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A single-cell liver atlas of relapsing human malaria [Bulk-seq]

ABSTRACT: Malaria-causing Plasmodium vivax parasites can linger in the human liver for weeks to years, and then reactivate to cause recurrent blood-stage infection. While an important target for malaria eradication, little is known about the molecular features of the replicative and non-replicative states of intracellular P. vivax parasites, or their human host-cell dependencies and the host responses to them. Here, we leverage a bioengineered human microliver platform to culture patient-derived P. vivax parasites in primary human hepatocytes and conduct transcriptional profiling. By coupling enrichment strategies with bulk and single-cell analyses, we captured both parasite and host transcripts in individual hepatocytes throughout the infection course. We define host- and state-dependent transcriptional signatures and identify previously unappreciated populations of replicative and non-replicative parasites, sharing features with sexual transmissive forms. We find that infection suppresses transcription of key hepatocyte function genes, and that P. vivax elicits an innate immune response that can be manipulated to control infection. Our work provides an extendible framework and resource for understanding host-parasite interactions and reveals new insights into the biology of P. vivax dormancy and transmission.

ORGANISM(S): Plasmodium vivax

PROVIDER: GSE197458 | GEO | 2022/02/25

REPOSITORIES: GEO

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Project description:After entering their mammalian host via the bite of an Anopheles mosquito, Plasmodium sporozoites migrate to the liver where they traverse several hepatocytes before invading the one inside which they will develop and multiply into thousands of merozoites. Although this constitutes an essential step in malaria infection, the requirements of Plasmodium parasites in liver cells and how they use the host cell for their own survival and development are poorly understood. To gain new insights into the molecular host-parasite interactions that take place during malaria liver infection, we have used high-throughput microarray technology to determine the transcriptional profile of P. yoelii-infected hepatocytes that were collected from P. yoelii-infected mice 24 and 40 h after infection. This in vivo microarray expression was compared with the microarray analysis of in vitro infected hepatoma cells infected with closely related rodent malaria parasite P. berghei. Differential expression patterns for host genes identify genes and pathways involved in the host response to rodent Plasmodium parasites. Keywords: gene expression Total RNA from sorted liver stage (LS) infected hepatocytes were isolated from PyGFP-infected BALB/c mice as described in Tarun et al (2008). RNA from LS-infected hepatocytes were isolated at two time points post-infection (pi): 24 hr pi (LS24) and 40 hr pi (LS40). As control, RNA from hepatocytes isolated from mock-infected mice (infected with salivary gland extract) at the same time points was also isolated following the same procedure. Total RNA was then subjected to two rounds of linear amplification using the Amino Allyl Message Amp II aRNA Amplification Kit (Ambion) according to manufaturerâs directions. The quality of total and amplified RNAs were examined with the Agilent 2100 BioanalyzerTM (Agilent Technologies) and the quantity of the RNA samples was assessed using a Nanodrop ND-1000 spectrophotometer prior to microarray hybridization. For each timepoint two independent biological replicates were obtained.

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A single-cell liver atlas of relapsing human malaria [Bulk-seq]

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