WEHI Wednesday Seminar hosted by Professor Alan Cowman
 

Associate Professor Chris Tonkin
Acting Division Head and Laboratory Head, Infectious Diseases & Immune Defence division – Infection, Inflammation & Immunity Theme, WEHI

A ubiquitin ligase complex controls latent-stage differentiation in Toxoplasma

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

Stage conversion (or differentiation) is central to the transmission of many pathogens. This is best exemplified in apicomplexan parasites which undergo differentiation into multiple different cell types as  parasites undergo their complex lifecycle moving between different hosts and tissue types. Malaria parasites must convert into different forms between human host and mosquito, whilst Toxoplasma critically requires  differentiation into latent forms to persist in humans and transmit to the next host. Indeed, the development of a latent infection results in Toxoplasma being one of the most common parasites on earth, infecting upwards of one third of the human population. A latent Toxoplasma infection then acts as a reservoir that can lead to reactivation into acute disease, causing progressive blindness (when infecting the retina) or massive tissue destructions in the central nervous system that can lead to death in the immunosuppressed. This is a particular problem as latent Toxoplasma infection is resistant to all therapies leading to no treatment options in at-risk patients.

Whilst several transcription factors have been identified that control differentiation in apicomplexan parasites, very little is understood about the other cellular processes required for sensing of the appropriate tissue type and triggering of stage conversion. We undertook a whole genome CRISPR screen to identify genes required for differentiation of Toxoplasma into latent forms both in vitro and in mice. Validation of gene hits identified several critical biological processes required for differentiation, including the re-wiring of central carbon metabolism, regulation of RNA/translation and ubiquitination. We show that Toxoplasma has a GID/CLTH E3 ubiquitin ligase complex and show that this is important for Toxoplasma differentiation into latent stages. Furthermore, we show that  the related malaria causing parasite Plasmodium falciparum also has a GID/CTLH E3 ubiquitin ligase complex which is required for differentiation into the sexual forms. Overall, our work unveils several new biological processes and molecular factors that control differentiation in Toxoplasma and related malaria parasites and provides the first evidence for the role for ubiquitination within this group of pathogens.

All welcome!