Plasmodium falciparum infection of human erythroblasts induces transcriptional changes associated with dyserythropoiesis.

During development down the erythroid lineage, hematopoietic stem cells undergo dramatic changes to cellular morphology and function in response to a complex and tightly regulated program of gene expression. In malaria infection, Plasmodium spp . parasites accumulate in the bone marrow parenchyma, and emerging evidence suggests erythroblastic islands are a protective site for parasite development into gametocytes. While it has been observed that Plasmodium falciparum infection of late-stage erythroblasts can delay terminal erythroid differentiation and enucleation, the mechanism(s) underlying this phenomenon are unknown. Here, we apply RNA-seq after fluorescence-activated cell sorting (FACS) of infected erythroblasts to identify transcriptional responses to direct and indirect interaction with Plasmodium falciparum . Four developmental stages of erythroid cells were analyzed: proerythroblast, basophilic erythroblast, polychromatic erythroblast, and orthochromatic erythroblast. We found extensive transcriptional changes in infected erythroblasts compared to uninfected cells in the same culture, including dysregulation of genes involved in erythroid proliferation and developmental processes. Whereas some indicators of cellular oxidative and proteotoxic stress were common across all stages of erythropoiesis, many responses were specific to cellular processes associated with developmental stage. Together, our results evidence multiple possible avenues by which parasite infection can induce dyserythropoiesis at specific points along the erythroid continuum, advancing our understanding of the molecular determinants of malaria anemia. Key Points: Erythroblasts at different stages of differentiation have distinct responses to infection by Plasmodium falciparum . P. falciparum infection of erythroblasts alters expression of genes related to oxidative and proteotoxic stress and erythroid development.

Plasmodium falciparum infection of human erythroblasts induces transcriptional changes associated with dyserythropoiesis.

During development down the erythroid lineage, hematopoietic stem cells undergo dramatic changes to cellular morphology and function in response to a complex and tightly regulated program of gene expression. In malaria infection, Plasmodium spp parasites accumulate in the bone marrow parenchyma, and emerging evidence suggests erythroblastic islands are a protective site for parasite development into gametocytes. Although it has been observed that Plasmodium falciparum infection in late-stage erythroblasts can delay terminal erythroid differentiation and enucleation, the mechanism(s) underlying this phenomenon are unknown. Here, we apply RNA sequencing after fluorescence-activated cell sorting of infected erythroblasts to identify transcriptional responses to direct and indirect interaction with P falciparum. Four developmental stages of erythroid cells were analyzed: proerythroblast, basophilic erythroblast, polychromatic erythroblast, and orthochromatic erythroblast. We found extensive transcriptional changes in infected erythroblasts compared with that in uninfected cells in the same culture, including dysregulation of genes involved in erythroid proliferation and developmental processes. Although some indicators of cellular oxidative and proteotoxic stress were common across all stages of erythropoiesis, many responses were specific to cellular processes associated with developmental stage. Together, our results evidence multiple possible avenues by which parasite infection can induce dyserythropoiesis at specific points along the erythroid continuum, advancing our understanding of the molecular determinants of malaria anemia.

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

The bone marrow is a critical site of host-pathogen interactions in malaria infection. The discovery of Plasmodium asexual and transmission stages in the bone marrow has renewed interest in the tissue as a niche for cellular development of both host and parasite. Despite its importance, bone marrow in malaria infection remains largely unexplored due to the challenge of modeling the complex hematopoietic environment in vitro. Advancements in modeling human erythropoiesis ex-vivo from primary human hematopoietic stem and progenitor cells provide a foothold to study the host-parasite interactions occurring in this understudied site of malaria pathogenesis. This review focuses on current in vitro methods to recapitulate and assess bone marrow erythropoiesis and their potential applications in the malaria field. We summarize recent studies that leveraged ex-vivo erythropoiesis to shed light on gametocyte development in nucleated erythroid stem cells and begin to characterize host cell responses to Plasmodium infection in the hematopoietic niche. Such models hold potential to elucidate mechanisms of disordered erythropoiesis, an underlying contributor to malaria anemia, as well as understand the biological determinants of parasite sexual conversion. This review compares the advantages and limitations of the ex-vivo erythropoiesis approach with those of in vivo human and animal studies of the hematopoietic niche in malaria infection. We highlight the need for studies that apply single cell analyses to this complex system and incorporate physical and cellular components of the bone marrow that may influence erythropoiesis and parasite development.

Auxin-induced degradation dynamics set the pace for lateral root development.

Auxin elicits diverse cell behaviors through a simple nuclear signaling pathway initiated by degradation of Aux/IAA co-repressors. Our previous work revealed that members of the large Arabidopsis Aux/IAA family exhibit a range of degradation rates in synthetic contexts. However, it remained an unresolved issue whether differences in Aux/IAA turnover rates played a significant role in plant responses to auxin. Here, we use the well-established model of lateral root development to directly test the hypothesis that the rate of auxin-induced Aux/IAA turnover sets the pace for auxin-regulated developmental events. We did this by generating transgenic plants expressing degradation rate variants of IAA14, a crucial determinant of lateral root initiation. Progression through the well-established stages of lateral root development was strongly correlated with the engineered rates of IAA14 turnover, leading to the conclusion that Aux/IAAs are auxin-initiated timers that synchronize developmental transitions.