Biology subjects

Tinto-Font, E.

Publications and source records attributed to Tinto-Font, E..

4 recordsLinked to original sources

bioRxiv2025

Thermal and non-thermal stress conditions activate the Plasmodium falciparum AP2-HS-dependent heat-shock response

To preserve proteome homeostasis and survive at higher-than-optimal temperatures, organisms have evolved the conserved heat shock (HS) response (HSR), characterised by increased expression of specific chaperone-encoding genes. In the human blood, malaria parasites are frequently exposed to elevated temperatures associated with host fever episodes. The protective HSR of Plasmodium falciparum, the parasite that produces the vast majority of malaria clinical cases and deaths, is regulated by the transcription factor AP2-HS. Here, we systematically investigated the conditions that trigger the AP2-HS-dependent HSR and found that even mild HS conditions that do not compromise parasite viability can activate this response. Similar to other organisms, activation of the HSR in P. falciparum is rapid, as it was observed after an only 10 min HS. Artemisinin (ART), a drug that produces proteome damage, also triggered the HSR, indicating that activation of the malarial HSR is not restricted to thermal stress. The AP2-HS-dependent HSR can be activated in all asexual blood stages, with the exception of very young rings, but not in intermediate or mature gametocyte stages. Accordingly, these gametocyte stages are highly sensitive to HS. Since mature gametocytes are the only stage that can mediate human-to-mosquito transmission, these results suggest that malaria patients with high fever may become transiently uninfective.

microbiology↗

bioRxiv2025

Elevated Plasmodium falciparum sexual conversion in HbAC and HbAS red blood cells without altered IgG/IgM levels to trophozoite and stage I gametocyte-specific antigens

Malaria transmission relies on the differentiation of asexual parasites into gametocytes, a process initiated by sexual conversion (SC). Mutations in the host hemoglobin beta (HBB) gene are known to influence parasite growth and disease outcome, yet their impact on SC remains unclear. We investigated the effect of HBB mutant genotypes on Plasmodium falciparum SC and humoral immunity in individuals from Nanoro, Burkina Faso. To measure SC rates in natural human malaria infections, we developed a new ex vivo SC assay (evSCA). We found that in human natural P. falciparum infections, SC rates were higher in individuals with HbAS or HbAC than in individuals with wild-type HBB (HbAA). Consistently, using an in vitro SC assay (ivSCA) based on the NF54-gexp02-Tom reporter line we found that cultures grown in HbAS red blood cells (RBCs) had higher SC rates than those grown in HbAA RBCs. Furthermore, IgG and IgM responses against trophozoite- and stage I gametocyte-infected RBC antigens, quantified by flow cytometry, did not differ between plasma from individuals with different HBB genotypes. These results demonstrate that exposure to RBCs with HBB mutations enhances SC, highlighting a host-genetic factor that may influence malaria transmission potential. AUTHOR SUMMARYTransmission of Plasmodium falciparum -a malaria causing parasite- depends on the parasites ability to produce gametocytes, the stage that infects mosquitoes. In many African regions where malaria is common, hemoglobin (Hb) variants such as hemoglobin S (the sickle-cell trait) and C are highly prevalent reflecting their role in protecting against severe disease. However, it remains unclear whether these variants also influence the parasites early shift toward gametocyte development (i.e., sexual conversion [SC]). In this study, we combined ex vivo and in vitro SC assays to measure SC in red blood cells with different hemoglobin genotypes. We found that SC was higher in parasites growing in red blood cells carrying hemoglobin AC and AS genotypes compared to normal AA hemoglobin. These findings provide experimental support for earlier epidemiological observations reporting that individuals with these hemoglobin variants often carry more gametocytes and are more infectious to mosquitoes. We also measured antibody levels in individuals with mutant RBCs and found no differences in immunity that could explain the variation in SC. Our results show that host genetic background can influence gametocyte development and may shape the infectious reservoir in high-burden settings. This knowledge is important for designing effective strategies for malaria elimination.

microbiology↗

bioRxiv2024

Heterochromatin dynamics during the initial stages of sexual development in Plasmodium falciparum

Asexual replication of Plasmodium falciparum in the human blood results in exponential parasite growth and causes all clinical symptoms of malaria. However, at each round of the replicative cycle, some parasites convert into sexual precursors called gametocytes, which are essential for transmission to mosquito vectors. After sexual conversion, parasites develop through the sexual ring stage and then gametocyte stages I to V before they are infective to mosquitoes. Heterochromatin, a type of chromatin generally refractory to gene expression, plays an important role in the regulation of sexual conversion by silencing the master regulator of the process, PfAP2-G, in asexual parasites. Additionally, previous reports have described changes in the genome-wide distribution of heterochromatin in stage II/III or older gametocytes, including expansion of heterochromatin at several subtelomeric regions and reduced occupancy at a few specific loci. However, it is not known if these changes occur concomitantly with sexual conversion or at a later time during gametocyte development. Using a transgenic line in which sexual conversion can be conditionally induced, here we show that the genome-wide distribution of heterochromatin at the initial stages of sexual development (i.e., sexual rings and stage I gametocytes) is almost identical to parasites at asexual blood stages, and major changes do not occur until stage II/III. We also show that transcriptional changes associated with sexual development typically precede, rather than follow, changes in heterochromatin occupancy at their loci, which raises the possibility that PfAP2-G operates as a pioneer factor. IMPORTANCEEpigenetic processes and chromatin structure play an important role in the regulation of gene expression in malaria parasites. In particular, a type of chromatin called heterochromatin is involved in the regulation (silencing) of many genes. Parasite sexual development is essential for transmission to mosquito vectors. Here we characterised the global distribution of heterochromatin at different stages of sexual development, and found that initially it is identical to asexual blood stages, but at later transmission stages it is altered. This informs about the putative roles of general heterochromatin redistribution in parasite life cycle progression. By integrating multi-omic datasets, we also found that changes in the expression of several genes precede changes in their heterochromatin occupancy. This indicates that during sexual development some genes can be activated in spite of having heterochromatin.

microbiology↗

bioRxiv2021

The PfAP2-HS transcription factor protects malaria parasites from febrile temperatures

Periodic fever is the most characteristic clinical feature of human malaria1-3, but how parasites survive febrile episodes is not known. While Plasmodium spp. genomes encode a full complement of chaperones4, they lack an ortholog of the conserved transcription factor HSF1, which in most eukaryotes activates the expression of key chaperones upon heat shock (HS)5-8. Here we identified PfAP2-HS, a transcription factor of the ApiAP2 family9-11, as the key regulator of the P. falciparum protective HS response. The PfAP2-HS-dependent HS response is largely restricted to rapid activation of hsp70-1, the predominant direct target of PfAP2-HS, and hsp90. Deletion of PfAP2-HS dramatically reduced HS survival and also resulted in severe growth defects at 37{degrees}C, but not at 35{degrees}C, and increased sensitivity to imbalances in protein homeostasis (proteostasis) produced by artemisinin, the current frontline antimalarial drug12,13. These results demonstrate that PfAP2-HS contributes to general maintenance of proteostasis and drives a rapid chaperone-based protective response against febrile temperatures. While several ApiAP2 transcription factors regulate life cycle transitions in malaria parasites11,14,15, PfAP2-HS is the first identified Plasmodium transcription factor that controls a protective response to a within-host environmental challenge.

microbiology↗