Biology subjects

Preiser, P. R.

Publications and source records attributed to Preiser, P. R..

4 recordsLinked to original sources

bioRxiv2026

Multi-omic profiling of Plasmodium knowlesi blood stages identifies host adaptation barriers

The zoonotic parasite Plasmodium knowlesi has emerged as a widespread cause of human malaria in Southeast Asia. We assembled a high-resolution transcriptome of zoonotic P. knowlesi across its intraerythrocytic developmental cycle and combined transcriptomics, quantitative proteomics and thermal stability measurements to compare parasites cultured in macaque and human red blood cells. We found that P. knowlesi accelerates through the ring stage to settle at the same developmental pace as P. falciparum during the trophozoite and schizont stages. Subsequent multi-omic analysis revealed broad transcriptional and proteomic adaptations of P. knowlesi to the human host cell environment. Parasites cultured in human cells expressed glutathione synthetase earlier and displayed changes in upstream processes that include NADPH production by the pentose phosphate pathway and glutamine synthesis. These changes were accompanied by further differences in the expression of ribosomal subunits and mitochondrial respiratory complexes. Together, our findings offer a systems-level view of non-genetic adaptations of P. knowlesi to the human red blood cell environment.

microbiology↗

bioRxiv2022

Cohesin is involved in transcriptional repression of stage-specific genes in the human malaria parasite

The most virulent human malaria parasite, Plasmodium falciparum, has a complex life cycle between its human host and mosquito vector. Each stage is driven by a specific transcriptional program, but with a relatively high ratio of genes to specific transcription factors, it is unclear how genes are activated or silenced at specific times. The P. falciparum genome is relatively euchromatic compared to the mammalian genome, except for specific genes that are uniquely heterochromatinized via HP1. There seems to be an association between gene activity and spatial organization; however, the molecular mechanisms behind genome organization are unclear. While P. falciparum lacks key genome-organizing proteins found in metazoans, it does have all core components of the cohesin complex. In other eukaryotes, cohesin is involved in sister chromatid cohesion, transcription, and genome organization. To investigate the role of cohesin in P. falciparum, we combined genome editing, mass spectrometry, chromatin immunoprecipitation and sequencing (ChIP-seq), and RNA sequencing to functionally characterize the cohesin subunit Structural Maintenance of Chromosomes protein 3 (SMC3). SMC3 knockdown in early stages of the intraerythrocytic developmental cycle (IDC) resulted in significant upregulation of a subset of genes involved in erythrocyte egress and invasion, which are normally expressed at later stages. ChIP-seq of SMC3 revealed that over the IDC, enrichment at the promoter regions of these genes inversely correlates with their expression and chromatin accessibility levels. These data suggest that SMC3 binding helps to repress specific genes until their appropriate time of expression, revealing a new mode of stage-specific, HP1-independent gene repression in P. falciparum.

molecular biology↗

bioRxiv2022

Erythrocyte signalling is critical for Plasmodium falciparum invasion

Successful Plasmodium falciparum merozoite invasion requires the activation of red blood cell (RBC) signalling pathways. The binding of parasite ligand reticulocyte binding protein homologue 5 (RH5) to its host receptor Basigin is essential for merozoite invasion and triggers a Ca2+ influx in RBCs. Here we observed that RH5-bound RBCs form a multimeric protein complex containing Basigin, CD44 and {beta}2-adrenergic receptor ({beta}2AR), suggesting that RH5-Basigin interaction is functionally associated with the host cAMP signalling pathway. Interestingly, we detected a characteristic rise in cAMP levels in the RBC upon RH5-Basigin interaction, which can be blocked by G protein and cAMP-synthesising adenylyl cyclase (AC) inhibitors. Furthermore, we demonstrated that RBC L-type Ca2+ channel inhibitor and cAMP signalling inhibitors are able to block merozoite invasion. Checkerboard invasion inhibition assay containing different combinations of signalling inhibitors also exhibited a drastic amplification of inhibition levels, indicating that these signalling proteins are functioning in a common signalling cascade to activate the L-type Ca2+ channels. Taken together, this study provides new insights into the role of a host cAMP-Ca2+ signalling pathway during merozoite invasion and sheds new light on antimalarial therapeutic strategies to tackle the high infection rate and growing threat of drug resistant parasites. Key PointsO_LIA pre-existing Basigin-associated membrane protein complex undergoes increased protein assembly upon RH5 binding on the RBC surface. C_LIO_LIPlasmodium falciparum merozoite exploits host cAMP signalling to initiate Ca2+ influx in the RBC. C_LI

microbiology↗

bioRxiv2019

Transcriptome-wide dynamics of extensive m6A mRNA methylation during Plasmodium falciparum blood-stage development

Malaria pathogenesis results from the asexual replication of Plasmodium falciparum within human red blood cells, which relies on a precisely timed cascade of gene expression over a 48-hour life cycle. Although substantial post-transcriptional regulation of this hardwired program has been observed, it remains unclear how these processes are mediated on a transcriptome-wide level. To this end, we identified mRNA modifications in the P. falciparum transcriptome and performed a comprehensive characterization of N6-methyladenosine (m6A) over the course of blood stage development. Using mass spectrometry and m6A RNA sequencing, we demonstrate that m6A is highly developmentally regulated, exceeding m6A levels known in any other eukaryote. We identify an evolutionarily conserved m6A writer complex and show that knockdown of the putative m6A methyltransferase by CRISPR interference leads to increased levels of transcripts that normally contain m6A. In accordance, we find an inverse correlation between m6A status and mRNA stability or translational efficiency. Our data reveal the crucial role of extensive m6A mRNA methylation in dynamically fine-tuning the transcriptional program of a unicellular eukaryote as well as a new epitranscriptomic layer of gene regulation in malaria parasites.

molecular biology↗