Search

The phylum Apicomplexa comprises a group of unicellular eukaryotic organisms including Plasmodium spp., Toxoplasma gondii and Cryptosporidium spp. Infection with Toxoplasma gondii causes severe congenital birth defects and disease in immunocompromised individuals and persists for life. Efforts to develop effective vaccines have been unsuccessful and emergence of drug resistance has reduced the utility of current antiparasitic compounds, highlighting the need for new therapeutics. My PhD focussed on two areas: Firstly, understanding degradative ubiquitination in apicomplexan parasites as a step towards developing first in class anti-apicomplexan PROTACS. PROTACS are heterobifunctional molecules which on one end bind an E3 ubiquitin ligase and force it to bind with a neo-substrate which is then degraded via the proteasome. This technique has shown great promise in developing new therapeutic approaches to treat disease like cancer but has never been tested against any apicomplexan parasite. The absence of conventionally used E3 ligases for PROTAC development became a challenge which I decided to overcome during my thesis. I developed a new system to screen for degradative parasite E3 ubiquitin ligases that can be used to enhance current therapies. The second part of my PhD focused on the role of ubiquitination during differentiation of Toxoplasma gondii into latent stages. We performed a whole genome CRISPR screen to identify genes required for differentiation into latent forms. The screen identified several genes involved in protein ubiquitination. These encompassed a complete multi protein E3 ubiquitin ligase complex that regulates differentiation from acute to latent forms and was the orthologue of the GID/CTLH E3 ligase complex which has been characterised in yeast and humans. Genetic removal of this complex resulted in markedly reduced cyst formation in vitro even in conditions favouring differentiation and reduced burden in the brain in vivo. Furthermore, we have

Presentamos el caso de un hombre de 39 años de Mali, que consultó por una Gonalgia izquierda y por una masa dura en la parte externa del tercio inferior del muslo. Hay una importante barrera del lenguaje El examen de la rodilla fue anodino con la integridad de todas las estructuras ligamentosas y meniscales y la atención se centró en la palpación de un tumor duro, plano y redondeado a nivel del tercio inferior y la cara externa del muslo izquierdo. Se refiere a haber sido tratado en la sala de emergencias del hospital hace unos meses por un accidente con contusión en la misma pierna. Revisamos la radiología realizada en el hospital donde se observó una imagen calcificada en espiral en el área correspondiente a la lesión palpable, que sería compatible con una forma adulta del nematodo calcificado Dracunculus medinensis., We present the case of a 39-year-old man from Mali, who consulted for a left Gonalgia and for a hard mass on the outside of the lower third of the thigh. There is an important language barrier The examination of the knee was anodyne with integrity of all the ligamentous and meniscal structures and attention was focused on the palpation of a hard, flat and rounded tumor at the level of the lower third and outer face of the left thigh He refers to having been treated in the hospital emergency room a few months ago for an accident with contusion on the same leg. We reviewed the radiology done at the hospital where a spiral calcified image was seen in the area corresponding to the palpable lesion, which would be compatible with an adult form of the calcified nematode Dracunculus medinensis.