Toxoplasma gondii develops a latent infection in the muscle and central nervous system that acts as a reservoir for acute-stage reactivation in vulnerable patients. Until now little is understood about how these parasites manipulate host cells during latent infection and the impact this has on survival. New research led by the Walter and Eliza Hall Institute of Medical Research, the University of Melbourne and the Wellcome Center for Anti-Infectives Research shows that Toxoplasma gondii is able to lay dormant and undetected inside neurons and muscle cells by releasing proteins that switch off the cells' ability to alert the immune system. This discovery could pave the way for new drug targets to treat patients suffering from chronic toxoplasmosis infections.
Microscopic cysts containing Toxoplasma gondii develop in the tissues of many vertebrates. Here, in mouse brain tissue, thousands of bradyzoites (stained red) are enveloped by a thin parasite cyst wall. Image credit: Jitinder P. Dubey.
Toxoplasmosis is a parasitic infection that affects humans and other mammals. It is caused by eating undercooked or contaminated meat, and from exposure to infected cat feces.
Toxoplasma gondii infections can cause congenital birth defects, blindness and neurological dysfunction in unborn children. In adults who are immunocompromised, it can cause blindness and even death.
"Toxoplasma gondii parasites often lay dormant (called bradyzoites) in the brain of the host animal, where they could reactivate to cause severe disease," said Ushma Ruparel, a Ph.D. student in the Walter and Eliza Hall Institute of Medical Research and the Department of Medical Biology at the University of Melbourne.
"We know that Toxoplasma gondii parasites make their own molecules and proteins that it exports into the host cell to protect itself from detection by the immune system."
"While this is well-understood in the acute, initial stage of infection, how Toxoplasma gondii hijacks its host cells in its dormant form was unknown."
With colleagues who have expertise in genomics and advanced imaging, Ruparel and colleagues showed that the parasite exports proteins called Inhibitor of STAT1 transcription (IST) to the host cell to suppress immune signals.
"IST plays a key role in limiting interferon signaling in bradyzoites, to protect host cells from immune-mediated cell death, which is essential to the body's fight against Toxoplasma gondii," said Dr. Chris Tonkin, also from the Walter and Eliza Hall Institute of Medical Research and the Department of Medical Biology at the University of Melbourne.
"Interferon is the beacon molecule of the immune system. It gives off a blinking sign to notify the immune system that the body has been infected with a range of diseases, including Toxoplasma gondii."
"Interferon is crucial in the fight against disease. However, the cunning parasite tries to turn this signal off during the latent period, as this is the only way it can survive."
"While the immune system is determined to rid the infection from the body, the parasite only has survival on its mind. So, it's essentially a tug-of-war, a molecular battle."
"Our next step is to figure out what it is about chronic infections that make those changes really unique to chronic infections," he added.
"We have found one specific parasite protein that seems to have a role, but it doesn't seem to account for all changes, and we want to explore if there are any others."
The findings were published in the journal Cell Host & Microbe.
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Simona Seizova et al. Transcriptional modification of host cells harboring Toxoplasma gondii bradyzoites prevents IFN gamma-mediated cell death. Cell Host & Microbe, published online December 17, 2021; doi: 10.1016/j.chom.2021.11.012
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