Invasion by the malaria merozoite depends on recognition of specific erythrocyte surface receptors by parasite ligands. Plasmodium falciparum uses multiple ligands, including at least two gene families, reticulocyte binding protein homologues (RBLs) and erythrocyte binding proteins/ligands (EBLs). The combination of different RBLs and EBLs expressed in a merozoite defines the invasion pathway utilized and could also play a role in parasite virulence. The binding regions of EBLs lie in a conserved cysteine-rich domain while the binding domain of RBL is still not well characterized. Here, we identify the erythrocyte binding region of the P. falciparum reticulocyte binding protein homologue 1 (PfRH1) and show that antibodies raised against the functional binding region efficiently inhibit invasion. In addition, we directly demonstrate that changes in the expression of RBLs can constitute an immune evasion mechanism of the malaria merozoite.
The human parasite Plasmodium falciparum has the potential to express a vast repertoire of variant proteins on the surface of the infected red blood cell (iRBC). Variation in the expression pattern of these proteins is linked to antigenic variation and thereby evasion of host antibody-mediated immunity. The genes in the stevor multigene family code for small variant antigens that are expressed in blood-stage parasites where they can be detected in membranous structures called Maurer's clefts (MC). Some studies have indicated that STEVOR protein may also be trafficked to the iRBC membrane. To address the location of STEVOR protein in more detail, we have analyzed expression in several cultured parasite lines and in parasites obtained directly from patients. We detected STEVOR expression in a higher proportion of parasites recently isolated from patients than in cultured parasite lines and show that STEVOR is trafficked in schizont-stage parasites from the MC to the RBC cytosol and the iRBC membrane. Furthermore, STEVOR protein is also detected at the apical end of merozoites. Importantly, we show that culture-adapted parasites do not require STEVOR for survival. These findings provide new insights into the role of the stevor multigene family during both the schizont and merozoite stages of the parasite and highlight the importance of studying freshly isolated parasites, rather than parasite lines maintained in culture, when investigating potential mediators of host-parasite interactions.
The deformability of red blood cells (RBCs) is an important property that allows the cells to squeeze through small capillary vessels and can be used as an indicator for disease. We present a microfluidic based technique to quantify the deformability of RBCs by stretching a collection of RBCs on a timescale of tens of microseconds in a microfluidic chamber. This confinement constrains the motion of the cell to the imaging plane of the microscope during a transient cavitation bubble event generated with a focused and pulsed laser. We record and analyze the shape recovery of the cells with a high-speed camera and obtain a power law in time, consistent with other dynamic rheological results of RBCs. The extracted exponents are used to characterize the elastic properties of the cells. We obtain statistically significant differences of the exponents between populations of untreated RBCs and RBCs treated with two different reagents: neuraminidase reduces the cell rigidity, while wheat germ agglutinin stiffens the cell confirming previous experiments. This cavitation based technique is a candidate for high-throughput screening of elastic cell properties because many cells can be probed simultaneously in situ, thus with no pre-treatment.
The nuclear pore complex (NPC) is a large macromolecular assembly of around 30 different proteins, so-called nucleoporins (Nups). Embedded in the nuclear envelope the NPC mediates bi-directional exchange between the cytoplasm and the nucleus and plays a role in transcriptional regulation that is poorly understood. NPCs display modular arrangements with an overall structure that is generally conserved among many eukaryotic phyla. However, Nups of yeast or human origin show little primary sequence conservation with those from early-branching protozoans leaving those of the malaria parasite unrecognized. Here we have combined bioinformatic and genetic methods to identify and spatially characterize Nup components in the rodent infecting parasite Plasmodium berghei and identified orthologs from the human malaria parasite P. falciparum, as well as the related apicomplexan parasite Toxoplasma gondii. For the first time we show the localization of selected Nups throughout the P. berghei life cycle. Largely restricted to apicomplexans we identify an extended C-terminal poly-proline extension in SEC13 that is essential for parasite survival and provide high-resolution images of Plasmodium NPCs obtained by cryo electron tomography. Our data provide the basis for full characterization of NPCs in malaria parasites, early branching unicellular eukaryotes with significant impact on human health.
Background: Malaria parasitemia is commonly used as a measurement of the amount of parasites in the patient's blood and a crucial indicator for the degree of infection. Manual evaluation of Giemsa-stained thin blood smears under the microscope is onerous, time consuming and subject to human error. Although automatic assessments can overcome some of these problems the available methods are currently limited by their inability to evaluate cases that deviate from a chosen "standard" model.
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