Sterile protection against malaria by repeated blood stage infection in the monkey model.

The malaria parasite remains a major global public health challenge, and no vaccine is approved for use in humans. Here, we assessed whether strain-transcendent immunity can be achieved by repeated infection in monkeys. Sterile immunity was achieved after two homologous infections, whereas subsequent heterologous challenge provided only partial protection.

Genetic validation of FKBP35 as an antimalarial drug target.

accounts for the majority of over 600,000 malaria-associated deaths annually. Parasites resistant to nearly all antimalarials have emerged and the need for drugs with alternative modes of action is thus undoubted. The FK506-binding protein FKBP35 has gained attention as a promising drug target due to its high affinity to the macrolide compound FK506 (tacrolimus).

adapts its investment into replication transmission according to the host environment.

The malaria parasite life cycle includes asexual replication in human blood, with a proportion of parasites differentiating to gametocytes required for transmission to mosquitoes. Commitment to differentiate into gametocytes, which is marked by activation of the parasite transcription factor , is known to be influenced by host factors but a comprehensive model remains uncertain. Here, we analyze data from 828 children in Kilifi, Kenya with severe, uncomplicated, and asymptomatic malaria infection over 18 years of falling malaria transmission.

Transcriptional differentiation of Trypanosoma brucei during in vitro acquisition of resistance to acoziborole.

Subspecies of the protozoan parasite Trypanosoma brucei are the causative agents of Human African Trypanosomiasis (HAT), a debilitating neglected tropical disease prevalent across sub-Saharan Africa. HAT case numbers have steadily decreased since the start of the century, and sustainable elimination of one form of the disease is in sight. However, key to this is the development of novel drugs to combat the disease.

Running on Empty: A Metabolomics Approach to Investigating Changing Energy Metabolism during Fasted Exercise and Rest.

Understanding the metabolic processes in energy metabolism, particularly during fasted exercise, is a growing area of research. Previous work has focused on measuring metabolites pre and post exercise. This can provide information about the final state of energy metabolism in the participants, but it does not show how these processes vary during the exercise and any subsequent post-exercise period.

Suramin exposure alters cellular metabolism and mitochondrial energy production in African trypanosomes.

Introduced about a century ago, suramin remains a frontline drug for the management of early-stage East African trypanosomiasis (sleeping sickness). Cellular entry into the causative agent, the protozoan parasite , occurs through receptor-mediated endocytosis involving the parasite's invariant surface glycoprotein 75 (ISG75), followed by transport into the cytosol via a lysosomal transporter. The molecular basis of the trypanocidal activity of suramin remains unclear, but some evidence suggests broad, but specific, impacts on trypanosome metabolism ( polypharmacology).

Plasmodium falciparum Gametocyte Density and Infectivity in Peripheral Blood and Skin Tissue of Naturally Infected Parasite Carriers in Burkina Faso.

Background: Plasmodium falciparum transmission depends on mature gametocytes that can be ingested by mosquitoes taking a blood meal on human skin. Although gametocyte skin sequestration has long been hypothesized as important contributor to efficient malaria transmission, this has never been formally tested.

Methods: In naturally infected gametocyte carriers from Burkina Faso, we assessed infectivity to mosquitoes by direct skin feeding and membrane feeding.

Revisiting gametocyte biology in malaria parasites.

Gametocytes are the only form of the malaria parasite that is transmissible to the mosquito vector. They are present at low levels in blood circulation and significant knowledge gaps exist in their biology. Recent reductions in the global malaria burden have brought the possibility of elimination and eradication, with renewed focus on malaria transmission biology as a basis for interventions.

Mapping the metabolism of five amino acids in bloodstream form using U-C-labelled substrates and LC-MS.

The metabolism of the parasite has been the focus of numerous studies since the 1940s. Recently it was shown, using metabolomics coupled with heavy-atom isotope labelled glucose, that the metabolism of the bloodstream form parasite is more complex than previously thought. The present study also raised a number of questions regarding the origin of several metabolites, for example succinate, only a proportion of which derives from glucose.

Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in Trypanosoma brucei.

The parasitic protozoan Trypanosoma brucei causes Human African Trypanosomiasis and Nagana in other mammals. These diseases present a major socio-economic burden to large areas of sub-Saharan Africa. Current therapies involve complex and toxic regimens, which can lead to fatal side-effects.

Metabolomic profiling of macrophages determines the discrete metabolomic signature and metabolomic interactome triggered by polarising immune stimuli.

Priming and activating immune stimuli have profound effects on macrophages, however, studies generally evaluate stimuli in isolation rather than in combination. In this study we have investigated the effects of pro-inflammatory and anti-inflammatory stimuli either alone or in combination on macrophage metabolism. These stimuli include host factors such as IFNγ and ovalbumin-immunoglobulin immune complexes, or pathogen factors such as LPS.

LC-MS-based absolute metabolite quantification: application to metabolic flux measurement in trypanosomes.

