Journal
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fcimb.2022.986314
Keywords
Plasmodium vivax; liver stage malaria; host-parasite interactions; hypnozoite; single-cell RNA sequencing (scRNAseq); 10X Genomics; primary human hepatocyte (PHH)
Categories
Funding
- Georgia Research Alliance (DK)
- Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council Independent Research Institute Infrastructure Support Scheme
- Agence Nationale de la Recherche [ANR-17CE13-0025]
- Australian National Health and Medical Research Council Leadership Fellowship [APP1194330]
- Bill & Melinda Gates Foundation [OPP1023601]
- Medicines for Malaria Venture [RD/2017/0042, RD/16/1082, RD/15/0022]
- Bill and Melinda Gates Foundation [OPP1023601] Funding Source: Bill and Melinda Gates Foundation
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By sequencing over 1,000 P. vivax-infected hepatocytes at single-cell resolution, we have revealed the transcriptome-wide signatures of the parasite and the infected host cell. Key differences in transcripts encoding RNA-binding proteins associated with cell fate were identified between replicating schizonts and hypnozoites at the transcriptional level. In infected hepatocytes, genes associated with energy metabolism and antioxidant stress response were upregulated, while those involved in the host immune response were downregulated. The transcriptional markers in schizonts, hypnozoites, and infected hepatocytes identified in this study can provide insights into potential factors underlying dormancy and inform therapeutic targets against P. vivax liver-stage infection.
The resilience of Plasmodium vivax, the most widely-distributed malaria-causing parasite in humans, is attributed to its ability to produce dormant liver forms known as hypnozoites, which can activate weeks, months, or even years after an initial mosquito bite. The factors underlying hypnozoite formation and activation are poorly understood, as is the parasite's influence on the host hepatocyte. Here, we shed light on transcriptome-wide signatures of both the parasite and the infected host cell by sequencing over 1,000 P. vivax-infected hepatocytes at single-cell resolution. We distinguish between replicating schizonts and hypnozoites at the transcriptional level, identifying key differences in transcripts encoding for RNA-binding proteins associated with cell fate. In infected hepatocytes, we show that genes associated with energy metabolism and antioxidant stress response are upregulated, and those involved in the host immune response downregulated, suggesting both schizonts and hypnozoites alter the host intracellular environment. The transcriptional markers in schizonts, hypnozoites, and infected hepatocytes revealed here pinpoint potential factors underlying dormancy and can inform therapeutic targets against P. vivax liver-stage infection.
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