Abstract
Invasion of the erythrocyte by the merozoites of the malaria parasite is a complex process involving a range of receptor-ligand interactions. Two protein families termed Erythrocyte Binding Like (EBL) proteins and Reticulocyte Binding Protein Homologues (RH) play an important role in host cell recognition by the merozoite. In the rodent malaria parasite, Plasmodium yoelii, the 235 kDa rhoptry proteins (Py235) are coded for by a multigene family and are members of the RH. In P. yoelii Py235 as well as a single member of EBL have been shown to be key mediators of virulence enabling the parasite to invade a wider range of host erythrocytes. One member of Py235, PY01365 is most abundantly transcribed in parasite populations and the protein specifically binds to erythrocytes and is recognized by the protective monoclonal antibody 25.77, suggesting a key role of this particular member in virulence. Recent studies have indicated that overall levels of Py235 expression are essential for parasite virulence. Here we show that disruption of PY01365 in the virulent YM line directly impacts parasite virulence. Furthermore the disruption of PY01365 leads to a reduction in the number of schizonts that express members of Py235 that react specifically with the mcAb 25.77. Erythrocyte binding assays show reduced binding of Py235 to red blood cells in the PY01365 knockout parasite as compared to YM. While our results identify PY01365 as a mediator of parasite virulence, they also confirm that other members of Py235 are able to substitute for PY01365.
Highlights
Invasion of the red blood cell and its subsequent destruction is a main contributor to malaria associated pathology
We have previously shown that reduced parasite virulence is linked to an increase in the selectivity index (SI) of the parasite [3], with a higher SI indicating a restricted host cell range
Previous studies looking at the transcriptional profile of Py235 in P. yoelii have shown that different members of Py235 are transcribed at different levels, with PY01365 being transcribed at the highest level in both virulent and avirulent parasite lines [27]
Summary
Invasion of the red blood cell (rbc) and its subsequent destruction is a main contributor to malaria associated pathology. The human parasite Plasmodium falciparum is able to invade rbc of all ages while P. vivax is only able to invade a relatively small subset of circulating rbc, the reticulocytes. This leads to a significantly lower overall parasite burden in P. vivax as compared to P. falciparum, resulting in differences in pathology due to parasitaemia. In P. yoelii the virulent YM strain is able to invade rbc of all ages [6] while the avirulent 17X1.1 and YA strains are mainly restricted to young erythrocytes [7], reflecting the invasion characteristics of P. falciparum and P. vivax, respectively. Comparisons of virulent and avirulent clones of P. yoelii have identified two protein families, Py235 (Plasmodium yoelii 235 kDa rhoptry protein family) and PyEBL (P. yoelii Erythrocyte Binding Like) as key mediators of invasion efficiency [8,9,10,11,12]
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