Molecular biology technique allows for discovery of novel targets for candidate vaccines against schistosomiasis
"Phage display had never been deployed for this purpose in research on parasitic diseases, which normally involves preselection of a few targets for testing of candidate vaccines. In this study, we screened 12,000 proteins of S. mansoni at the same time to identify which ones were targeted by the macaque's antibodies, both after initial infection and reinfection and after reinfection and self-cure, a key innovation. Both the technique and the model for the study were innovative," said Murilo Sena Amaral, a researcher at Butantan Institute's Laboratory of Cell Cycle.
Amaral is the penultimate author of the article. The last author, as principal investigator for the study, is Sergio Verjovski-Almeida, also a researcher at Butantan Institute and a professor at the University of São Paulo's Institute of Chemistry (IQ-USP).
The researchers investigated the immune response of ten macaques infected by S. mansoni during the stages of self-cure and resistance to reinfection using a recently developed technique called peptide library-based phage immunoprecipitation sequencing (PhIP-Seq).
They constructed a phage display library that comprised 119,747 DNA sequences encoding 11,641 known proteins from S. mansoni in all stages of its life cycle. The library was incubated with antibodies collected from rhesus macaques in a previous study at different points during the process of self-cure and resistance to reinfection. The aim was to isolate and identify specific targets of the animal's immune response to the parasite.
Library screening with antibodies from the early phase of parasite infection identified significantly enriched epitopes of parasite extracellular proteins known to be expressed in the host's digestive tract, shifting toward intracellular proteins during the late phase of parasite clearance (released owing to its death). Epitope refers to the specific target against which an individual antibody binds. When an antibody binds to a protein, it bonds not to the entire protein but to a segment known as an epitope.
The enriched peptides were analyzed with bioinformatics tools to identify potential candidates for vaccines. The most promising candidates were tested in a pilot vaccination assay, in which mice were immunized with a selected pool of PhIP-Seq-enriched phage-displayed peptides. The result was a significant reduction of worm burden in the immunized mice.
"You often hear the argument that a schistosomiasis vaccine isn't feasible, but our discoveries have revealed a great deal of the immune response and opened up promising prospects for the development of an effective vaccine. We worked with the 12,000 proteins key to all stages of the parasite's life cycle and succeeded in identifying the most reactive targets," Verjovski-Almeida told Agência FAPESP. The technique can be used for other types of parasite, he added.
In an article published in May 2023, the group described their discovery of a way to "separate" male and female parasites so as to prevent reproduction and egg release. Male-female pairing, with the female living inside the male, is essential to their survival. Without it, they die. In the study, the researchers showed that male-female separation could be obtained by silencing specific long noncoding RNAs (lncRNAs), which are therefore a promising target for treatment of the disease.
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