Host cell maturation modulates parasite invasion and sexual differentiation in Plasmodium berghei

Abstract

Malaria remains a global health problem causing more than 400,000 deaths annually. Plasmodium parasites, the causative agents of malaria, replicate asexually in red blood cells (RBCs) of their vertebrate host, while a subset differentiates into sexual stages (gametocytes) for mosquito transmission. Parasite replication and gametocyte maturation in the erythropoietic niches of the bone marrow and spleen contribute to pathogenesis and drive transmission, but the mechanisms underlying this organ enrichment remain unknown. Here, we performed a comprehensive analysis of rodent P. berghei infection by flow cytometry and single-cell RNA sequencing. We identified CD71 as a host receptor for reticulocyte invasion and found that parasites metabolically adapt to the host cell environment. Transcriptional analysis and functional assays further revealed a nutrient-dependent tropism for gametocyte formation in reticulocytes. Together, we provide a thorough characterization of host-parasite interactions in erythropoietic niches and define host cell maturation state as the key driver of parasite adaptation.

Single-cell views of the Plasmodium life cycle

“…In an intriguing developmental parallel with blood-stage parasites, the transcription factor AP2-G and several sexual-stage genes were found to be expressed in a small subset of hepatic parasites, supporting the concept of hepatic sexual commitment [15]. Dual profiling of host and parasite transcriptomes also found evidence of a correlation between the metabolic state of the host cell and AP2-G expression [15], which is consistent with the view that sexual commitment depends on parasite nutrient-sensing mechanisms that translate signals from the host environment into transcriptional changes [26,27]. As these examples demonstrate, the ability to survey gene expression patterns across the developmental trajectories of different parasite species provides an opportunity to shed light on the functional strategies that drive both conserved and species-specific developmental outcomes.…”

“…Like CEL-Seq2 and MARS-seq, it uses UMIs. Seq-Well: low-cost scRNA-seq platform in which single cells and barcoded mRNA capture beads are sealed in an array of nano-wells using a semipermeable membrane, enabling in gene expression during ookinete maturation [5,7,20], sporozoite development [7,21,22], sexual commitment [23][24][25][26], as well as the asexual intraerythrocytic developmental cycle [5,6,17,26].…”

“…In another example, Ramos and colleagues drew on the MCA to annotate rodent Plasmodium chabaudi single-cell transcriptomes originating from wild type and gluconeogenesis deficient mice and were thus able to establish sexual conversion as a developmental adaptation to host hypoglycemia [33]. Hentzschel et al found evidence of an inverse correlation between host cell maturation and sexual commitment after assigning developmental stages through integration of query and reference P. berghei transcriptomes and contrasting the trajectories of parasites developing in normocytes versus reticulocytes [26].…”

“…Most single-cell sequencing studies applied to malaria research have so far given us a parasitecentric view of the life cycle. There is ample evidence, however, that parasites are impacted by cues from host local environments [27,37,38] and, conversely, host systems are extensively rewired during infection [15,26,39]. Thus, a better representation of the life cycle is one that captures the interdependency between parasite and host states across biological scales, from single infected cells to whole organs.…”

Uncovering a Cryptic Site of Malaria Pathogenesis: Models to Study Interactions Between Plasmodium and the Bone Marrow

“…Single cell RNA-seq (scRNA-seq) of bone marrow HSPCs from P. berghei- infected mice revealed a shift in lineage commitment toward the myeloid and basophil lineages at the expense of erythroid and megakaryocyte production, revealing a potential mechanism of impaired red cell production during infection ( Haltalli et al., 2020 ). In another study of P. berghei infection in the hematopoietic niche, infected cells from the spleen, bone marrow, and liver were analyzed by CITE-seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) using antibodies against markers of erythroid maturation ( Hentzschel et al., 2022 ). The authors found differences in parasite metabolism and likelihood of gametocyte commitment based on the maturation state of the host cell.…”