id" :" kwrd0060" }," $$" :[{" #name" :" text" ," _" :" Day 8 postinfection D21" },{" #name" :" keyword" ," $" :{" id" :" kwrd0070" }," $$" :[{" #name" :" text" ," _" :" Day 21 postinfection DMSO" },{" #name" :" keyword" ," $" :{" id" :" kwrd0080" }," $$" :[{" #name" :" text" ," _" :" Dimethyl sulfoxide EVs" },{" #name" :" keyword" ," $" :{" id" :" kwrd0090" }," $$" :[{" #name" :" text" ," _" :" Extracellular vesicles FRG KO (FRG huHEP)" },{" #name" :" keyword" ," $" :{" id" :" kwrd0100" }," $$" :[{" #name" :" text" ," _" :" C57Bl/6 mice with a triple mutation (FAH?/?Rag2?/?IL2Rγnull) and repopulated with primary human hepatocytes ID" },{" #name" :" keyword" ," $" :{" id" :" kwrd0110" }," $$" :[{" #name" :" text" ," _" :" identifier IFA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0120" }," $$" :[{" #name" :" text" ," _" :" Immunofluorescence assay IV" },{" #name" :" keyword" ," $" :{" id" :" kwrd0130" }," $$" :[{" #name" :" text" ," _" :" intravenous infection MB" },{" #name" :" keyword" ," $" :{" id" :" kwrd0140" }," $$" :[{" #name" :" text" ," _" :" mosquito bite PI4K" },{" #name" :" keyword" ," $" :{" id" :" kwrd0150" }," $$" :[{" #name" :" text" ," _" :" phosphatidylinositol kinase PIK3C2B" },{" #name" :" keyword" ," $" :{" id" :" kwrd0160" }," $$" :[{" #name" :" text" ," _" :" phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta PR" },{" #name" :" keyword" ," $" :{" id" :" kwrd0170" }," $$" :[{" #name" :" text" ," _" :" protein ratio SEC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0180" }," $$" :[{" #name" :" text" ," _" :" size-exclusion chromatography TBS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0190" }," $$" :[{" #name" :" text" ," _" :" Tris-buffered saline TQ" },{" #name" :" keyword" ," $" :{" id" :" kwrd0200" }," $$" :[{" #name" :" text" ," _" :" tafenoquine |
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