Cell-cell communication is an important mechanism for information exchange promoting cell survival for the control of features such as population density and differentiation. We determined that ...Plasmodium falciparum-infected red blood cells directly communicate between parasites within a population using exosome-like vesicles that are capable of delivering genes. Importantly, communication via exosome-like vesicles promotes differentiation to sexual forms at a rate that suggests that signaling is involved. Furthermore, we have identified a P. falciparum protein, PfPTP2, that plays a key role in efficient communication. This study reveals a previously unidentified pathway of P. falciparum biology critical for survival in the host and transmission to mosquitoes. This identifies a pathway for the development of agents to block parasite transmission from the human host to the mosquito.
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•Malaria-infected red blood cells communicate using exosome-like vesicles•Communication via exosome-like vesicles promotes differentiation to sexual forms•Pathway of P. falciparum biology for survival in host and mosquito transmission•Identification of a pathway for development of agents to block parasite transmission
The malaria-causing pathogen Plasmodium falciparum infects red blood cells and uses exosome-like vesicles to directly communicate within a population. These vesicles transmit information required for parasite survival, population density, and sexual differentiation within the host.
Malaria: Biology and Disease Cowman, Alan F.; Healer, Julie; Marapana, Danushka ...
Cell,
10/2016, Letnik:
167, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Malaria has been a major global health problem of humans through history and is a leading cause of death and disease across many tropical and subtropical countries. Over the last fifteen years ...renewed efforts at control have reduced the prevalence of malaria by over half, raising the prospect that elimination and perhaps eradication may be a long-term possibility. Achievement of this goal requires the development of new tools including novel antimalarial drugs and more efficacious vaccines as well as an increased understanding of the disease and biology of the parasite. This has catalyzed a major effort resulting in development and regulatory approval of the first vaccine against malaria (RTS,S/AS01) as well as identification of novel drug targets and antimalarial compounds, some of which are in human clinical trials.
Malaria is a major global health problem and a leading cause of disease and death. Efforts toward eradicating malaria involve a better understanding of the molecular mechanisms of disease to be able to develop novel antimalarial drugs and more efficacious vaccines.
Malaria is a major disease of humans caused by protozoan parasites from the genus Plasmodium. It has a complex life cycle; however, asexual parasite infection within the blood stream is responsible ...for all disease pathology. This stage is initiated when merozoites, the free invasive blood-stage form, invade circulating erythrocytes. Although invasion is rapid, it is the only time of the life cycle when the parasite is directly exposed to the host immune system. Significant effort has, therefore, focused on identifying the proteins involved and understanding the underlying mechanisms behind merozoite invasion into the protected niche inside the human erythrocyte.
Plasmodium species cause malaria by proliferating in human erythrocytes. Invasion of immunologically privileged erythrocytes provides a relatively protective niche as well as access to a rich source ...of nutrients. Plasmodium spp. target erythrocytes of different ages, but share a common mechanism of invasion. Specific engagement of erythrocyte receptors defines target cell tropism, activating downstream events and resulting in the physical penetration of the erythrocyte, powered by the parasite's actinomyosin-based motor. Here we review the latest in our understanding of the molecular composition of this highly complex and fascinating biological process.
Malaria parasites invade erythrocytes, a host cell that provides a protective niche and rich source of nutrients. In this review, Cowman et al. examine this invasion process and the roles of multiple ligand-receptor interactions that define target cell tropism, and activate downstream events resulting in physical penetration of the erythrocyte.
During blood stage Plasmodium falciparum infection, merozoites invade uninfected erythrocytes via a complex, multistep process involving a series of distinct receptor-ligand binding events. ...Understanding each element in this process increases the potential to block the parasite's life cycle via drugs or vaccines. To investigate specific receptor-ligand interactions, they were systematically blocked using a combination of genetic deletion, enzymatic receptor cleavage and inhibition of binding via antibodies, peptides and small molecules, and the resulting temporal changes in invasion and morphological effects on erythrocytes were filmed using live cell imaging. Analysis of the videos have shown receptor-ligand interactions occur in the following sequence with the following cellular morphologies; 1) an early heparin-blockable interaction which weakly deforms the erythrocyte, 2) EBA and PfRh ligands which strongly deform the erythrocyte, a process dependant on the merozoite's actin-myosin motor, 3) a PfRh5-basigin binding step which results in a pore or opening between parasite and host through which it appears small molecules and possibly invasion components can flow and 4) an AMA1-RON2 interaction that mediates tight junction formation, which acts as an anchor point for internalization. In addition to enhancing general knowledge of apicomplexan biology, this work provides a rational basis to combine sequentially acting merozoite vaccine candidates in a single multi-receptor-blocking vaccine.
The malaria parasite is the most important member of the Apicomplexa, a large and highly successful phylum of intracellular parasites. Invasion of host cells allows apicomplexan parasites access to a ...rich source of nutrients in a niche that is largely protected from host defenses. All Apicomplexa adopt a common mode of host-cell entry, but individual species incorporate unique features and utilize a specific set of ligand-receptor interactions. These adhesins ultimately connect to a parasite actin-based motor, which provides the power for invasion. While some Apicomplexa can invade many different host cells, the disease-associated blood-stage form of the malaria parasite is restricted to erythrocytes.
