L-lactate is a regulator of gametocytogenesis in Plasmodium falciparum
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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 .
Author summary
Malaria in humans often causes elevated blood lactate: a phenomenon called hyperlactataemia. This occurs because, during malarial disease, both malaria parasites and human tissues tend to respire by glycolysis instead of oxidative respiration. For bloodstream parasites this is their only mode of respiration, while human tissues become hypoxic when parasitized cells adhere in capillaries and impede the flow of oxygenated blood. Hyperlactataemia predicts severe and fatal malarial disease because it causes respiratory distress.
Here, we show that malaria parasites in culture can sense and respond to elevated lactate – mimicking hyperlactataemia – by increasing their conversion to sexual cells, which are vital for transmission to mosquitoes. When a human host is at risk of death, it could be advantageous for the parasite to boost its chances of transmission thus. The switch occurs by increasing expression of genes that promote sexual conversion: genes that are known to be silenced or activated epigenetically. Epigenetic changes are chromatin marks that are made without changing the underlying DNA sequence: they are fast, flexible and reversible, making them ideal for responding to changing situations in a human host. Thus, a blood metabolite that is characteristically raised during malaria can epigenetically influence an important virulence phenotype in malaria parasites.
