Unit | Malaria Gene Regulation

  • Gene Regulation

The Malaria Gene Regulation Unit aims to understand the molecular basis of two of the most important survival strategies of malaria blood-stage parasites - antigenic variation and gametocyte formation. Antigenic variation allows the parasites to evade the human immune response and establish a chronic blood infection. Gametocyte formation ensures the transmission of malaria from one human host to the next via the mosquito vector.

Our Research Focus: Epigenetics of Antigenic Variation and Sexual Commitment

Antigenic variation and sexual commitment are absolutely essential for parasite survival. While antigenic variation secures the long-term survival of the parasite population in the bloodstream, sexual commitment provides a continuous source of gametocytes, ultimately facilitating human-to-human transmission of malaria. Interestingly, these seemingly unrelated processes are controlled by a similar logic in the regulation of gene expression.

Both antigenic variation and sexual commitment are based on clonally variant gene expression, and both processes are epigenetically controlled by heterochromatin protein 1 (HP1), an evolutionarily conserved silencing factor. In P. falciparum, HP1 silences hundreds of genes encoding variable surface antigens, including all members of the var/PfEMP1 family. Stochastic activation and switches in their expression are responsible for antigenic variation and immune evasion. Apart from antigenic variation genes, HP1 also silences the locus encoding AP2-G, a master transcription factor (TF) essential for sexual commitment and gametocyte differentiation. It appears that HP1-dependent silencing of ap2-g keeps parasites in asexual proliferation mode, whereas targeted activation of ap2-g triggers sexual conversion, cell cycle exit and gametocyte differentiation.

Our research seeks to dissect and understand the molecular players and pathways that regulate these vital processes.

Till Voss

Till Voss

Associate Professor for Molecular Parasitology, PhD

Exploring Early Sexual Differentiation in the Malaria Parasite

The SNSF-funded research project focuses on gametocytes, the transmissible forms of the malaria parasite Plasmodium falciparum. The team, together with external collaborators, will apply CRISPR/Cas9 gene editing, super-resolution microscopy techniques and various –omics approaches to study the early phase of gametocyte differentiation and the mechanisms underlying gametocyte sex determination. With this project, the researchers aim to generate novel insight into the molecular and cellular events driving gametocytogenesis, offering potential avenues for the development of urgently needed new interventions for malaria elimination. Read more

Function of Heterochromatin Protein 1

We aim to deliver a detailed understanding of HP1 function in malaria parasites by conducting functional complementation assays and by identifying and characterising interacting partners and post-translational modifications of HP1.

Gametocyte Conversion and Differentiation

In this project, we try to understand the molecular pathways and epigenetic control mechanisms congregating at the ap2-g locus to control the switch from asexual proliferation to sexual commitment and early differentiation of P. falciparum gametocytes.

Antigenic Variation

We investigate several regulatory proteins and DNA elements potentially implicated in the silencing and clonally variant expression of the var/PfEMP1 family. We hope such knowledge will help us to understand how P. falciparum controls antigenic variation, i.e. how it manages to express only a single var gene at a time and to switch expression between var gene loci.

Freville A et al. Expression of the MSPDBL2 antigen in a discrete subset of Plasmodium falciparum schizonts is regulated by GDV1 but may not be linked to sexual commitment. mBio. 2024;15(5):e0314023. DOI: 10.1128/mbio.03140-23

Voss T.S, Brancucci N.M. Regulation of sexual commitment in malaria parasites - a complex affair. Curr Opin Microbiol. 2024;79:102469. DOI: 10.1016/j.mib.2024.102469

Wyss M, Thommen B.T, Kofler J, Carrington E, Brancucci N.M.B, Voss T.S. The three Plasmodium falciparum Aurora-related kinases display distinct temporal and spatial associations with mitotic structures in asexual blood stage parasites and gametocytes. bioRxiv. 2024:2024.05.27.596013. DOI: 10.1101/2024.05.27.596013

Gockel J, Voss T.S, Bártfai R. The troubled puberty of malaria parasites. Trends Parasitol. 2023;39(3):155-157. DOI: 10.1016/j.pt.2023.01.006

Kuehnel R.M et al. A Plasmodium membrane receptor platform integrates cues for egress and invasion in blood forms and activation of transmission stages. Sci Adv. 2023;9(24):eadf2161. DOI: 10.1126/sciadv.adf2161