Research Area D

host Genetics and Drug Discovery

Host susceptibility to Plasmodium infections varies substantially and is a major contributing factor for the propensity to develop severe complications in clinical malaria. These host variations partially explain the broad spectrum of illness including uncomplicated malaria and respiratory distress, hyper-parasitemia and severe anemia, and cerebral malaria and multi-organ failure. The fundamental concept of selection of balanced polymorphisms in human populations, which partially afford enormous fitness costs but protect against infectious diseases, was first established for malaria and still reflects the unprecedented selection pressure on the human genome in previous and current malaria-endemic countries. It also lends support for intervention strategies that target  the parasite through the host. Five projects in this research area will provide a comprehensive assessment of host cell factors that are vital for parasite population expansion and dispensable for the host. Access to iron is a limiting factor for virtually every microbial pathogen, but to which extent polymorphisms in host iron regulation affect Plasmodium growth remains unexplored.


Project D1 - 1st Cohort

Polymorphisms of iron regulation in susceptibility and manifestation of malaria

FRANK MOCKENHAUPT (Charité) in partnership with Melanie Rug (ANU) and Gaétan Burgio (ANU)

The project will assess candidate polymorphisms and iron deficiency in patients exhibiting a wide range of malaria symptoms and will characterize the impact of variants in iron regulation on parasite growth in co-culture assays. Following results from a genome-wide forward genetics screen for malaria susceptibility.

Julia Jäger

Project D1 - 2nd Cohort

Susceptibility to and Manifestation of Malaria: Role of Iron Deficiency and Polymorphisms of Iron Regulation

FRANK MOCKENHAUPT (Charité) in partnership with Brendan McMorran (ANU)

Iron deficiency (ID) inhibits Plasmodium growth, increases parasite phagocytosis, and reduces malaria risk. Upregulation of the iron master-regulator hepcidin due to malaria or inflammation reduces hepatic parasite survival. Several host polymorphisms influence iron status whereas hepcidin is regulated by inflammation. We have previously shown that ID as well as a common ferroportin polymorphism associate with relative resistance to malaria.

Rafael Oliviera

Project D3 - 1st Cohort

Familial flavin deficient erythrocytes and malaria susceptibility

KEVIN SALIBA (ANU) in partnership with Frank Seeber (RKI, HUB)

The project originates from the identification of a local focus of familial flavin deficiency that is likely linked to previous malaria endemicity. Employing biochemical assays, the prevalence of flavin-deficient erythrocytes in SubSaharan Africa will be explored to identify genetic markers and correlate flavin deficiency with malaria incidence and disease progression.

Ayman Hemasa

Project D3 -2nd Cohort

The Antiplasmodial Activity of Riboflavin Analogues

KEVIN SALIBA (ANU) in partnership with Frank Seeber (RKI, HUB)

Riboflavin (vitamin B2) is converted into flavin mononucleotide (FMN) by riboflavin kinase, and subsequently metabolised into flavin adenine-dinucleotide (FAD) by FAD synthetase.  FMN and FAD, referred to as flavins, serve as cofactors for a number of essential enzymes. Several riboflavin analogues have been shown to possess antiplasmodial activity during the intraerythrocytic stage of the malaria parasite. We have been focusing on the antiplasmodial activity of two specific riboflavin analogues, roseoflavin and 8-amino-riboflavin. Roseoflavin has been shown to be metabolised into antimetabolites of FMN and FAD, whereas 8-amino-riboflavin appears to only be converted into an FMN antimetabolite.


Project D5

Cross-species association of genotype and transcriptome response as driver of susceptibility and virulence

EMANUEL HEITLINGER (HUB) in partnership with Gaétan Burgio (ANU)

The project goes beyond allelic variations and explores the effects of regulatory networks and correlated gene expression on infection outcome. This analysis permits the identification of congruent pathways that are conserved across a range of Plasmodium species infecting rodents and humans.

Parnika Mukherjee

Project D6 - 2nd cohort

Cholesterol as the molecular key to antiparasitic drug delivery

MALCOLM MCLEOD (ANU) in partnership with MARTIN BLUME (RKI), Alexander Maier (ANU), Melanie Rug (ANU)


The collective fight against malaria has been an ongoing battle for many thousands of years. From early naturally derived compounds, to modern synthetic drug therapies; it is a molecular siege of epic proportions which continues to take hundreds of thousands of lives each year. As the malarial parasite continues to evolve, so must our approach towards finding new strategies to combat this brutal disease. Cholesterol-drug conjugation presents itself as a new tactic to overcome poor selectivity and enhance the potency of current and emerging antimalarial drugs. Cholesterol is imported by the malarial parasite from host sources in large quantities. The mechanism by which this import occurs can by hijacked by cholesterol linked conjugates to deliver drugs to parasite targets. Understanding the molecular nature of this delivery is vital to the development of improved drug conjugates. Towards this end, a series of drug linked cholesterol analogues with a wide range of varied structural and chemical features have been synthesized to probe this transport using medicinal chemistry. Furthermore, the development of a metabolically activated fluorescent-dye conjugate has been achieved in an attempt to visualize import and metabolism of cholesterol linked constructs using microscopy. Future studies seeking to further elucidate this unlocking and entry of cholesterol into T. gondii will involve metabolomic profiling of drug-treated parasites using targeted and untargeted metabolomic studies to understand the phenotype of drug-treated parasites and the fate of drug and sterol components.

Blake Curtis

Project D7 - 2nd cohort

A Chemical Biology Toolbox for Interrogating Malaria Biology and Identifying Novel Therapeutics