A5033252555- Malaria Research and Control
- Mosquito-borne diseases and control
- Trypanosoma species research and implications
- Drug Transport and Resistance Mechanisms
- Complement system in diseases
- HIV Research and Treatment
- Invertebrate Immune Response Mechanisms
- Iron Metabolism and Disorders
- Research on Leishmaniasis Studies
- Endoplasmic Reticulum Stress and Disease
- Hemoglobinopathies and Related Disorders
- Signaling Pathways in Disease
- Lysosomal Storage Disorders Research
- Vector-borne infectious diseases
- Amoebic Infections and Treatments
- Lipid Membrane Structure and Behavior
- HIV-related health complications and treatments
- Computational Drug Discovery Methods
- Toxoplasma gondii Research Studies
- HIV/AIDS drug development and treatment
- Pancreatic function and diabetes
- Prenatal Screening and Diagnostics
The Francis Crick Institute
2023-2024
Imperial College London
2018-2023
The University of Melbourne
2015
Walter and Eliza Hall Institute of Medical Research
2015
Deakin University
2010-2013
Bernhard Nocht Institute for Tropical Medicine
2005-2009
University of Lübeck
2005
University Hospital Schleswig-Holstein
2005
A key process in the lifecycle of malaria parasite Plasmodium falciparum is fast invasion human erythrocytes. Entry into host cell requires apical membrane antigen 1 (AMA-1), a type I transmembrane protein located micronemes merozoite. Although AMA-1 evolving leading blood-stage vaccine candidate, its precise role still unclear. We investigate function using live video microscopy absence and presence an inhibitory peptide. This data reveals crucial during primary contact period upstream...
Plasmodium parasites remodel their vertebrate host cells by translocating hundreds of proteins across an encasing membrane into the cell cytosol via a putative export machinery termed PTEX. Previously PTEX150, HSP101 and EXP2 have been shown to be bona fide members Here we validate that PTEX88 TRX2 are also genuine PTEX provide evidence expression components expressed in early gametocytes, mosquito liver stages, consistent with observations protein is not restricted asexual stages. Although...
A short motif termed Plasmodium export element (PEXEL) or vacuolar targeting signal (VTS) characterizes proteins exported into the host cell. These mediate cell modifications essential for parasite survival and virulence. However, several PEXEL-negative indicate that currently predicted malaria exportome is not complete it unknown whether how these relate to PEXEL-positive export. Here we show N-terminal 10 amino acids of protein REX2 (ring-exported 2) are necessary its a single-point...
Parasites from the genus Plasmodium are causative agents of malaria. The mobility, infectivity, and ultimately pathogenesis falciparum rely on a macromolecular complex, called glideosome. At core glideosome is an essential divergent Myosin A motor (PfMyoA), first order drug target against Here, we present full-length structure PfMyoA in two states its cycle. We report novel interactions that for priming mode recognition light chains (PfELC MTIP) by degenerate IQ motifs. Kinetic motility...
Phenotypic cell-based screens are critical tools for discovering candidate drugs development, yet identification of the cellular target and mode action a drug is often lacking. Using an imaging-based screen, we recently discovered N-[(4-hydroxychroman-4-yl)methyl]-sulphonamide (N-4HCS) compound, DDD01035881, that blocks male gamete formation in malaria parasite life cycle subsequent transmission to mosquito with nanomolar activity. To identify target(s) N-4HCS class compounds more broadly,...
Summary The Golgi apparatus forms the heart of secretory pathway in eukaryotic cells where proteins are modified, processed and sorted. transport from endoplasmic reticulum (ER) to cis‐ side complex takes place at specialized ER sub‐domains known as transitional (tER). We used Plasmodium falciparum orthologue Sec13p analyse tER organization. show that distribution Pf is restricted defined areas membrane. These foci juxtaposed might represent sites. To further cis ‐ trans ‐Golgi architecture,...
Plasmodium knowlesi, a zoonotic parasite causing severe-to-lethal malaria disease in humans, has only recently been adapted to continuous culture with human red blood cells (RBCs). In comparison the most virulent malaria, falciparum, there are, however, few cellular tools available study its biology, particular direct investigation of RBC invasion by blood-stage P. knowlesi merozoites. This leaves our current understanding biological differences across pathogenic spp. incomplete. Here, we...
All symptoms of malaria disease are associated with the asexual blood stages development, involving cycles red cell (RBC) invasion and egress by Plasmodium spp. merozoite. Merozoite is rapid actively powered a parasite actomyosin motor. The current accepted model for force generation envisages arrays myosins, pushing against short actin filaments connected to external milieu that drive merozoite forwards into RBC. In falciparum , most virulent human species, Myosin A (PfMyoA) critical...
