Toxoplasma polymorphic effectors determine macrophage polarization and intestinal inflammation

Area of Science:

• * Parasitology
• * Immunology
• * Molecular Biology

Background:

• * Toxoplasma gondii, an intracellular parasite, exhibits distinct clonal lineages (Type I, II, III) with varying virulence.
• * Understanding strain-specific differences and effector functions is crucial for comprehending chronic infection.
• * Macrophages play a key role in host immunity against Toxoplasma.

Purpose of the Study:

• * To investigate how different Toxoplasma gondii strains modulate macrophage activation.
• * To identify the specific parasite effector proteins responsible for differential macrophage activation.
• * To determine the impact of these effectors on host-parasite interactions and disease outcome.

Main Methods:

• * Macrophage activation assays (alternative vs. classical) in response to infection with different T. gondii strains.
• * Molecular analysis of signaling pathways (STAT6, NF-κB) activated by parasite effectors.
• * Genetic manipulation of parasite strains to express heterologous effector proteins.
• * In vivo studies in mice to assess protection against Toxoplasma-induced ileitis.

Main Results:

• * Type I and III T. gondii strains induce alternative macrophage activation, while Type II induces classical activation.
• * The rhoptry kinase ROP16 (activating STAT6) drives alternative activation.
• * The dense granule protein GRA15 (activating NF-κB) promotes classical activation by Type II parasites.
• * ROP16 and GRA15 antagonistically regulate overlapping gene sets.
• * Mice infected with Type II parasites expressing Type I ROP16 showed protection against ileitis.

Conclusions:

• * Polymorphisms in T. gondii effector proteins significantly influence macrophage activation states.
• * Differential modulation of macrophage activation by parasite effectors impacts the establishment of chronic infection.
• * Targeting these effector-host interactions offers potential strategies for controlling Toxoplasma infections.