New vulnerabilities in the malaria pathogen?
A cross-institutional research team has identified previously overlooked vulnerabilities in Plasmodium falciparum, the most dangerous of the malaria parasites, which provide new insights into the parasite’s control centre. In laboratory experiments, the researchers mapped more than 200 proteins that the parasite uses to control whether it continues to multiply in the blood or transitions to a stage in which it is ingested by mosquitoes and spread further. The study was carried out at the Bernhard Nocht Institute for Tropical Medicine (BNITM) in Hamburg and at Radboud University in Nijmegen, the Netherlands, and has been published in the journal 'Cell Host & Microbes'.
Malaria remains one of the world’s most serious infectious diseases and causes hundreds of thousands of deaths every year, particularly amongst children in Africa. The most severe form of the disease is caused by the single-celled parasite Plasmodium falciparum, which multiplies in red blood cells and is transmitted by Anopheles mosquitoes.
Malaria pathogens can adapt their behaviour with remarkable flexibility: at times they multiply rapidly in the blood, at other times they prepare for transmission by mosquitoes. This is controlled by a sort of ‘control centre’ within their genetic material. It is there that it is determined which genes are currently ‘on’ or ‘off’ – in other words, which path the parasite takes in its life cycle.
However, whether a gene in the parasite is switched on or off depends not only on the DNA sequence, but also on how the DNA is packaged within the cell nucleus. Experts refer to this packaging of DNA and proteins as chromatin. Chemical marks and specific chromatin proteins act as switches in this process: they determine which genes are active and thus shape the parasite’s entire life cycle.
How the malaria pathogen switches its behaviour
The team from Hamburg and Nijmegen has now taken a close look at this very control centre: using modern ‘proximity labelling’ techniques and mass spectrometry, the researchers investigated which proteins are bound to three key chromatin states in P. falciparum:
– dense heterochromatin, where genes are inactive,
– loosely packed euchromatin, where genes are active, and
– the (peri-)centromeric region, which ensures the precise distribution of chromosomes during cell division.
In total, the researchers identified 214 proteins that are characteristically associated with these chromatin states, including many factors that had not previously been described at all. The authors validated 20 of these proteins in detail through further experiments. In doing so, they found, amongst other things:
● A novel heterochromatin protein (HIC7) that is located at the edge of silenced gene regions and helps determine whether the parasite continues to replicate in the blood or transitions to the sexual stage for transmission to the mosquito.
● A protein complex in euchromatin that incorporates specific histone variants (H2A.Z/H2B. Z) into the DNA, thereby controlling the accessibility and packaging of genes.
● Several previously unknown proteins at the centromeres, including a regulatory protein similar to the spindle-regulating protein Bub1, which in other organisms ensures that chromosomes are correctly separated during cell division and which was previously thought not to be present in malaria parasites.
“For the first time, we are now seeing the range of tools that the malaria pathogen uses to put genes on hold or activate them,” says Dr Tobias Spielmann, head of the Malaria Cell Biology Research Group at the Bernhard Nocht Institute for Tropical Medicine (BNITM). “Using these proteins in the ‘control centre’ of the genome, the parasite ‘decides’ whether to continue multiplying in the blood, transition to the mosquito stage, or cleanly separate its chromosomes. If we could specifically disrupt these sites, the pathogen would be thrown off course. This is precisely where potential targets lie. Close collaboration with our colleagues in Nijmegen was crucial to this: in Hamburg, we contribute our expertise in parasite cell biology, whilst in the Netherlands they provide the most advanced methods of proteomics research.”
The fragile control centre of the malaria pathogen
The new data provide a sort of reference map of the gene switches in the malaria parasite. For the first time on this scale, it shows which proteins are located at silenced, active or division-related sections of the genome and how they interact. At the same time, it reveals which ‘toolbox’ the parasite has at its disposal to control its genes and which tools it uses in which situations.
A key finding: one of the newly discovered proteins, HIC7, is located at the boundary between silenced and active sections of the parasite’s genome. If HIC7 is removed from the cell nucleus, this fine-tuning is disrupted – and the pathogen switches to the stage in which it can be ingested by mosquitoes significantly more frequently. In the experiments, the proportion of parasites forming such transmission stages (gametocytes) rose from less than one per cent to around eight per cent. The study thus reveals the precise point in the pathogen’s genome where it switches between ‘continuing to multiply in the blood’ and ‘being ready for the mosquito’.
Another finding concerns the regions of the genome where active genes are located. There, the researchers discovered a complex of several proteins that functions like a sort of installation team: it ensures that specific components of the DNA packaging are positioned precisely at the sites where genes are switched on or off. Similar ‘switch teams’ are also known from other organisms. The results show that the malaria parasite utilises comparable systems, some of which, however, are structured in a way that is entirely unique – and thus provide a potential starting point for active substances designed to target only the parasite.
©Ramón-Zamorano et al., 2026, Cell Host & Microbe 34, 1–20. CC BY 4.0
Another exciting discovery concerns the parasite’s cell division. The researchers were able to identify a protein that resembles a known regulatory protein found in other organisms and is located at a control site on the chromosomes. It had long been assumed that the malaria parasite lacked such a safety mechanism during the division of its genetic material. The new study now suggests that there is, in fact, a form of control that checks whether the genetic material is correctly distributed to the daughter parasites. If this control protein is switched off, the resulting offspring are missing pieces of genetic material – and are therefore unable to survive. This brings the protein into focus as a potential new vulnerability of the pathogen.
Based on the new chromatin atlas, the researchers now intend to conduct further targeted functional investigations into individual proteins and complexes.
Parasite biology meets high-throughput proteomics
The study is the result of close collaboration between the BNITM in Hamburg and Radboud University in Nijmegen. BNITM carried out the genetic manipulation and culture of the parasites, while the Nijmegen groups contributed their long‑standing expertise in chromatin biology and quantitative mass spectrometry.
This collaboration was funded by the Leibniz Association through the Leibniz Competition's “Cooperative Excellence” programme. The programme supports particularly innovative projects that are built on close cooperation within and/or beyond the Leibniz Association.
Original publication:
Ramón-Zamorano G et al.: Protein landscape of the chromatin states in the malaria parasite Plasmodium falciparum. Cell Host & Microbe (in press): https://doi.org/10.1016/j.chom.2026.07.016
Contact person
Dr Tobias Spielmann
Research group leader
Phone : +49 40 285380-486
Email : spielmann@bnitm.de
Julia Rauner
Public Relations
Phone : +49 40 285380-264
Email : presse@bnitm.de
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