The Toxoplasma gondii parasite can only reproduce in cats, so it causes infected mice to lose their fear of cats.
(Credit: Pixabay)
The parasite, which causes a disease called toxoplasmosis, can infect almost any warm blooded animal but must reproduce in cats, can control the behaviour of its host and is thought to infect as much as half the world’s human population. The work is a major step towards developing a cure.
If there is one constant in the natural world it is that predators hunt prey and that that prey doesn’t like being eaten and so will seek to avoid their predators if at all possible – in other words, the prey runs away. Take the mouse for example: mice are pretty low on the food chain and, as such, are hunted (and devoured) by a veritable army of predatory nemeses – one of which is the humble domestic cat. If there is one animal that can be guaranteed to steer clear of anywhere a cat might be, or might have been, it is the mouse.
One pretty big clue that there might be a cat in the vicinity is the presence of feline urine. So mice are hardwired to avoid anywhere they detect the heady aroma of cat pee. But every so often a mouse will come along that has lost its fear of cats and, rather than being repelled by the smell of cat pee, is attracted to it – actively seeking it out and then hanging around until the cat suddenly finds itself presented with a remarkably compliant snack.
So why would an animal with countless generations of predator avoidance programmed into it suddenly break that programming and offer itself up as a meal? The answer is a singled-celled microscopic organism called Toxoplasma gondii.
T. gondii is not a bacterium or a virus, but is actually a parasite distantly related to the one that causes malaria. T. gondii can live within almost any warm blooded animal (in fact it was recently detected within beluga whales in the Arctic) but it can only reproduce within the digestive system of cats, which means that, whatever animal it has infected, if it isn’t a cat, it wants to find its way into a cat.
The parasite’s lifecycle begins inside a cat where it produces millions of egg-like pods called oocysts. These are released into its host’s faeces ready to be spread around when the unwitting animal next goes to the toilet. Other animals can then become infested by making contact with the faeces directly or, more likely, when the oocysts make their way into soil or water, where they can survive for months, or years – making their way into the food chain and into the next host. If the next host is not a cat, they make their way through the body until they find a nice cosy cell in which they make a new home to settle down, replicate and wait for their host to be eaten by a cat.
The Toxoplasma gondii parasite as seen using the OCTOPUS laser at CLF.
(Credit: Javier Periz et al, CLF)
Although T. gondii can sit dormant and wait for years, the parasite does have the ability to take more direct action by making its way into the brain of its host and actually altering its behaviour. In the case of small prey animals such as mice, T. gondii can cause them to be attracted to cat urine and, in some cases, walk straight into the jaws of hungry felines where the parasite can begin its lifecycle once more.
It is thought that T. gondii achieves its mind control trick by forming cysts in regions of the brain that process fear and decision making and may also affect behaviour by increasing levels of the neurotransmitter dopamine, which is involved in reward-motivated behaviour and risk-taking.
It’s not just furry mammals and whales that can get Toxoplasma gondii and the disease it causes, toxoplasmosis – humans can be carriers too. In fact, according to some estimates, as much as half of the all the people on Earth could be harbouring the parasite, with infection rates being much higher in countries where sanitation is poor or people eat more raw meat (T. gondii likes to hide in muscle tissue).
Because it can’t complete its lifecycle in humans, for the most part we are unaware that we might be infected. In healthy people, toxoplasmosis causes a mild flu-like illness or no symptoms at all but, for those with weakened immune systems the disease can, occasionally, be fatal. T. gondii can form cysts inside human brain neurons and in immunocompromised individuals (such as HIV sufferers) the cysts might grow and replicate – causing fatal brain inflammation, dementia and psychosis.
The disease can’t be passed between humans but it may be passed between a pregnant mother and the unborn infant, which makes getting toxoplasmosis during pregnancy particularly dangerous. This is because a developing infant is only protected by the mother’s antibodies, but her T cells, which are the most effective weapons against bacteria and parasites, can’t cross into foetus (if they did, they would treat it as if it were a huge parasite and attack it). Without T cells to control the spread of the parasites they may multiply uncontrollably causing brain damage or even miscarriage.
It may also be that even those of us with healthy immune systems are not entirely immune to T. gondii’s influence. There is some evidence that toxoplasmosis might alter people’s personalities – increasing risk-taking behaviours and maybe increasing the chance of developing mental disorders such as schizophrenia, autism and Alzheimer’s disease.
As it stands, there is currently no cure available for toxoplasmosis because, until relatively recently, it was believed that, with the exception of a few cases, the disease was pretty benign. Now, however, T. gondii has become the focus of some pretty intensive investigation by parasitologists, biologists and, thanks to its potential behaviour-altering characteristics, by psychiatrists. One of the latest studies to investigate the parasite was recently carried out using the OCTOPUS facility at the Central Laser Facility (CLF). OCTOPUS (Optics Clustered to Output Unique Solutions) uses laser light to act as a super powerful microscope able to capture images of living biological material at a molecular level.
In order for a cure to be developed it is important to understand how the parasite infests its host cells and how it replicates. It is known that T. gondii has a series of specialised organelles (tiny structures that perform specific tasks within a cell) called micronemes that, when they release their contents, allow the parasite to stick to host cells, move around and then invade them. Once inside the cell, the parasite divides multiple times until the mature parasites are fully formed and able to burst the host cells.
What is not understood is how the parasite divides in order to produce a mature parasite that is capable of infecting new host cells. The new research was carried out by Dr Javier Periz of the University of Glasgow’s Institute of Infection, Immunity and Inflammation, Prof. Markus Meissner of Ludwig Maximilian University of Munich, and Dr Lin Wang of STFC’s Central Laser Facility. The study, published in the journal Nature Communications, focused on answering two key questions about this process. Firstly, how the parasite ensure that the microneme organelles are located at the right position on the mature parasite to ensure maximum infection; and, secondly, what happens to these organelles after each round of division.
By using super-resolution microscopy techniques available at CLF, the team was able to track the location of the micronemes with a few tens of nanometer precision during the process of division. They were able to show that there is a network of mobile tracks that the parasite uses to transport the proteins, called adhesins, it uses as a sort glue to stick to the host cell.
The complex lifecycle of the Toxoplasma gondii parasite.
(Credit: Creative Commons)
They also found that the organelles are produced in each round of division and passed on from the mother cell to the daughter cells. This recycling of organelles means that the parasite is able to recover valuable materials that are needed for T. gondii to propagate and become a mature infective parasite. This also means that, despite being a parasite (which, by definition, exploit the resources of others), T. gondii is able to recycle its own resources and see that nothing is wasted to ensure its survival inside the infected cell. To see a parasite using its resources so efficiently is a unique finding.
This breakthrough will open up a new area of research that will have the potential to develop treatments that could interrupt this process and prevent the parasite from replicating and developing. Understanding the role of adhesins means that scientists could develop molecular tools to disrupt the network and ‘tear up’ and break the tracks to stop their transport, prevent the parasite from adhering to its host cells and thus render it non-infectious.
Click here to read the original article.
Click here to read the original paper.
Periz, J., Rosario, M., McStea, A. et al. A highly dynamic F-actin network regulates transport and recycling of micronemes in Toxoplasma gondii vacuoles. Nat Commun 10, 4183 (2019) doi:10.1038/s41467-019-12136-2
