A5103240734- Research on Leishmaniasis Studies
- Trypanosoma species research and implications
- Parasites and Host Interactions
- Cellular transport and secretion
- Lysosomal Storage Disorders Research
- Toxin Mechanisms and Immunotoxins
- Heat shock proteins research
- Calcium signaling and nucleotide metabolism
- Immune Cell Function and Interaction
- Protein Kinase Regulation and GTPase Signaling
- Malaria Research and Control
- Retinoids in leukemia and cellular processes
- Genetic and Kidney Cyst Diseases
- Complement system in diseases
- Chemical Synthesis and Analysis
- Helminth infection and control
- Neurogenesis and neuroplasticity mechanisms
- Vector-Borne Animal Diseases
- Monoclonal and Polyclonal Antibodies Research
- Enzyme function and inhibition
- Transgenic Plants and Applications
- Parasite Biology and Host Interactions
- Signaling Pathways in Disease
- Insect Resistance and Genetics
- Parasitic Infections and Diagnostics
University of York
2008-2020
Hull York Medical School
2005-2017
Cambridge University Press
2014
National Institute for Biological Standards and Control
2011
Imperial College London
1999-2008
Wellcome Trust
2000-2008
Biology of Infection
2006
Eunice Kennedy Shriver Center
2001-2004
University of Massachusetts Chan Medical School
2003-2004
ActionAid
1994
The essential role of Toll-like receptors (TLR) in innate immune responses to bacterial pathogens is increasingly recognized, but very little known about the TLRs host defense against infections with eukaryotic pathogens. For present study, we investigated whether contribute and acquired response infection intracellular protozoan parasite Leishmania major. Our results show that TLR4 contributes control growth both phases response. We also addressed mechanism killing or parasites. Control...
Although asexual reproduction via clonal propagation has been proposed as the principal reproductive mechanism across parasitic protozoa of Leishmania genus, sexual recombination long suspected, based on hybrid marker profiles detected in field isolates from different geographical locations. The recent experimental demonstration a cycle within sand flies confirmed occurrence hybridisation, but knowledge parasite life wild still remains limited. Here, we use whole genome sequencing to...
Visceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post azar dermal (PKDL) a stigmatizing skin condition that often occurs in patients after successful treatment VL. Lack effective appropriately targeted cell mediated immunity, including CD8+ T responses, underlies progression VL to PKDL, can limit therapeutic efficacy anti-leishmanial drugs. Hence, addition need prophylactic vaccines against development...
Kupffer cells (KCs) represent the major phagocytic population within liver and provide an intracellular niche for survival of a number important human pathogens. Although KCs have been extensively studied in vitro, little is known their vivo response to infection capacity directly interact with antigen-specific CD8+ T cells. Here, using combination approaches including whole mount thin section confocal microscopy, adoptive cell transfer intra-vital 2-photon we demonstrate that only...
Abstract Vaccination against visceral leishmaniasis has received limited attention compared with cutaneous leishmaniasis, although the need for an effective vaccine is pressing. In this study, we demonstrate first time that a recombinant stage-specific hydrophilic surface protein of Leishmania donovani, acylated B1 (HASPB1), able to confer protection experimental challenge. Protection induced by rHASPB1 does not require adjuvant and, unlike soluble Ag + IL-12, extends control parasite burden...
Co-translational modification of eukaryotic proteins by <i>N</i>-myristoylation aids subcellular targeting and protein-protein interactions. The enzyme that catalyzes this process,<i>N</i>-myristoyltransferase (NMT), has been characterized in the kinetoplastid protozoan parasites, <i>Leishmania</i> and<i>Trypanosoma brucei</i>. In <i>Leishmania major</i>, single copy <i>NMT</i> gene is constitutively expressed all parasite stages as a 48.5-kDa protein localizes to both membrane cytoplasmic...
The surface of the protozoan parasiteLeishmania is unusual in that it consists predominantly glycosylphosphatidylinositol-anchored glycoconjugates and proteins. Additionally, a family hydrophilic acylated proteins (HASPs) has been localized to extracellular face plasma membrane infective parasite stages. These polypeptides lack recognizable endoplasmic reticulum secretory signal sequence, transmembrane spanning domain, or glycosylphosphatidylinositol-anchor consensus indicating novel...
The stage-regulated HASPB and SHERP proteins of Leishmania major are predominantly expressed in cultured metacyclic parasites that competent for macrophage uptake survival. role these parasite development the sand fly vector has not been explored, however. Here, we confirm expression is detected only stages, correlating with metacyclic-specific lipophosphoglycan providing first definitive protein marker this infective stage. Similarly, metacyclics but also at low levels preceding short...
N-Myristoyltransferase (NMT) catalyses the attachment of 14-carbon saturated fatty acid, myristate, to amino-terminal glycine residue a subset eukaryotic proteins that function in multiple cellular processes, including vesicular protein trafficking and signal transduction. In these pathways, N-myristoylation facilitates association substrate with membranes or hydrophobic domains other partner peptides. NMT is essential for viability all cell types tested date, demonstrating this enzyme has...
Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors protozoan NMTs, we chose screen diverse subset Pfizer corporate collection against Plasmodium falciparum Leishmania donovani NMTs. Primary screening hits either enzyme were tested selectivity over both human NMT isoforms (Hs1 Hs2) broad-spectrum anti-protozoan activity from Trypanosoma...
N-Myristoyltransferase (NMT) modulates protein function through the attachment of lipid myristate to N terminus target proteins, and is a promising drug in eukaryotic parasites such as Leishmania donovani. Only small number NMT substrates have been characterized Leishmania, global picture N-myristoylation lacking. Here, we use metabolic tagging with an alkyne-functionalized myristic acid mimetic live followed by downstream click chemistry analysis identify lipidated proteins both...
Summary Sphingolipids are structural components of the eukaryotic plasma membrane that involved, together with cholesterol, in formation lipid microdomains (rafts). Additionally, sphingolipid metabolites have been shown to modulate a wide variety cellular events, including differentiation and apoptosis. To investigate role de novo biosynthesis Leishmania , we focused on serine palmitoyltransferase (SPT), which catalyses first, rate‐limiting step synthetic pathway. Genetic ablation one SPT...
N-Myristoyl transferase-mediated modification with azide-bearing substrates is introduced as a highly selective and practical method for in vitro vivo N-terminal labelling of recombinant protein using bioorthogonal ligation chemistry.
A 1700 nucleotide DNA sequence derived from Xenopus vitellogenin mRNA has been cloned in the bacterial plasmid pBR322. The identity of was verified two ways. Firstly, shown to hybridise an RNA correct size (6,700 nucleotides). This by situ hybridisation electrophoretically separated and also formation "R-loops" with purified mRNA. Then, using a novel procedure which covalently bound diazotised paper is used select complementary sequences, directed synthesis when translated reticulocyte...
Therapeutic vaccines, when used alone or in combination therapy with antileishmanial drugs, may have an important place the control of a variety forms human leishmaniasis. Here, we describe development adenovirus-based vaccine (Ad5-KH) comprising synthetic haspb gene linked to kmp11 via viral 2A sequence. In nonvaccinated Leishmania donovani–infected BALB/c mice, HASPB- and KMP11-specific CD8+ T cell responses were undetectable, although IgG1 IgG2a antibodies evident. After therapeutic...