Biology subjects

Yang, A. S. P.

Publications and source records attributed to Yang, A. S. P..

4 recordsLinked to original sources

bioRxiv2026

Targeting PTRAMP-CSS potently inhibits P. falciparum across blood, liver and mosquito stages

Malaria, caused by Plasmodium falciparum spans liver, blood, and mosquito stages, limiting the effectiveness of single-stage vaccines. The PTRAMP-CSS heterodimer, a core component of the essential PCRCR invasion complex, is expressed on merozoites, mature gametocytes, and salivary gland sporozoites, enabling single-antigen targeting across multiple lifecycle stages. Nanobodies against PTRAMP-CSS block merozoite invasion of erythrocytes, reduce mosquito infection in membrane-feeding assays, and inhibit sporozoite invasion of primary human hepatocytes. High-resolution crystal structures of inhibitory and non-inhibitory nanobody-antigen complexes identify conserved inhibitory epitopes and guide the design of bispecific nanobody Fc constructs with enhanced potency. In semi-immune Kenyan CHMI samples, higher baseline IgG to PTRAMP-CSS and Ripr is associated with improved parasite control. By demonstrating conserved vulnerability across all three major lifecycle stages, PTRAMP-CSS offers a realistic path to single-antigen, multistage vaccines and biologics that aim to prevent disease and block transmission.

microbiology↗

bioRxiv2024

Modulation of host signalling pathways reveal a major role for Wnt signalling in the maturation of Plasmodium falciparum liver schizonts

After infection of the human host, the initial stage of the Plasmodium falciparum (Pf) lifecycle takes place in the liver. However, understanding of the host-parasite interaction has been limited by the rapid loss of functionality in cultured primary human hepatocytes (PHHs). Here, we link loss of hepatic functionality to drastic loss in Pf permissiveness, which we effectively prevent by using a novel medium containing serum-replacement and signal transduction inhibitors. Integrating transcriptomic analysis and phenotypic assessment of infection outcome, we identified several host signalling pathways that influence Pf liver stage development. Inhibition of the Wnt pathway in particular plays a major role in determining the size and maturity of Pf-liver schizonts, via retaining metabolic activity and epithelial nature of hepatocytes. Host signalling pathways determining Pf liver stage permissiveness provide insight into the complex host-parasite interaction and may accelerate development of novel therapeutic strategies for Pf-liver stages. (145)

microbiology↗

bioRxiv2023

Comparative assessment of mosquito size and receptiveness to P. falciparum infection of two rearing procedures for Anopheles mosquitoes

Malaria is transmitted when Anopheline mosquitoes ingest Plasmodium parasites during blood-feeding. Artificial feeding assays allow mosquitoes to take up blood from membrane feeders, and are widely used to study malaria transmission. These assays require large quantities of mosquitoes; insectaries optimize their rearing procedures to generate high yields of permissive, homogeneous mosquito populations. Rearing of Anopheline stephensi mosquitoes was protocolized at the Radboudumc in the 1980s, yet infection outcomes remain heterogeneous. This study explores possible improvements in mosquito rearing to improve homogeneity of the resulting mosquito populations. It compares the current mass-rearing standard with an adapted alternative approach from another institute that optimizes larval density per tray and applies a diet that has previously been reported. Differences between procedures were assessed by measuring mosquito size by proxy of wing-length and imbibed blood meal volume. To assess receptiveness to P. falciparum infection mosquitoes were fed cultured gametocytes. We observed a slight decrease in mosquito size when applying the alternative rearing procedure, but generated equally parasite-receptive P. falciparum mosquitoes compared to the standard procedure. We conclude that both rearing protocols can be used to generate susceptible mosquitoes for conducting malaria research.

systems biology↗

bioRxiv2020

Novel functional insights from the Plasmodium falciparum sporozoite-specific proteome by probabilistic integration of 26 studies

Plasmodium species, the causative agent of malaria, have a complex life cycle involving two hosts. The sporozoite life stage is characterized by an extended phase in the mosquito salivary glands followed by free movement and rapid invasion of hepatocytes in the human host. This transmission stage has been the subject of many transcriptomics and proteomics studies and is also targeted by the most advanced malaria vaccine. We applied Bayesian data integration to determine which proteins are not only present in sporozoites but are also specific to that stage. Transcriptomic and proteomic Plasmodium data sets from 26 studies were weighted for how representative they are for sporozoites, based on a carefully assembled gold standard for Plasmodium falciparum (Pf) proteins known to be present or absent during the sporozoite life stage. Of 5418 Pf genes for which expression data were available at the RNA level or at the protein level, 1105 were identified as enriched in sporozoites and 90 specific to them. We show that Pf sporozoites are enriched for proteins involved in type II fatty acid synthesis in the apicoplast and GPI anchor synthesis, but otherwise appear metabolically relatively inactive, in the salivary glands of mosquitos. Newly annotated hypothetical sporozoite-specific and sporozoite-enriched proteins highlight sporozoite specific functions. They include PF3D7_0104100 that we identified to be homologous to the prominin family, which in human has been related to a quiescent state of cancer cells. We document high levels of genetic variability for sporozoite proteins, specifically for sporozoite-specific proteins that elicit antibodies in the human host. Nevertheless, we can identify nine relatively well-conserved sporozoite proteins that elicit antibodies and that together can serve as markers for previous exposure. Our understanding of sporozoite biology benefits from identifying key pathways that are enriched during this life stage. This work can guide studies of molecular mechanisms underlying sporozoite biology and potential well-conserved targets for marker and drug development. Author SummaryWhen a person is bitten by an infectious malaria mosquito, sporozoites are injected into the skin with mosquito saliva. These sporozoites then travel to the liver, invade hepatocytes and multiply before the onset of the symptom-causing blood stage of malaria. By integrating published data, we contrast sporozoite protein expression with other life stages to filter out the unique features of sporozoites that help us understand this stage. We used a "guideline" that we derived from the literature on individual proteins so that we knew which proteins should be present or absent at the sporozoite stage, allowing us to weigh 26 data sets for their relevance to sporozoites. Among the newly discovered sporozoite-specific genes are candidates for fatty acid synthesis while others might play a role keeping the sporozoites in an inactive state in the mosquito salivary glands. Furthermore, we show that most sporozoite-specific proteins are genetically more variable than non-sporozoite proteins. We identify a set of conserved sporozoite proteins against which antibodies can serve as markers of recent exposure to sporozoites or that can serve as vaccine candidates. Our predictions of sporozoite-specific proteins and the assignment of previously unknown functions give new insights into the biology of this life stage.

microbiology↗