Proteases in host cell invasion by the malaria parasite

Blackman, Michael J.

doi:10.1111/j.1462-5822.2004.00437.x

Cited by 43 publications

(48 citation statements)

References 98 publications

(113 reference statements)

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“…Clearly, the processes involved in the cleavage and shedding of the surface coat are specific and not universal or nonselective; instead, they act against a subset of proteins. A further understanding of the molecular basis of merozoite protein processing might reveal attractive targets for the development of antimalarial inhibitors, and several proteases that inhibit invasion have been reported in the literature (6,13). Furthermore, with merozoite surface proteins being the targets of vaccine development, clear characterization of individual proteins during and after invasion informs vaccine development by identifying periods when parasite proteins are most likely to be targeted by the immune system (32,33).…”

Section: Discussionmentioning

confidence: 99%

Sequential Processing of Merozoite Surface Proteins during and after Erythrocyte Invasion by Plasmodium falciparum

et al. 2014

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e Plasmodium falciparum causes malaria disease during the asexual blood stages of infection when merozoites invade erythrocytes and replicate. Merozoite surface proteins (MSPs) are proposed to play a role in the initial binding of merozoites to erythrocytes, but precise roles remain undefined. Based on electron microscopy studies of invading Plasmodium merozoites, it is proposed that the majority of MSPs are cleaved and shed from the surface during invasion, perhaps to release receptor-ligand interactions. In this study, we demonstrate that there is not universal cleavage of MSPs during invasion. Instead, there is sequential and coordinated cleavage and shedding of proteins, indicating a diversity of roles for surface proteins during and after invasion. While MSP1 and peripheral surface proteins such as MSP3, MSP7, serine repeat antigen 4 (SERA4), and SERA5 are cleaved and shed at the tight junction between the invading merozoite and erythrocyte, the glycosylphosphatidylinositol (GPI)-anchored proteins MSP2 and MSP4 are carried into the erythrocyte without detectable processing. Following invasion, MSP2 rapidly degrades within 10 min, whereas MSP4 is maintained for hours. This suggests that while some proteins that are shed upon invasion may have roles in initial contact steps, others function during invasion and are then rapidly degraded, whereas others are internalized for roles during intraerythrocytic development. Interestingly, anti-MSP2 antibodies did not inhibit invasion and instead were carried into erythrocytes and maintained for approximately 20 h without inhibiting parasite development. These findings provide new insights into the mechanisms of invasion and knowledge to advance the development of new drugs and vaccines against malaria.

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Section: Discussionmentioning

confidence: 99%

Sequential Processing of Merozoite Surface Proteins during and after Erythrocyte Invasion by Plasmodium falciparum

et al. 2014

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“…Many P. falciparum proteins, including MSPs, are modified extensively during schizogony through sequential proteolytic events mediated by proteases to ensure successful invasion of the merozoite into human erythrocytes (48). In addition, the peripheral merozoite surface proteins MSP3, MSP6, MSP-DBL1, MSPDBL2, and MSP7 do not have a transmembrane domain or GPI anchor and therefore interact with anchored proteins to be presented on the merozoite surface.…”

Section: Discussionmentioning

confidence: 99%

Multiple Plasmodium falciparum Merozoite Surface Protein 1 Complexes Mediate Merozoite Binding to Human Erythrocytes

Lin

Uboldi

Epp

et al. 2016

Journal of Biological Chemistry

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Successful invasion of human erythrocytes by Plasmodium falciparum merozoites is required for infection of the host and parasite survival. The early stages of invasion are mediated via merozoite surface proteins that interact with human erythrocytes. The nature of these interactions are currently not well understood, but it is known that merozoite surface protein 1 (MSP1) is critical for successful erythrocyte invasion. Here we show that the peripheral merozoite surface proteins MSP3, MSP6, MSPDBL1, MSPDBL2, and MSP7 bind directly to MSP1, but independently of each other, to form multiple forms of the MSP1 complex on the parasite surface. These complexes have overlapping functions that interact directly with human erythrocytes. We also show that targeting the p83 fragment of MSP1 using inhibitory antibodies inhibits all forms of MSP1 complexes and disrupts parasite growth in vitro.

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“…In this study, we focused on the subtilisin-like serine protease or subtilase CpSUB1. Although subtilases have been identified in a number of apicomplexan parasites, the best-characterized subtilases are those of Plasmodium falciparum and Toxoplasma gondii (7,10,22,41). For P. falciparum, three subtilases are currently annotated in PlasmoDB, but only PfSUB1 and PfSUB2 have been characterized (41).…”

Section: Discussionmentioning

confidence: 99%

“…Proteolytic processing of surface and apical complex proteins by parasite proteases is required for invasion of host cells, for assembly and trafficking of proteins, and for egress from host cells (6,7,10,22). A number of these proteins are processed by serine proteases, which are characterized by the presence of a conserved serine residue in the active site (18).…”

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confidence: 99%

Role of CpSUB1, a Subtilisin-Like Protease, in Cryptosporidium parvum Infection In Vitro

et al. 2009

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The apicomplexan parasite Cryptosporidium is a significant cause of diarrheal disease worldwide. Previously, we reported that a Cryptosporidium parvum subtilisin-like serine protease activity with furin-type specificity cleaves gp40/15, a glycoprotein that is proteolytically processed into gp40 and gp15, which are implicated in mediating infection of host cells. Neither the enzyme(s) responsible for the protease activity in C. parvum lysates nor those that process gp40/15 are known. There are no furin or other proprotein convertase genes in the C. parvum genome. However, a gene encoding CpSUB1, a subtilisin-like serine protease, is present. In this study, we cloned the CpSUB1 genomic sequence and expressed and purified the recombinant prodomain. Reverse transcriptase PCR analysis of RNA from C. parvum-infected HCT-8 cells revealed that CpSUB1 is expressed throughout infection in vitro. In immunoblots, antiserum to the recombinant CpSUB1 prodomain revealed two major bands, of ϳ64 kDa and ϳ48 kDa, for C. parvum lysates and proteins "shed" during excystation. In immunofluorescence assays, the antiserum reacted with the apical region of sporozoites and merozoites. The recombinant prodomain inhibited protease activity and processing of recombinant gp40/15 by C. parvum lysates but not by furin. Since prodomains are often selective inhibitors of their cognate enzymes, these results suggest that CpSUB1 may be a likely candidate for the protease activity in C. parvum and for processing of gp40/15. Importantly, the recombinant prodomain inhibited C. parvum infection of HCT-8 cells. These studies indicate that CpSUB1 plays a significant role in infection of host cells by the parasite and suggest that this enzyme may serve as a target for intervention.

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Proteases in host cell invasion by the malaria parasite

Cited by 43 publications

References 98 publications

Sequential Processing of Merozoite Surface Proteins during and after Erythrocyte Invasion by Plasmodium falciparum

Sequential Processing of Merozoite Surface Proteins during and after Erythrocyte Invasion by Plasmodium falciparum

Multiple Plasmodium falciparum Merozoite Surface Protein 1 Complexes Mediate Merozoite Binding to Human Erythrocytes

Role of CpSUB1, a Subtilisin-Like Protease, in Cryptosporidium parvum Infection In Vitro

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