Active Infection & Immunity Genetics & Molecular Biology

A systems-biology approach to identify Toxoplasma effectors that co-opt host cell transcription and their function in immune system suppression.

In plain English

AI plain-English summary

A single-celled parasite called *Toxoplasma gondii* has evolved a molecular toolkit of roughly 200 secreted proteins that it injects into host cells to hijack their genetic machinery, but scientists do not know which of these tools actually do the job. This matters because *Toxoplasma* infects about 30% of the global human population and any nucleated cell of any warm-blooded animal. Some strains cause severe disease in humans but not in other species, and vice versa. The difference likely lies in which effector proteins the parasite uses to suppress the host's immune response, but the specific proteins responsible for these transcriptional changes remain unknown. The researchers have developed a new technique called EffectorSEQ that can test many parasite mutants at once and correlate each with the host cell's resulting gene activity. They will use it to identify which of the ~200 effector proteins alter transcription in different cell types and species, then focus on those that promote anti-inflammatory immune environments favourable to parasite growth. This is fundamental science. Understanding how *Toxoplasma* co-opts host cell transcription across such a broad host range could eventually reveal new targets for drugs or vaccines, but the immediate goal is to map the parasite's molecular strategy for immune suppression.

View original technical description
Toxoplasma gondii infects any nucleated cell of any warm-blooded animal and ~30% of the human population. Why some Toxoplasma strains cause disease in humans but not in other species and vice versa is poorly understood, but linked to effector proteins the parasite secretes to remodel its host cell. A substantial proportion of host cell remodelling occurs on the transcriptional level, but which of Toxoplasma’s ~200 putative effector proteins mediate these changes, and how they affect different cell types and hosts is largely not known. We will use a novel technology we devised (EffectorSEQ) to correlate host cell transcriptomic changes to infection by various Toxoplasma mutants in a highly multiplexed manner. We will i) identify most, if not all, Toxoplasma effectors important for host cell transcriptional responses in different cell types and species and ii) use bioinformatics approaches to identify those that promote anti-inflammatory immune responses. iiI) We will investigate in detail the effector proteins that change infected immune cells signalling behaviour and thereby promote an immune environment that favours parasite growth and pathogenesis. Our result will lead to a comprehensive understanding how this important pathogen infects and causes disease in such a broad host range.

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Researchers

Moritz Treeck (EPMC Awardee)

Related Research

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Original classification

Investigator Award in Science

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