Sexual differentiation in human malaria parasites is regulated by competition between phospholipid metabolism and histone methylation

Harris, Chantal T.; Tong, Xinran; Morillo, Riward Campelo; Marreiros, Inês M.; Vanheer, Leen N.; Nahiyaan, Navid; Zuzarte‐Luís, Vanessa; Deitsch, Kirk W.; Mota, Maria M.; Rhee, Kyu Y.; Kafsack, Björn F.C.

doi:10.1038/s41564-023-01396-w

“…In the present study, addition of choline to serum-free medium had a significant suppressive effect on proportions of schizonts expressing MSPDBL2 in the HB3 parasite line, consistent with the known effect of choline in suppressing gdv1 expression (22). The physiological mechanisms whereby choline concentration affects parasite sexual commitment is an area of recent investigation (37,38), which may also be of relevance for studying regulation of MSPDBL2.…”

Section: Discussionsupporting

confidence: 88%

Expression of the MSPDBL2 antigen in a discrete subset ofPlasmodium falciparumschizonts is regulated by GDV1 but not linked to sexual commitment

Freville,

Stewart,

Tetteh

et al. 2023

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ThePlasmodium falciparummerozoite surface protein MSPDBL2 is a polymorphic antigen targeted by acquired immune responses, and normally expressed in only a minority of mature schizonts. The potential relationship of MSPDBL2 to sexual commitment is examined, as variablemspdbl2transcript levels and proportions of MSPDBL2-positive mature schizonts in clinical isolates have previously correlated with levels of many sexual stage parasite gene transcripts, although not with the master regulatorap2-g. It is demonstrated that conditional overexpression of GDV1, which promotes sexual commitment, also substantially increases the proportion of MSPDBL2-positive schizonts in culture. Conversely, truncation of thegdv1gene is shown to prevent any expression of MSPDBL2. However, across diverseP. falciparumcultured lines the variable proportions of MSPDBL2 positivity in schizonts does not correlate significantly with variable gametocyte conversion rates, indicating it is not involved in sexual commitment. Confirming this, examining a line with endogenous HA-tagged AP2-G showed that the individual schizonts expressing MSPDBL2 are mostly different to those expressing AP2-G. Using a selection-linked integration system, modifiedP. falciparumlines were engineered to express an intact or disrupted version of MSPDBL2, showing the protein is not required for sexual commitment or early gametocyte development. Asexual parasite multiplication rates were also not affected by expression of either intact or disrupted MSPDBL2 in a majority of schizonts. Occurring alongside sexual commitment, the role of the discrete MSPDBL2-positive schizont subpopulation requires further investigation in natural infections where it is under immune selection.

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“…Distinct Plasmodium parasites present in the same host might alter their respective regulation to compete more efficiently for scarce resources or modify their sexual commitment to improve transmission and outcrossing [19][20][21][22] , similar to the well-known mating type regulation in yeast or the mechanisms limiting selffertilization in plants. In this regard, it is important to note that sexual commitment is, at least partially, determined by environmental factors [23][24][25][26][27][28] , supporting the hypothesis that the parasites are able to sense their environment to modify their asexual development and sexual differentiation.…”

Section: Introductionmentioning

confidence: 67%

Single-cell analyses of polyclonal Plasmodium vivax infections and their consequences on parasite transmission

Hazzard,

Sá,

Bogale

et al. 2024

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Most Plasmodium vivax infections contain genetically distinct parasites, but the consequences of this polyclonality on the development of asexual parasites, their sexual differentiation, and their transmission remain unknown. We describe infections of Saimiri monkeys with two strains of P. vivax and the analyses of 117,350 parasites characterized by single cell RNA sequencing and individually genotyped. In our model, consecutive inoculations fail to establish polyclonal infections. By contrast, simultaneous inoculations of two strains lead to sustained polyclonal infections, although without detectable differences in parasite regulation or sexual commitment. Analyses of sporozoites dissected from mosquitoes fed on coinfected monkeys show that all genotypes are successfully transmitted to mosquitoes. However, after sporozoite inoculation, not all genotypes contribute to the subsequent blood infections, highlighting an important bottleneck during pre-erythrocytic development. Overall, these studies provide new insights on the mechanisms regulating the establishment of polyclonal P. vivax infections and their consequences for disease transmission.

