Most people know toxoplasma gondii as the “cat parasite”, usually passed to humans through contact with infected cat poo – like when you clean out the cat tray and forget to wash your hands. But it can also be transmitted via contaminated or undercooked meat, or from handling soil that has come into contact with infected cat poo or infected dead animals.
It is thought that around one-third of the UK population carries a dormant form of the parasite, but symptoms of infection in healthy adults tend to go unnoticed because they are so mild or are mistaken for the common cold.
But for those with compromised immune systems, such as people with Aids or cancer, the parasite can cause a disease called toxoplasmosis. When the toxoplasma “wakes up” from its dormant stage, which happens in those with weakened immune systems, it can cause stroke and death – and in infants it can cause severe brain damage. This is because the active parasite replicates inside cells in the brain until these cells “break”. Toxoplasmosis is particularly dangerous to unborn babies if the mother gets infected for the first time during pregnancy and can cause miscarriage and birth defects.
In 2015, one of the main toxoplasmosis drugs, Daraprim, hit the headlines in America after drug manufacturer Turing Pharmaceuticals raised the price from $13.50 to $750 a tablet. Treatments for toxoplasmosis often have serious side effects such as toxicity in the liver and suppression of bone marrow that helps produce blood cells. There are also no drugs currently available that clear out the dormant form of the parasite.
But now a team of researchers at the University of Glasgow has conducted a study highlighting the importance of thioredoxins – enzymes that have unique characteristics in the toxoplasma parasite that are different from human and animal enzymes.
The team discovered that these thioredoxins are essential for the parasite’s survival and we are now working with industry partners to create new drugs which will effectively target this enzyme and kill the parasite without affecting the human host. Discovering this enzyme means we have found this potentially deadly parasite’s Achilles heel.
More and more studies highlight the fact that toxoplasma parasites are sensitive to redox imbalance – a condition inside cells that the thioredoxin enzymes respond to. Redox is a chemical state that exists in the parasite cell (as it does in human cells too). Redox imbalance is a sort of chemical stress that interferes with the normal activities of the cell; in humans for example, it is believed to contribute to the ageing process. In toxoplasma, the discovered enzyme helps the cell adjust to this stress and continue to survive.
In the same way, other members of the group of parasites to which toxoplasma belongs are also sensitive to redox changes, which makes the environment inside them too chemically stressful, so they die because they can no longer perform their normal activities.
The toxoplasma parasite is an important experimental model for this group, and it is often used to learn about the biology of other parasites, such as those that cause malaria. This is because the cells of toxoplasma and malaria-causing parasites contain the same unique structures.
Having found that the parallel thioredoxin in the malaria-causing parasite has similar characteristics to the toxoplasma one, but are also different from the human enzyme, we are hopeful this work can also be translated to the malaria parasite. The team is now conducting new research to confirm that this malaria enzyme is essential for the malaria parasite’s survival, potentially paving the way for the development of more effective anti-malarial drugs.
In malaria – as with toxoplasmosis – we lack treatments that kill the parasite at the stage where it does not produce symptoms. Targeting the parasite’s thioredoxin enzyme may make the parasites vulnerable at stages of their life that are crucial for infection and dissemination, which means it could be stopped in its tracks.
As an academic research group, our original interest in this work was not about drug discovery, but to learn about how parasites function and how evolution has provided them with special tools to survive. But stumbling across this particular enzyme which is a promising target for new drugs has provided us with an opportunity to explore their potential – and a very welcome bonus that highlights how crucial basic research is to the progress of healthcare and technology.