Plasmodium falciparum, the causative agent of malaria, relies on a complex protein-secretion system for protein targeting into numerous subcellular destinations. Recently, homologue Golgi re-assembly stacking (GRASP) was identified and used to characterise organisation in this parasite. Here, we report presence splice variant that leads expression GRASP isoform. Although first (GRASP1) well-conserved myristoylation motif, (GRASP2) displays different N-terminus, similar GRASPs found fungi....
Protein export into the host red blood cell is one of key processes in pathobiology malaria parasite Plasmodiumtrl falciparum, which extensively remodels to ensure its virulence and survival. In this study, we aimed shed further light on protein mechanisms rodent P. berghei provide proof conserved nature remodeling Plasmodium spp. Based presence an motif (R/KxLxE/Q/D) termed PEXEL (Plasmodium element), have generated transgenic lines expressing GFP chimera putatively exported proteins...
ABSTRACT One of the key processes in pathobiology malaria parasite is invasion and subsequent modification human erythrocyte. In this complex process, an unknown number proteins are involved, some which leading vaccine candidates. The majority that play pivotal roles either stored apical secretory organelles or located on surface merozoite, invasive stage parasite. Using transcriptional structural features these known proteins, we performed a genomewide search identified 49 hypothetical with...
Proteins of the actin-depolymerizing factor (ADF)/cofilin family have been shown to be crucial for motility and survival apicomplexan parasites. However, mechanisms by which ADF proteins fulfill their function remain poorly understood. In this study, we investigate comparative activities from Toxoplasma gondii Plasmodium falciparum, human malaria parasite, using a conditional T. ADF-knockout line complemented with variants either species. We show that P. falciparum ADF1 can fully restore...
Recent studies highlight the emerging role of lipids as important messengers in malaria parasite biology. In an attempt to identify interacting proteins and regulators these dynamic versatile molecules, we hypothesised involvement phospholipid translocases their substrates infection host erythrocyte by Plasmodium spp. Here, using a data base searching approach Genomics Resources (www.plasmodb.org), have identified putative (PL) scramblase P. falciparum (PfPLSCR) that is conserved across...
The cGMP-dependent protein kinase (PKG) is the sole cGMP sensor in malaria parasites, acting as an essential signalling hub to govern key developmental processes throughout parasite life cycle. Despite importance of PKG clinically relevant asexual blood stages, many aspects malarial regulation, including phosphorylation, remain poorly understood. Here we use genetic and biochemical approaches show that reduced binding cyclic nucleotide domain B does not affect vitro activity but prevents...
The proliferation of the malaria parasite Plasmodium falciparum within human host is dependent upon invasion erythrocytes. This process accomplished by merozoite, a highly specialized form parasite. Secretory organelles including micronemes and rhoptries play pivotal role in storing releasing proteins. mechanism protein sorting to these compartments unclear. Using transgenic approach we show that trafficking most abundant micronemal proteins (members EBL-family: EBA-175, EBA-140/BAEBL,...
Protozoan parasites that cause malaria export hundreds of proteins into their host red blood cell cytosol, and some even beyond to the extracellular environment. These have a wide range functions are crucial parasite virulence and/or survival in human host. It has been thought for time common link all these is mechanism by which they exported. Recently, we revealed much how this occurs, including discovery novel translocon through exported must pass. As portal many essential becomes strongly...
Most cases of α-thalassemia result from large deletions at the α-globin locus (1). The gene cluster contains a tandem array 2 nearly identical genes ( HBA ; Fig. 1A⇓ ) (2). α-thalassemias are characterized by that inactivate both given chromosome, whereas in α+-thalassemias, one remains functional. most widespread α+-thalassemias those designated −α3.7 and −α4.2, according to lengths deleted fragments (3). The cannot be diagnosed on clinical grounds, routine laboratory tests fail, except...
Summary All symptoms of malaria disease are associated with the asexual blood stages development, involving cycles red cell (RBC) invasion and egress by Plasmodium spp. merozoite. Merozoite is rapid actively powered a parasite actomyosin motor. The current accepted model for force generation envisages arrays myosins, pushing against short actin filaments connected to external milieu that drive merozoite forwards into RBC. In falciparum , most virulent human species, Myosin A (PfMyoA)...
ABSTRACT Phenotypic cell-based screens are critical to the discovery of new antimalarial lead compounds. However, identification and validation cellular targets compounds is required following in a phenotypic screen. We recently discovered Plasmodium transmission-blocking N-((4-hydroxychroman-4-yl)methyl)-sulfonamide (N-4HCS) compound, DDD01035881 , its potent derivatives have been shown block male gamete formation (microgametogenesis) with nanomolar activity. Here, we synthesised...
Abstract The cGMP-dependent protein kinase (PKG) is the sole cGMP sensor in malaria parasites, acting as an essential signalling hub to govern key developmental processes throughout parasite life cycle. Despite importance of PKG clinically relevant asexual blood stages, many aspects malarial regulation, including phosphorylation, remain poorly understood. Here we use genetic and biochemical approaches show that reduced binding cyclic nucleotide domain B does not affect vitro activity but...