Final Report Summary - HOSTINGTOXO (Toxoplasma gondii secretes an armada of effector proteins to co-opt its host cell transcriptome and microRNome to promote sustained parasitism)
Toxoplasma gondii belongs to the world champion class of protozoan parasites with a striking ability to colonize most warm-blooded animals worldwide. Not only the developmental program of this parasite in wildlife and livestock animals can result in potentially negative socio-economic impact, but remarkably, in about a third of the human population Toxoplasma also experiences prolonged quasi-silent persistence in tissues such as brain and retina. While the asymptomatic parasitism that proceeds typically offers life-long equilibrium and protection in immune competent hosts, sustained immune dysfunction is known to break parasite dormancy, promoting bradyzoite to tachyzoite transition and further T. gondii tachyzoite population expansion, these combined processes eventually resulting in encephalitis and meningitis as major damages. HostingTOXO was focusing on elucidating the molecular mechanisms by which T. gondii is orchestrating immune evasion and lifelong persistence in hosts. Once intracellular, parasites actively reprogram gene expression of the immune cells they infect by subverting host transcription factors activity or by modulating the epigenetic status of target genes. Secreted effectors were thought to be involved. HostingTOXO led to the discovery of new exported Toxoplasma effectors and to the characterization of their activities. Those are singularly exported beyond the vacuole-containing parasites and reach the host cell nucleus/cytoplasm to reshape the host genetic program. These effectors may adopt at least three alternatives, although not mutually exclusive, strategies to subvert host gene expression. They may (i) modulate upstream signaling pathways (ii) directly target host transcription factor protein levels/activity and/or (iii) affect histone packing and chromatin configuration. While studying their modus operandi in the infected cells, we learned how they contribute to immune evasion and parasite persistence.