WEHI Special Infection and Global Health Seminar hosted by Dr Simona Seizova

Bishara Marzook

Postdoctoral Fellow – Sateriale Laboratory, The Francis Crick Institute, UK

A microscopy-based CRISPR screen reveals the essential host genome for Cryptosporidium parvum growth and development in vitro

In-person presentation

Davis Auditorium

Including Q&A session

Bishara is a virologist-turned-parasitologist who has never strayed from being a cell biologist. She completed her PhD at The University of Sydney with A/Prof Tim Newsome, where she uncovered divergent roles for the cytoplasmic isoforms of G-actin in vaccinia virus-induced actin polymerisation. She then moved to the UK to the University of Cambridge to pursue postdoctoral research on the biochemistry of actin polymerisation during cell membrane remodelling events. Realising she missed studying host-pathogen interactions too much, she moved to The Francis Crick Institute in London, where she now works on understanding the cell biology of infection of the small intestinal parasite Cryptosporidium.

Cryptosporidium species are a leading cause of diarrheal disease in new-borns, the immune-compromised, and commercial livestock. They are part of the apicomplexan phylum of intracellular parasites, including malaria-causing Plasmodium and feline-infesting Toxoplasma. Cryptosporidium (“Crypto”) needs to complete both asexual and sexual stages of its complex life cycle in intestinal epithelial cells, however the precise host conditions that enable Crypto to invade host cells, survive within its intracellular vacuole, replicate, and switch to its sexual stage of development are largely unknown. We therefore devised a novel microscopy-based CRISPR-Cas9 screen to examine the effect of the loss of every protein-coding human gene during a 48-hour Crypto infection. I will present work on our first major finding from this screen, which is that growth and sexual development of this obligate intracellular parasite hinges on one metabolite in the host cholesterol biosynthesis pathway called squalene. We find that a build-up of host squalene produces a reducing environment in host cells. This is particularly beneficial for Crypto as we found the parasite relies on host cell glutathione, since it cannot synthesise this essential metabolite on its own. These results have led to a promising new drug treatment targeting host squalene synthesis, which has proven effective in mouse models of Crypto infection. This CRISPR screen has opened up many new avenues of research into the basic cell biology of infection of Cryptosporidium, ranging from studying parasite invasion to sexual stage development.

All Welcome!