Deciphering the host defence mechanisms targeting Toxoplasma in retinal epithelial cells

Toxoplasma strains are restricted to a few clonal variants in Europe and North America and infections are usually asymptomatic unless individuals are immunosuppressed. This contrasts with the occurrence of multiple diverse Toxoplasma strains in South America where clinical disease manifests as ocular and congenital toxoplasmosis even in immunocompetent individuals, leading to high morbidity and mortality.

We have previously shown that Toxoplasma strains actively invade and proliferate within endothelial cells, with a proportion of parasites being eliminated in an acidified vacuole after immune stimulation of the cells by interferon gamma (IFNg)¹. In macrophages, however, we have demonstrated that parasites are killed by a mechanism involving GBP1-mediated vacuole breakage and Caspase 8-dependent apoptotic host cell death².

Our study explores IFNg-driven control of diverse Toxoplasma strains in retinal pigment epithelial cells (ARPE-19), where the mechanism of host defence and parasite elimination is not well understood. We show that IFNg-stimulation of these non-immune cells initiates cell death after infection with type I RH Toxoplasma and a variety of South American strains. Host defence molecules are also recruited to parasite vacuoles in an IFNg-dependent manner. We are delineating the pathways that cause infection-driven host cell death and the host proteins driving this at the vacuolar membrane in order to better understand the drivers of ocular toxoplasmosis.

1 Clough, B. Wright, J.D., Pereira, P.M., Hirst, E.M., Johnston, A.C., Henriques, R and Frickel E-M. (2016) K63-Linked ubiquitination targets Toxoplasma gondiifor endo-lysosomal destruction in IFNg-stimulated human cells. PLoS Pathogens https://doi.org/10.1371/journal.ppat.1006027 2 Fisch, D.F., Bando, H., Clough, B., Hornung, V., Yamamoto, M., Shenoy, A.R. and Frickel E-M. (2019) Human GBP1 is a microbe‐specific gatekeeper of macrophage apoptosis and EMBO J 38: e100926 https://doi.org/10.15252/embj.2018100926