Biology subjects

Jabre, I.

Publications and source records attributed to Jabre, I..

3 recordsLinked to original sources

bioRxiv2026

L-lactate is a regulator of gametocytogenesis in Plasmodium falciparum

Epigenetic processes play important roles in the biology of the malaria parasite Plasmodium falciparum. We recently showed that Plasmodium histones are not only acetylated and methylated but also lactylated. This new epigenetic mark could form a particularly important axis of host-parasite signalling because severe malaria is often characterised by hyperlactataemia. In the human host this can cause respiratory distress, which is potentially fatal. For the parasite, it could be advantageous to sense this state of pathology and respond by modulating virulence. Virulence processes known to be under epigenetic control include antigenic variation, invasion switching and conversion to sexual gametocytes, i.e. gametocytogenesis. Here, we investigated the influence of lactate on gametocytogenesis. Hyperlactataemia in malaria patients is defined as [≥] 5mM blood lactate and we confirmed that in laboratory culture, adding 5mM L-lactate was sufficient to boost gametocytogenesis. Expression of the GDV-1 gene increased within one cell cycle of asexual parasites being exposed to L-lactate, suggesting that the canonical epigenetic switch for gametocytogenesis was involved: GDV-1 regulates epigenetic de-repression of the gene encoding the master transcription factor for gametocytogenesis, AP2-G. Indeed, parasite histones became rapidly lactylated after L-lactate exposure and chromatin profiling by CUT&Tag detected inducible lactylation of chromatin specifically upstream of the AP2-G gene, and also of the antisense RNA that regulates GDV-1. Thus L-lactate joins S-adenosylmethionine as a metabolite that can epigenetically regulate gametocytogenesis in P. falciparum.

microbiology↗

bioRxiv2026

Lactylated histones mark virulence gene families in the malaria parasite Plasmodium falciparum

Epigenetic pathways have many important roles controlling virulence in human malaria parasites. Histone acetylation and methylation have been closely studied in this context but the novel epigenetic mark of lactylation has not yet been examined. Here, for the first time, we profiled lactyl-histone marks across the P. falciparum genome and found them strongly enriched at virulence genes, including genes involved in cytoadhesion and other host-cell remodelling functions. Many genes were dynamically and inducibly lactylated across the cell cycle. Thus, P. falciparum could use histone lactylation to control its virulence pathways in response to the prevailing metabolic environment in its host. We extended our chromatin profiling to parasites isolated directly from human patients, showing that here too, virulence gene families were strongly lactylated. This represents the first comprehensive profiling of P. falciparum chromatin from parasites in sub-millilitre blood samples, opening up exciting new avenues to study parasite chromatin across human disease states.

microbiology↗

bioRxiv2024

Histone lactylation: a new epigenetic mark in the malaria parasite Plasmodium

Epigenetic processes play important roles in the biology of the malaria parasite Plasmodium falciparum. Here, we characterised a new epigenetic mark, histone lactylation, recently discovered in humans: it was found in two human malaria parasites, P. falciparum and P. knowlesi, and also in vivo in two rodent malaria models. Histones were lactylated rapidly in response to elevated lactate levels, and rapidly delactylated when lactate levels fell. Thus, this mark is well-placed to act as a metabolic sensor, since severe falciparum malaria characteristically leads to hyperlactataemia. Mass spectrometry showed that lysines on several parasite histones could be lactylated, as well as many non-histone chromatin proteins. Histone lactylation was less abundant and less inducible in P. knowlesi than P. falciparum, suggesting that P. falciparum may have evolved particular epigenetic responses to this characteristic feature of its pathology. Finally, in the rodent model P. yoelii, hyperlactataemia correlated with parasite transcriptomic programmes that suggested metabolic dormancy.

microbiology↗