Epigenetic regulation of antigenic variation in the malaria parasite Plasmodium falciparum

• Applicants: Dr. Anna Bachmann; Dr. Michaela Petter
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433302244

Malaria due to Plasmodium falciparum remains one of the major global health problems and a leading cause of death worldwide, particularly among children under the age of five. When parasites are transmitted from one individual to another through the Anopheles mosquito vector, the parasites face a new environment, which is shaped by host genetics, immune status, and metabolism. To adapt to such differences, malaria parasites encode diverse families of contingency genes that are involved in erythrocyte invasion, antigenic variation, and drug resistance. It is unknown how the expression of these genes is regulated to enable rapid adaptation to a new host. Controlled human malaria infection studies (CHMI) using direct intravenous sporozoite injections indicated that ex vivo parasites at the onset of blood infection of naïve volunteers differ significantly from the parental population before mosquito passage in their gene expression patterns, and are characterized by activation of a broad subset of variant antigens on a population level. This indicates that transmission leads to the resetting of variant antigen expression and that a highly diverse population of parasites exits the liver which can explore the novel host cell niche and is then further selected by host-pathogen interactions. Variant antigen expression in asexual blood stage parasites is primarily regulated by epigenetic mechanisms. Our preliminary data indicate that the chromatin structure of malaria parasites, particularly with respect to variant antigens, is globally remodeled during transmission. These findings lead us to hypothesize that chromatin remodeling drives epigenetic resetting of contingency genes in the parasite’s transmission stages. To test this hypothesis we aim to characterize the P. falciparum epigenome with respect to several histone modifications and histone variants in trophozoites, gametocytes, sporozoites and liver stage parasites using genome-wide RNA and chromatin sequencing (ChIPseq) (Aim 1). We will correlate these results with gene expression profiles in ex vivo parasites obtained from volunteers with different immune status (Aim 2). This will provide unique insight into the molecular mechanisms underlying antigenic variation, and will show how immunity influences gene expression patterns on a population level. The outcomes of this research will significantly advance our scarce understanding of the unique gene control mechanisms in malaria parasites and will be highly relevant for future research towards novel therapeutic strategies and vaccine development.

• DFG Programme: Research Grants
• International Connection: Denmark, USA
• Cooperation Partners: Dr. Stephen Hoffman, Ph.D.; Professor Thomas Lavstsen, Ph.D.