ABSTRACT
BACKGROUNDThe biology of Plasmodium vivax is markedly different from that of P. falciparum; how this shapes the immune response to infection remains unclear. To address this shortfall, we inoculated human volunteers with a clonal field isolate of P. vivax and tracked their response through infection and convalescence.METHODSParticipants were injected intravenously with blood-stage parasites and infection dynamics were tracked in real time by quantitative PCR. Whole blood samples were used for high dimensional protein analysis, RNA sequencing, and cytometry by time of flight, and temporal changes in the host response to P. vivax were quantified by linear regression. Comparative analyses with P. falciparum were then undertaken using analogous data sets derived from prior controlled human malaria infection studies.RESULTSP. vivax rapidly induced a type I inflammatory response that coincided with hallmark features of clinical malaria. This acute-phase response shared remarkable overlap with that induced by P. falciparum but was significantly elevated (at RNA and protein levels), leading to an increased incidence of pyrexia. In contrast, T cell activation and terminal differentiation were significantly increased in volunteers infected with P. falciparum. Heterogeneous CD4+ T cells were found to dominate this adaptive response and phenotypic analysis revealed unexpected features normally associated with cytotoxicity and autoinflammatory disease.CONCLUSIONP. vivax triggers increased systemic interferon signaling (cf P. falciparum), which likely explains its reduced pyrogenic threshold. In contrast, P. falciparum drives T cell activation far in excess of P. vivax, which may partially explain why falciparum malaria more frequently causes severe disease.TRIAL REGISTRATIONClinicalTrials.gov NCT03797989.FUNDINGThe European Union's Horizon 2020 Research and Innovation programme, the Wellcome Trust, and the Royal Society.
Subject(s)
Malaria, Falciparum , Malaria, Vivax , Malaria , Humans , Plasmodium vivax , Plasmodium falciparum , Lymphocyte ActivationABSTRACT
Hematopoiesis provides an accessible system for studying the principles underlying cell-fate decisions in stem cells. Proposed models of hematopoiesis suggest that quantitative changes in lineage-specific transcription factors (LS-TFs) underlie cell-fate decisions. However, evidence for such models is lacking as TF levels are typically measured via RNA expression rather than by analyzing temporal changes in protein abundance. Here, we used single-cell mass cytometry and absolute quantification by mass spectrometry to capture the temporal dynamics of TF protein expression in individual cells during human erythropoiesis. We found that LS-TFs from alternate lineages are co-expressed, as proteins, in individual early progenitor cells and quantitative changes of LS-TFs occur gradually rather than abruptly to direct cell-fate decisions. Importantly, upregulation of a megakaryocytic TF in early progenitors is sufficient to deviate cells from an erythroid to a megakaryocyte trajectory, showing that quantitative changes in protein abundance of LS-TFs in progenitors can determine alternate cell fates.
Subject(s)
Erythropoiesis/physiology , Hematopoietic Stem Cells/physiology , Proteomics/methods , Antigens, CD34/metabolism , Cell Differentiation , Cell Lineage , Cells, Cultured , Gene Expression Regulation , Hematopoiesis , Humans , Mass Spectrometry , Single-Cell Analysis , Transcription Factors/metabolism , Transcriptional Activation , Umbilical Cord/cytologyABSTRACT
Replication is a process which provides two copies of genetic material to a mother cell that are essential for passing complete genetic information to daughter cells. Despite the extremely precise control of this process, regulation of replication can be impaired. This may trigger e.g. re-replication which leads to an increase in the total DNA content in a cell and, depending on the intensity, may result in gene amplification, genomic instability or apoptosis. Both replication and re-replication require pre-replication complex assembly, licensing, firing and initiation of DNA synthesis. Implications of each process in a cell are very different and all such possibilities are under intensive research because in both processes the same protein apparatus is used to carry out DNA synthesis. Therefore this article is meant to show the consequences of the same mechanism underlying two different processes.
