Single-Cell Analysis Reveals Profound Divergence in Transcriptional Regulatory Programs Between Laboratory and Field Isolates of \textit{Plasmodium falciparum

Abstract: Understanding the transcriptional regulatory mechanisms governing the complex asexual blood-stage development of \textit{Plasmodium falciparum} is crucial, particularly how these mechanisms differ between controlled laboratory environments and natural human infections. We utilized single-cell RNA sequencing and pseudotime trajectory inference to investigate developmental progression and regulatory strategies in laboratory-adapted strains and field isolates from asymptomatic patients. Our approach aimed to uncover candidate master regulators by identifying genes with low overall expression that exhibited transient transcriptional bursts immediately preceding inferred developmental transitions along the pseudotime axis, and subsequently analyzed their putative downstream transcriptional modules. Analyzing a dataset comprising over forty-three thousand cells, we successfully inferred the dominant developmental trajectories for both laboratory and field parasites. Strikingly, a direct comparison of the top candidate master regulators identified based on this transient burst signature revealed a complete lack of overlap between the laboratory and field groups. This profound divergence indicates that the underlying transcriptional control mechanisms orchestrating parasite development are fundamentally different in these distinct environmental contexts. Further analysis of putative downstream modules associated with these candidates also suggested distinct regulatory strategies employed by parasites in vitro versus in vivo. Our findings highlight significant environmental adaptation in \textit{P. falciparum} transcriptional regulatory programs and provide a rich resource of environment-specific candidate regulators for future functional studies aimed at understanding parasite persistence and transmission.

Subjects:	q-bio.GN; q-bio.QM
Cite as:	PX:2508.00020