Parasite Genetics and Adaptations

Project B1 - 2nd Cohort

RNA Processing and Turnover in Apicomplexan Organelles

CHRISTIAN SCHMITZ-LINNEWEBER (HUB) in partnership with Melanie Rug (ANU) and Alexander Maier (ANU)

Apicoplasts and mitochondria contain their own genetic information. Gene expression in these organelles is essential for parasite survival. Antibiotics targeting gene expression in the apicoplast and mitochondrion serve as potent antimalarials. Very little is known about the organellar gene expression machinery in Apicomplexans. We recently identified a family of RNA binding proteins named heptatricopeptide repeat proteins. Members of this family were demonstrated to reside in RNA granules in human mitochondria and play a role in rRNA and mRNA processing. Initial gene tagging and knock-out approaches demonstrated that these proteins reside in mitochondria and are essential for parasite survival. Their exact functions in mitochondrial RNA metabolism remains enigmatic. In general, RNA turnover and its regulation is hardly addressed in Apicomplexans, neither in organelles nor in the nucleo-cytoplasmic compartment. This project aims at filling this gap in our knowledge.

Zala Gluhic

Project B2 - 2nd Cohort 

Characterising Lipid droplets (LD) in various life cycle stages of Plasmodium sp. 

MELANIE RUG (ANU) in partnership with Elena Levashina (MPIIB) and Kai Matuschewski (HUB)

During the intraerythrocytic cell cycle, P. falciparum manipulates lipid-dependent processes, which include intracellular signalling, protein trafficking, membrane biogenesis, and haemoglobin degradation, resulting in significant alteration of lipid composition. Lipid droplets (LDs) are known to be a vital source of energy and an essential element for metabolic homeostasis. The core of LD is composed with neutral lipids and surrounded by a monolayered phospholipids and associated proteins. LDs are not only viewed as a place for lipid storage but also as an active organelle which interacts with other organelles, and with central roles in cellular metabolism. Due to their essential roles, Plasmodium lipid synthesis proteins are emerging as potential drug targets. And yet, important questions such as the mechanisms controlling the formation and dynamics of LDs remain elusive. In recent times, there has been a great development in lipid labelling techniques and microscopy techniques and the combination of these techniques has the potential to provide a complete characterisation of the organisation and metabolism of intracellular lipids. Here, we set out to study lipid transport between organelles and identify the morphology and composition of lipid droplets (LDs) in various life cycle stages of P. falciparum. 

Jiwon Lee

Project B3 - 2nd Cohort 

Characterizing Plasmodium Protein Function at the Parasite-Host Interface During both Liver and Blood Infection Stages

ALYSSA INGMUNDSON (HUB) in partnership with Melanie Rug (ANU) and Alexander Maier (ANU) 

While protein export and host cell membrane remodeling are processes conserved across Plasmodium species, their influence on the ability of parasites to thrive in their hosts has been primarily studied in Plasmodium falciparum. While P. falciparum is the deadliest malaria species, it is evolutionarily distinct from the other human-infecting species, such as P. vivax and P. knowlesi. We have been studying P. berghei proteins that are conserved in most human- or rodent-infecting species, but absent from P. falciparum. These proteins are expressed in both the liver and blood stages of infection and are exported into the host red blood cell where they localize to membranes formed in the host cytoplasm and influence the ability of infected red blood cells to sequester in the microvasculature.

Florian Kirscht

Project B4 - 2nd Cohort

Tubulin - A Novel Lead to Antimalarial Drug Discovery

SIMONE REBER (HUB) in partnership with Kevin Saliba (ANU)

The highly dynamic microtubulecytoskeleton plays an essential  role in the structural integrity of malarial parasites. Consistent with its important role, microtubule-disruptive drugs have great potential as anti-malarial agents. The current therapeutic options

of microtubule-disruptive drugs, however, are limited by their high toxicity to mammalian cells. The aim of this PhD project is to characterize Plasmodium tubulin biochemically and biophysically in order to improve its druggability and to advance the potential of Plasmodium tubulin as anti-malarial.

Dominik Fachet

Project B6 - 2nd Cohort

Structural Elucidation of the Interaction of Apicoplast-Resident Ferredoxin with its Interacting Proteins

FRANK SEEBER (HUB) in partnership with Christina Spry (ANU) and Kevin Saliba (ANU)

Previously, methodology for a two-hybrid screen of genetically encoded cyclic peptides was established in E. coli with the aim of identifying molecules that specifically inhibit the binding of Fd to LipA. In this project, we want to screen camelid single chain antibodies (nanobodies) for antibody molecules promoting (or preventing) interactions. Previously, nanobodies binding to one or both partners of a complex have been crucial for stabilizing transient complex structures, eventually allowing their 3D-structures to be solved. Currently, no 3D-structure of the complex between PfFd and PfFNR exists. Moreover, a 3D-structure of the transient interaction between Fd and LipA (or LytB or GcpE) would allow us to understand how a small protein like Fd can make specific contacts with such diverse interacting proteins and it would help in the design of novel drugs binding to Fd.

Ojo-Ajogu Akuh

Project B7 - 2nd Cohort

Metabolic Characterisation and Chemotherapeutic Targeting of Persistent T. gondii and P. falciparum Parasites

MARTIN BLUME (Robert-Koch-Institute), Kai Matuschewski (Dept. of Biology, Humboldt University Berlin), Kevin Saliba (Department Research School of Biology, ANU, Canberra)

Phenotypic variation in protozoan parasites is an important strategy to evade the immune responses and antimicrobial treatments. The apicomplexans Toxoplasma gondii and Plasmodium falciparum employ this strategy through the formation of tissue cysts and dormant blood stages, respectively. These stages are marked by attenuated growth and drug resistance. The ability to persist facilitates transmission to the next host. In order to successfully target these evasive stages we need to understand how resistance to antimicrobials is achieved. To this end we aim to characterize the metabolism of dormant parasites by using untargeted metabolomics and test their susceptibility to novel inhibitors.

Thomas Andersen 

Project B8 - 2nd Cohort 

Exploring Species and Stage-Dependent Differences in the Pantothenate Requirement of Malaria Parasite

CHRISTINA SPRY, KEVIN SALIBA (ANU) in partnership with Alyssa Ingmundson (HUB) and Martin Blume (RKI)

Intraerythrocytic-stage P. falciparum has an absolute requirement for pantothenate, the precursor to the fundamental enzyme cofactor coenzyme A (CoA). We have previously shown that P. falciparum converts exogenous pantothenate into CoA and that the CoA synthesized in the host erythrocyte is unlikely to meet the parasite’s requirement. Despite this, the enzymes predicted to catalyze the first three steps of the pathway have been demonstrated to be dispensable during the blood stage of mouse malaria parasites and essential only for development in the mosquito. In this study we aim to understand the apparent species and stage-dependent differences in the pantothenate requirement of Plasmodium parasites, which in turn will inform drug discovery efforts targeting pantothenate utilization.

TBA