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“…This effect was only detected when the proportion of MSPDBL2+ schizonts was above 10% in the controls without choline treatment, and no effect could be detected on NF54 which has a consistently low baseline proportion of MSPDBL2+ schizonts. The physiological mechanisms whereby choline concentration affects parasite sexual commitment is an area of recent investigation ( 37 , 38 ), which may also be of relevance for studying regulation of MSPDBL2.…”

Section: Discussionmentioning

confidence: 99%

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

Freville,

Stewart,

Tetteh

et al. 2024

mBio

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The Plasmodium falciparum merozoite surface protein MSPDBL2 is a polymorphic antigen targeted by acquired immune responses, and normally expressed in only a minority of mature schizonts. The potential relationship of MSPDBL2 to sexual commitment is examined, as variable mspdbl2 transcript levels and proportions of MSPDBL2-positive mature schizonts in clinical isolates have previously correlated with levels of many sexual stage parasite gene transcripts, although not with the master regulator ap2-g . It is demonstrated that conditional overexpression of the gametocyte development protein GDV1, which promotes sexual commitment, also substantially increases the proportion of MSPDBL2-positive schizonts in culture. Conversely, truncation of the gdv1 gene is shown to prevent any expression of MSPDBL2. However, across diverse P. falciparum cultured lines, the variable proportions of MSPDBL2 positivity in schizonts do not correlate significantly with variable gametocyte conversion rates, indicating it is not involved in sexual commitment. Confirming this, examining a line with endogenous hemagglutinin-tagged AP2-G showed that the individual schizonts expressing MSPDBL2 are mostly different from those expressing AP2-G. Using a selection-linked integration system, modified P. falciparum lines were engineered to express an intact or disrupted version of MSPDBL2, showing the protein is not required for sexual commitment or early gametocyte development. Asexual parasite multiplication rates were also not affected by expression of either intact or disrupted MSPDBL2 in a majority of schizonts. Occurring alongside sexual commitment, the role of the discrete MSPDBL2-positive schizont subpopulation requires further investigation in natural infections where it is under immune selection. IMPORTANCE Malaria parasites in the blood are remarkably variable, able to switch antigenic targets so they may survive within humans who have already developed specific immune responses. This is one of the challenges in developing vaccines against malaria. MSPDBL2 is a target of naturally acquired immunity expressed in minority proportions of schizonts, the end stages of each 2-day replication cycle in red blood cells which contain merozoites prepared to invade new red blood cells. Results show that the proportion of schizonts expressing MSPDBL2 is positively controlled by the expression of the regulatory gametocyte development protein GDV1. It was previously known that expression of GDV1 leads to increased expression of AP2-G which causes parasites to switch to sexual development, so a surprising finding here is that MSPDBL2-positive parasites are mostly distinct from those that express AP2-G. This discrete antigenic subpopulation of mostly asexual parasites is regulated alongside sexually committed parasites, potentially enabling survival under stress conditions.

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Sexual differentiation in human malaria parasites is regulated by competition between phospholipid metabolism and histone methylation

Cited by 23 publications

References 60 publications

Expression of the MSPDBL2 antigen in a discrete subset ofPlasmodium falciparumschizonts is regulated by GDV1 but not linked to sexual commitment

Expression of the MSPDBL2 antigen in a discrete subset ofPlasmodium falciparumschizonts is regulated by GDV1 but not linked to sexual commitment

Single-cell analyses of polyclonal Plasmodium vivax infections and their consequences on parasite transmission

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

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