Human African trypanosomiasis is a neglected tropical disease caused by the protozoan parasite, . In the mammalian bloodstream, the trypanosome's metabolism differs significantly from that of its host. For example, the parasite relies exclusively on glycolysis for energy source.

Probing the metabolic network in bloodstream-form Trypanosoma brucei using untargeted metabolomics with stable isotope labelled glucose.

Metabolomics coupled with heavy-atom isotope-labelled glucose has been used to probe the metabolic pathways active in cultured bloodstream form trypomastigotes of Trypanosoma brucei, a parasite responsible for human African trypanosomiasis. Glucose enters many branches of metabolism beyond glycolysis, which has been widely held to be the sole route of glucose metabolism. Whilst pyruvate is the major end-product of glucose catabolism, its transamination product, alanine, is also produced in significant quantities.

Trypanosoma brucei: meet the system.

African trypanosomes cause devastating diseases in humans and domestic animals. The parasites evolved early in the eukaryotic lineage and have numerous biochemical peculiarities that distinguish them from other systems. These include unconventional mechanisms for expressing nuclear and mitochondrial genes as well as unusual subcellular localizations for a variety of enzymes.

The silicon trypanosome: a test case of iterative model extension in systems biology.

The African trypanosome, Trypanosoma brucei, is a unicellular parasite causing African Trypanosomiasis (sleeping sickness in humans and nagana in animals). Due to some of its unique properties, it has emerged as a popular model organism in systems biology. A predictive quantitative model of glycolysis in the bloodstream form of the parasite has been constructed and updated several times.

Handling uncertainty in dynamic models: the pentose phosphate pathway in Trypanosoma brucei.

Dynamic models of metabolism can be useful in identifying potential drug targets, especially in unicellular organisms. A model of glycolysis in the causative agent of human African trypanosomiasis, Trypanosoma brucei, has already shown the utility of this approach. Here we add the pentose phosphate pathway (PPP) of T.

Explicit consideration of topological and parameter uncertainty gives new insights into a well-established model of glycolysis.

Previous models of glycolysis in the sleeping sickness parasite Trypanosoma brucei assumed that the core part of glycolysis in this unicellular parasite is tightly compartimentalized within an organelle, the glycosome, which had previously been shown to contain most of the glycolytic enzymes. The glycosomes were assumed to be largely impermeable, and exchange of metabolites between the cytosol and the glycosome was assumed to be regulated by specific transporters in the glycosomal membrane. This tight compartmentalization was considered to be essential for parasite viability.

Modeling challenges in the synthetic biology of secondary metabolism.

The successful engineering of secondary metabolite production relies on the availability of detailed computational models of metabolism. In this brief review we discuss the types of models used for synthetic biology and their application for the engineering of metabolism. We then highlight some of the major modeling challenges, in particular the need to make informative model predictions based on incomplete and uncertain information.

mzMatch-ISO: an R tool for the annotation and relative quantification of isotope-labelled mass spectrometry data.

Motivation: Stable isotope-labelling experiments have recently gained increasing popularity in metabolomics studies, providing unique insights into the dynamics of metabolic fluxes, beyond the steady-state information gathered by routine mass spectrometry. However, most liquid chromatography-mass spectrometry data analysis software lacks features that enable automated annotation and relative quantification of labelled metabolite peaks. Here, we describe mzMatch-ISO, a new extension to the metabolomics analysis pipeline mzMatch.

Dynamic modelling under uncertainty: the case of Trypanosoma brucei energy metabolism.

Kinetic models of metabolism require detailed knowledge of kinetic parameters. However, due to measurement errors or lack of data this knowledge is often uncertain. The model of glycolysis in the parasitic protozoan Trypanosoma brucei is a particularly well analysed example of a quantitative metabolic model, but so far it has been studied with a fixed set of parameters only.

A Boolean probabilistic model of metabolic adaptation to oxygen in relation to iron homeostasis and oxidative stress.

Background: In aerobically grown cells, iron homeostasis and oxidative stress are tightly linked processes implicated in a growing number of diseases. The deregulation of iron homeostasis due to gene defects or environmental stresses leads to a wide range of diseases with consequences for cellular metabolism that remain poorly understood. The modelling of iron homeostasis in relation to the main features of metabolism, energy production and oxidative stress may provide new clues to the ways in which changes in biological processes in a normal cell lead to disease.

AutoClass@IJM: a powerful tool for Bayesian classification of heterogeneous data in biology.

Recently, several theoretical and applied studies have shown that unsupervised Bayesian classification systems are of particular relevance for biological studies. However, these systems have not yet fully reached the biological community mainly because there are few freely available dedicated computer programs, and Bayesian clustering algorithms are known to be time consuming, which limits their usefulness when using personal computers. To overcome these limitations, we developed AutoClass@IJM, a computational resource with a web interface to AutoClass, a powerful unsupervised Bayesian classification system developed by the Ames Research Center at N.