Toxoplasma gondii, an obligate intracellular parasite that causes toxoplasmosis, is responsible for substantial disease burden worldwide. Drugs against acute infection are limited by toxicity whilst chronic forms are completely drug resistant. During and after invasion of the parasite into the host cell, T. gondii relies heavily on the ability to export effector proteins into the host cell that manipulate signalling pathways to ensure parasite survival and long-term persistence. Host cell death pathways are an attractive avenue for the parasite to manipulate as programmed cell death is an important host defence mechanism against infection.
To investigate the role of programmed cell death pathways in T. gondii infection, we infected mice deficient for various combinations of mediators of programmed cell death pathways. We discovered that receptor interacting serine/threonine kinase 3 (RIPK3) and mixed lineage kinase domain like pseudokinase (Mlkl) (important for necroptosis), caspases-1, -11, and -12 (important for pyroptosis), and caspase-8 (important for apoptosis) are individually dispensable for control of T. gondii infection. However, combined loss of necroptosis and apoptosis resulted in reduced survival, suggesting that these pathways play an important role in mediating resistance to infection in the host. Loss of effector protein export rescued the survival of mice deficient in all pathways to a degree, but this was not an apoptosis- or pyroptosis-specific phenotype, implying that parasite protein export is not required to subvert host apoptotic pathways. The mechanism of how apoptosis is altered upon infection remains unknown.