Research Area D

host genetics and responses

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.

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 D4

Screening for inhibitors of parasite growth using circular peptides and previously identified host targets

SIMON FOOTE (ANU) in partnership with Frank Seeber (RKI)

The concept of host directed therapy of Plasmodium blood infection will be experimentally tested for the first time in the project. Employing a circular peptide library, inhibitors of interactions between erythrocyte cytoskeletal proteins will be selected and further characterized in P. falciparum cell culture assays. A range of additional targets that were identified from in silico and forward genetics screens will be included in the screening pipeline.

Project D2 - 1st Cohort

Unravelling the host response to malaria infection

GAÉTAN BURGIO (ANU) in partnership with Frank Mockenhaupt (Charité) and Emanuel Heitlinger (HUB)

The project will validate novel host resistance candidates by reverse genetics and analyse the effects of host genotypes on the response to artemisinin treatment and on parasite development and disease progression in a murine infection model.