IMPC: GPNMB in Toxoplasma gondii infection: beneficial to parasite or host?

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Toxoplasma gondii is a parasite that infects around 30% of the global human population. It is acquired following consumption of
contaminated water or produce, or meat from infected animals. The parasite travels from the intestine to the brain, where it forms cysts
that persist for the lifetime of the infected individual. In many cases T. gondii causes only mild flu-like illness during the acute phase of
the disease, but infection can also have severe health consequences. For example, reactivation of cysts in the brains of people whose
immune systems are compromised can result in severe encephalitis and death. Spontaneous abortion, still birth and severe birth defects
can occur if the infection is caught during pregnancy and transmitted to the foetus, and ocular disease can occur in both congenitally
infected infants and otherwise healthy adults. Treatment for toxoplasmosis is available, but it can cause severe side effects and is
ineffective against brain cysts. Thus, the development of novel treatments is an important research goal.
T. gondii is an intracellular parasite, and actively invades cells in its mammalian hosts. Once it has infected a host cell, it is capable of
changing the behaviour of that cell by changing the levels of specific host cell proteins. This allows the parasite to (1) enhance host cell
migration and use host cells as a dedicated shuttle service to reach the brain, and (2) to protect itself by turning down the host immune
response and ensuring that the host cell in which it resides does not die. The purpose of this project is to understand which host proteins
T. gondii targets to achieve this. We may then be able to design novel therapies for toxoplasmosis, that are directed against these host
proteins, and prevent T. gondii from using them for its own benefit.
We have recently discovered that T. gondii infection results in increased levels of a protein, GPNMB, in the infected host cell. This protein
has previously been shown to play roles in cell migration and regulation of immune responses. We therefore hypothesise that T. gondii is
using this protein to modify host cell migration to spread through its host and/or to dampen the immune response. We will test this by assessing immune responses, and the formation of brain cysts with following T. gondii infection in the absences or presence of the GPNMB gene. We will also determine whether GPNMB enhances host cell migration following T. gondii infection. Ultimately, these experiments will allow us to identify if GPNMB may be a good target for novel therapies. GPNMB is already being investigated as a drug target in cancer, and it may be possible to adapt these novel therapeutics for control of T. gondii infection.