Profiling the expression dynamics of virulence-associated genes in clinical Plasmodium falciparum isolates

• Applicant: Dr. Anna Bachmann
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 323759012

Infections with the human malaria parasite Plasmodium falciparum are a great burden on global health. Fundamental questions regarding the molecular regulation of virulence and persistence of P. falciparum remain unresolved, in particular, as most analyses have been performed with long-term cultured laboratory strains. Therefore, in the present study we aim to analyze parasites directly isolated from infected travelers returning to Germany. This group of malaria patients constitutes a unique cohort of immunologically naïve individuals, whose parasite development, gene expression and antigenic variation is not influenced by immune responses due to previous Plasmodia infections. We are particularly interested in the variant surface antigen PfEMP1, which enables adherence of P. falciparum infected red blood cells to endothelial receptors exposed on blood vessel walls. This allows infected red blood cells to avoid passage through the spleen, which would otherwise kill the parasites. However to avoid acquired immunity the parasite must sequentially expose diverse PfEMP1 variants on the surface of infected erythrocytes. The planned study focuses on gene expression of consecutive parasite generations by quantitative RNA sequencing. The results are expected to elucidate if sequences coding for particular PfEMP1 domains with defined receptor binding properties are enriched in non-immune malaria patients. Furthermore, the switching frequency of different PfEMP1 variants exposed on the surface of infected erythrocytes will be determined at the RNA level and validated selectively at the protein level. With respect to our previous findings, it is anticipated that gene expression varies substantially between parasites analyzed ex vivo and those that have been adapted to in vitro cultivation. We will test the hypothesis that expression of PfEMP1-encoding genes follows a hierarchical pattern resulting in an immune evasion program similar in different P. falciparum isolates, and that this expression program is modulated by the human immune system and by selection of parasites with particular cytoadherence properties.

• DFG Programme: Research Grants
• International Connection: Australia
• Cooperation Partner: Michael F. Duffy, Ph.D.