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Phosphatidylthreonine Synthase and metabolically attenuated vaccine against coccidial parasites


Kurzfassung

The present invention relates to coccidian parasites wherein expression of phosphatidylthreonine synthase (PTS) is disrupted. Also disclosed is a polynucleotide comprising a nucleotide sequence encoding a phosphatidylthreonine synthase (PTS), a phosphatidylthreonine synthase (PTS) enzyme, and a phosphatidylthreonine (PtdThr) lipid. PtdThr is made by a novel coccidian-specific enzyme, PtdThr synthase (PTS), which has evolved from the otherwise universal phosphatidylserine synthase. Our study shows that PtdThr is required for asexual reproduction and virulence of the parasite in vivo, and a metabolically-attenuated mutant of Toxoplasma lacking PtdThr could protect vaccinated mice against acute and currently-incurable chronic toxoplasmosis. PtdThr, PTS enzyme and genetically-attenuated parasites offer possibilities of commercial exploitation at many levels including life science research and veterinary healthcare.


Hintergrund

Lipids are essential components of all biological membranes, and most organisms across the tree of life harbor a repertoire of lipids in their membranes. Initial work of the inventors has revealed the natural and abundant presence of an exclusive lipid phosphatidylthreonine (PtdThr) in Toxoplasma gondii, a ubiquitous protozoan parasite of humans and animals. Other related coccidian parasites of high veterinary relevance, including Neospora and Eimeria, also contain this rare lipid.


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Lösung

PtdThr and PTS genes have many applications and can be developed into successful commercial products, as briefed below.


Anwendungsbereiche

1. Genetically Attenuated Vaccine (TLR 4-5): The Toxoplasma mutant lacking the PTS gene lost virulence in mice model and can be potentially used as a whole-cell vaccine to treat pigs and sheep. Later, the same phospholipid was also found in Eimeria and Neospora, expanding the application to a range of domestic animals (chicken, dogs etc.).

2. Cell Biology Probes (TLR 4): The PTS genes and PtdThr can be used to produce click-chemistry and fluorescent probes for a repertoire of cell biology and biochemical studies. Such probes will have wider applications to study localization, protein interactions, and lipid function studies.

3. Biochemical assays (TLR 6): The PTS gene can be used to produce PtdThr in heterologous models, which can be used to study the biochemical and functional relevance of other related lipids. For example, PtdThr is structurally similar to PtdSer, hence ectopic overexpression of PTS in a given cell type can be used as a decoy to study the subcellular/physiological roles of PtdSer.

 

4. Commercial lipids (TLR 6-7): Lipids are commonly used in life science and clinical research. Especially, the vaccine industry utilized vast amount of lipids. Given the functional uniqueness of PtdThr (extra methyl group compared to PtdSer), it can improve vaccine formulations and also offer a reference standard for routine mass-spec based lipidomics studies. There is a possibility to produce various PtdThr species either from aforesaid parasites or recombinant systems.


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Humboldt-Universität zu Berlin

Dr. Viola Muth
+49 (0)30 2093 12922
viola.muth@uv.hu-berlin.de
http://forschung.hu-berlin.de
Adresse
Ziegelstr. 13c
10117 Berlin



Entwicklungsstand

Prototyp


Patentsituation

  • EP 3 193 920 B1 erteilt

Stichworte

Coccidian parasites, Toxoplasma, Eimeria, Neospora, Phosphatidylthreonine Synthase, Phosphatidylthreonine, Whole-Cell Vaccine, Lipids for Vaccine Delivery, Lipid Probes, Lipids, Parasitology, Vaccines

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