A drug originally designed to lower cholesterol could be an effective new weapon against Cryptosporidium, a debilitating and potentially deadly parasite.
Mapping the Cryptosporidium parasite, highlighted in green, in cells from the gut. Credit: The Francis Crick Institute.
“These infections can be life threatening, especially in children,” explains Adam Sateriale, head of the Crick’s Cryptosporidiosis Lab. “Even mild bouts carry the risk of prolonged malnutrition that can stunt children’s growth and cause other long term consequences.”
Despite being estimated to cause more than 50,000 deaths worldwide each year, there are no fully effective treatments. To try and change this, Bishara Marzook, a researcher in Adam’s team, set out to map the parasite’s survival routes.
What does the parasite need from our intestinal cells in order to survive, and can these pathways be blocked to stop infection?
To understand which components of gut cells were enabling Cryptosporidium to survive, Bishara teamed up with Ok-Ryul Song from the Crick’s Screening and Automated Science facility to design a genome-scale experiment, using CRISPR gene editing to systematically disable nearly 20,000 protein coding genes in human intestinal cells, to see how each affected parasite survival.
Looking at the results, one host metabolite stood out from the rest: squalene. Squalene is a building block that is used to manufacture essential cellular components, such as cholesterol, but is also known to be a potent antioxidant, shielding cells from damage by reactive oxygen species.
This initial finding led the team to realise that Cryptosporidium relies on its host’s antioxidant production to protect it from damage. “This could be a clever way for Cryptosporidium to save its energy for other processes, but we’ve shown that it could also be its downfall,” explains Bishara.
Searching for ways to cut off this lifeline, the team tested a previously abandoned cholesterol lowering drug, lapaquistat, which directly blocks squalene production. In mice, it reduced infection and stopped Cryptosporidium from damaging intestinal cells.
“There is already a huge amount of safety data for lapaquistat, making it easier to fast track clinical trials,” adds Adam. He has now teamed up with researchers and clinicians in Zambia to explore how to put this forgotten drug to the test.
