Parasite genetics and adaptations

During coevolution with the invertebrate and vertebrate hosts Plasmodium parasites adopted a wide range of tailored variations of a typical eukaryotic cell inventory, ranging from unique proteins and expression regulation, to specialized organelles and remodelling of the infected host cell. A better molecular understanding of these adaptations can aid in interpretations of malaria-related pathology and expose novel Achilles’ heels for malaria therapy. A prominent example of how distinct adaptations can be exploited includes Plasmodium susceptibility to a range of antibiotics that inhibit the essential function of the non-photosynthetic plastid organelle, termed apicoplast. In this research area six projects study the composition, function, and regulation of key features, including organelles, membrane structures and protein complexes, in Plasmodium parasites and in their host cells.


projects


Analysis of a novel family of organelle-directed RNA binding proteins in Plasmodium falciparum

CHRISTIAN SCHMITZ-LINNEWEBER (HUB) in partnership with Giel van Dooren (ANU)

The project combines RNA biochemistry and experimental genetics towards a systematic analysis of Plasmodium organellar RNA metabolism. By organelle enrichment combined with proteomics and genome-wide profiling of signature binding sites the study will focus on a novel family of apicomplexan organellar RNA binding proteins and their functions in ribosome biogenesis and mRNA turnover. 


Tubulin – A novel lead to antimalarial drug discovery

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

The highly dynamic microtubule

cytoskeleton 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 Plasmdium tubulin as anti-malarial.

Characterisation of the virulence complex of the malaria parasite

MELANIE RUG (ANU) in partnership with Kai Matuschewski (HUB) and Alyssa Ingmundson (HUB)

Inside erythrocytes, Plasmodium refurbishes its host cell by inducing novel organelles, such as Maurer’s clefts, which are trafficking hubs for the export of virulence factors.In this project previously unrecognized proteins of the exported virulence complex will be analysed by state-of-the-art  imaging tools, including correlative light and electron microscopy, in the human and murine model pathogens.


Cross-species RNA-protein interactions in the malaria-infected cell

BENEDIKT BECKMANN (HUB) in partnership with Melanie Rug (ANU) and Brendan McMorran (ANU)

The first description of an RNA atlas of exosomes from P. falciparum -infected erythrocytes will be the focus of the project, which combines expertise in genome-wide pathogen RNA profiling, high-end imaging, and genetic characterization of selected targets.

Characterizing protein function at the parasite-host interface during both liver and blood infection stages.

ALYSSA INGMUNDSON (HUB) in partnership with Melanie Rug (ANU)

Host cell remodelling also occurs in Plasmodium-infected liver cells, and in the complementary project novel P. berghei proteins at the parasite-host interface that are shared between liver and blood stages will be studied by experimental genetic and biochemical techniques to characterize the molecular repertoire of parasite-induced host cell structures.


Dissecting the distinct metabolic roles of the ferredoxin redox system

FRANK SEEBER (RKI) in partnership with Christina Spry (ANU), Kevin Saliba (ANU), and Alexander Maier (ANU)

The project will investigate a nexus between central metabolic pathways within the apicoplast and functionally dissect the vital roles of the redox regulator ferredoxin for distinct metabolic pathways that have already been validated as therapeutic targets.