B2 Reduced susceptibility to antimalarial drugs and accelerated selection of drug resistance due to variant red blood cells (Mockenhaupt)
|Institute of Tropical Medicine and International Health
|Charité – Universitätsmedizin Berlin, Spandauer Damm 130, 14050 Berlin
|Professor Dr. med. Frank P. Mockenhaupt
Plasmodium falciparum has developed resistance to virtually all available drugs, but the mechanisms are not fully elucidated. Variant red blood cells can affect treatment outcome due to their malaria-protective properties but also by modifying drug accumulation or by drug inactivation. In this regard, hardly anything is known with respect to the very common but mild forms of RBC variants. Considering their abundance, the actual relevance for treatment outcome and resistance selection may be substantial. We hypothesize that common mild RBC variants (HbS, alpha-thalassaemia, G6PD deficiency) affect susceptibility and resistance formation towards components of first-line antimalarial drugs. We will examine this by i) assessing in vitro drug susceptibility using variant and non-variant RBCs as host cells, ii) determining the pace (and markers) of resistance formation when P. falciparum is cultured under drug pressure in variant vs. normal RBCs, and iii) by comparing resistance markers and treatment outcomes in malaria patients with and without RBC variants. Read-outs will be MICs, IC50s, time to resistance formation, stability and degree of resistance, accompanying molecular markers, distribution of genotypes and molecular markers across treatment outcomes (available patient cohorts).
This project requires a highly autonomous and self-contained student with sound expertise in cell (in best case, P. falciparum) culture and molecular biology techniques. Methods include organization (RBC donors, work place), microscopy, FACS, PCR, sequence analysis, HPLC (cooperation partners).