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.


Projects


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.


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.

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.


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.

Familial flavin deficient erythrocytes and malaria susceptibility

KEVIN SALIBA (ANU) in partnership with Frank Mockenhaupt (Charité)

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.