A novel parasite vulnerability could usher in new treatments for toxoplasmosis and malaria

Toxoplasma gondaii within an infected host cell. Credit: Ke Hu and John M. Murray.

Toxoplasmosis is a disease caused by Toxoplasma gondaii, an intracellular parasite capable of infecting warm-blooded animals, spread through undercooked contaminated meat, infected cat faeces and from mother-to-child in pregnancy. One of the most common parasitic infections in the developed world, with one-third of the UK population believed to have a latent form of infection, but as the symptoms are so mild the infection often goes unnoticed in healthy adults. Due to this, treatment is not normally given as most people are unaware they are carriers and there is no measurable detriment to quality of life.

For those with compromised immune systems, however, the dormant T. gondaii are more likely to be activated due to its opportunistic nature, leading to toxoplasmosis. This can be fatal, with symptoms including disorientation, reflex impairment, convulsions and stroke.

Cats are the definitive host for T gondaii, meaning the parasite can only sexually reproduce within members of the cat family, starting and completing its life-cycle. It infects the epithelial cells of the cat’s intestine where it reproduces, producing millions of oocytes that are passed into the environment through faeces. These oocytes can then infect an intermediate host, such as a rat or human, where they asexually reproduce leading to tissue cyst formation and a chronic infection.

One of T. gondaii’s most interesting traits is its ability to alter host behaviour. This ‘manipulation hypothesis’ is supported by studies demonstrating a reduced aversion to cats and their scents, making them easier to prey upon. This helps to ensure the completions of the parasite’s life cycle and therefore makes T. gondaii a more successful species. This phenomenon has been observed in humans as well, with less risk-averse behaviour and psychomotor impairment seen in infected individuals.

Treatment for toxoplasmosis can have severe side effects, such as liver damage and bone marrow loss, and there are no current drugs that can cure the dormant infection. Pyrimethamine, a major toxoplasmosis treatment that is also used for malaria, has been in the news recently after the manufacturer raised the price by 5456% to $750 per pill, inciting wide-spread criticism.

A recent study from researchers at the University of Glasgow investigated the importance of thioredoxins for T. gondaii survival, enzymes that control the cellular redox state. The redox state is the balance between reduced and oxidised forms of molecules in the cell. Imbalance occurs when the cell is under stress, creating a toxic intracellular environment and eventual cell death if not controlled. The thioredoxins aid with the adjustment of the redox state to different stresses and environments that the cell may be in, keeping it alive.

The authors identified two pathways in T. gondaii that are controlled by two thioredoxins, both of which are essential for parasite survival. Both thioredoxins contribute to a different functional aspects of apicoplasts, an organelle believed to be involved in fatty acid synthesis, allowing the parasite to produce components essential for invasion of new cells and survival.  They found that the two thioredoxins control apicoplast protein import and gene expression, and that they are distinct from human thioredoxins, making them a highly specific drug target, reducing toxicity and side effects. These potential treatments can target latent T. gondaii as well as the active form, something that is not possible with current treatments.

These results can also be applied to other apicoplast containing parasites, such as Eimeria and Plasmodium which cause eimeriosis and malaria respectively, as their unique nature and importance for parasite survival makes apicoplasts good drug targets. New research is currently being conducted to ascertain if the thioredoxins in Plasmodium are just as essential to parasite survival as they are in T. gondaii. A new class of anti-malarial drugs that target thioredoxins and the apicoplast could be discovered from this research, allowing for the effective treatment of the disease in asymptomatic carriers who act as a pool of infected blood for mosquitos, aiding dissemination of the disease.

The hope is that the thioredoxin’s potential as a drug target will result in novel therapies to help eradicate these widespread and potentially deadly parasitic infections, reducing the health burden on many of the worlds poorest nations.