Plasmodium falciparum parasites in the merozoite stage invade human erythrocytes and cause malaria. Invasion requires multiple interactions between merozoite ligands and erythrocyte receptors. ...P. falciparum reticulocyte binding homolog 5 (PfRh5) forms a complex with the PfRh5-interacting protein (PfRipr) and Cysteine-rich protective antigen (CyRPA) and binds erythrocytes via the host receptor basigin. However, the specific role that PfRipr and CyRPA play during invasion is unclear. Using P. falciparum lines conditionally expressing PfRipr and CyRPA, we show that loss of PfRipr or CyRPA function blocks growth due to the inability of merozoites to invade erythrocytes. Super-resolution microscopy revealed that PfRipr, CyRPA, and PfRh5 colocalize at the junction between merozoites and erythrocytes during invasion. PfRipr, CyRPA, and PfRipr/CyRPA/PfRh5-basigin complex is required for triggering the Ca2+ release and establishing the tight junction. Together, these results establish that the PfRh5/PfRipr/CyRPA complex is essential in the sequential molecular events leading to parasite invasion of human erythrocytes.
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•P. falciparum PfRh5-binding partners PfRipr and CyRPA are essential for merozoite invasion•PfRipr and CyRPA are linked to release of calcium into the erythrocyte•PfRh5/PfRipr/CyRPA complex binding to host receptor basigin is required for Ca2+ release•PfRh5/PfRipr/CyRPA complex forms at the interface between the merozoite and erythrocyte
Plasmodium falciparum PfRipr and CyRPA form a complex with PfRh5, which mediates erythrocyte invasion. The specific role of PfRipr and CyRPA is unclear. Volz et al. (2016) show that PfRipr and CyRPA are essential for invasion and required for Ca2+ release during the sequential molecular events for invasion of erythrocytes.
Epigenetic processes are the main conductors of phenotypic variation in eukaryotes. The malaria parasite Plasmodium falciparum employs antigenic variation of the major surface antigen PfEMP1, encoded ...by 60 var genes, to evade acquired immune responses. Antigenic variation of PfEMP1 occurs through in situ switches in mono-allelic var gene transcription, which is PfSIR2-dependent and associated with the presence of repressive H3K9me3 marks at silenced loci. Here, we show that P. falciparum heterochromatin protein 1 (PfHP1) binds specifically to H3K9me3 but not to other repressive histone methyl marks. Based on nuclear fractionation and detailed immuno-localization assays, PfHP1 constitutes a major component of heterochromatin in perinuclear chromosome end clusters. High-resolution genome-wide chromatin immuno-precipitation demonstrates the striking association of PfHP1 with virulence gene arrays in subtelomeric and chromosome-internal islands and a high correlation with previously mapped H3K9me3 marks. These include not only var genes, but also the majority of P. falciparum lineage-specific gene families coding for exported proteins involved in host-parasite interactions. In addition, we identified a number of PfHP1-bound genes that were not enriched in H3K9me3, many of which code for proteins expressed during invasion or at different life cycle stages. Interestingly, PfHP1 is absent from centromeric regions, implying important differences in centromere biology between P. falciparum and its human host. Over-expression of PfHP1 results in an enhancement of variegated expression and highlights the presence of well-defined heterochromatic boundaries. In summary, we identify PfHP1 as a major effector of virulence gene silencing and phenotypic variation. Our results are instrumental for our understanding of this widely used survival strategy in unicellular pathogens.
One of the most fascinating and remarkable features of Plasmodium parasites, which cause malaria, is their choice of erythrocytes as the principal host cells in which to reside during infection of a ...vertebrate host. Parasites completely renovate the terminally differentiated cells, which lack most of the normal organelles and functions of other cells, such as a nucleus and the machinery to express and transport proteins to subcellular locations. Erythrocyte remodeling begins immediately after invasion by the Plasmodium parasite, by expression and export of many hundreds of proteins that assemble into molecular machinery in the host cell that permit protein trafficking, harvesting of nutrients, and mechanisms to evade host immune responses. In this review, we discuss recent studies on erythrocyte remodeling, including mechanisms of protein export as well as the identity, functions, and subcellular locations of key exported proteins.
The global agenda for malaria eradication would benefit from development of a highly efficacious vaccine that protects against disease and interrupts transmission of Plasmodium falciparum . It is ...likely that such a vaccine will be multi-component, with antigens from different stages of the parasite life cycle. In this review, inclusion of blood stage antigens in such a vaccine is discussed. Erythrocyte binding-like (EBL) and P. falciparum reticulocyte binding-like (PfRh) proteins are reviewed with respect to their function in erythrocyte invasion, their role in eliciting antibodies contributing to protective immunity and reduction of invasion, leading subsequently to inhibition of parasite multiplication.
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