The Rhoptry Proteins ROP18 and ROP5 Mediate Toxoplasma gondii Evasion of the Murine, But Not the Human, Interferon-Gamma Response

PLoS Pathogens

Wendy Niedelman¹  Ailan Farid Arenas¹  Emily E. Rosowski¹  Daniel A. Gold¹  Joris K. Sprokholt¹  Michael B. Yaffe¹  Daniel Lim²  Eric Spooner³  Mariane B. Melo⁴  Jeroen P. J. Saeij⁵ 

[1] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America;Department of Cell Biology and Immunology, Wageningen University and Research Centre, Wageningen, The Netherlands;Group of Molecular Parasitology, Universidad del Quindio, Quindio, Colombia;Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America;Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America

关键词: Parasitic diseases;    Toxoplasma;    Coatings;    Virulence factors;    Vacuoles;    Genetic loci;    Mammalian genomics;    RNA sequencing;   

DOI  :  10.1371/journal.ppat.1002784

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The obligate intracellular parasite Toxoplasma gondii secretes effector proteins into the host cell that manipulate the immune response allowing it to establish a chronic infection. Crosses between the types I, II and III strains, which are prevalent in North America and Europe, have identified several secreted effectors that determine strain differences in mouse virulence. The polymorphic rhoptry protein kinase ROP18 was recently shown to determine the difference in virulence between type I and III strains by phosphorylating and inactivating the interferon-γ (IFNγ)-induced immunity-related GTPases (IRGs) that promote killing by disrupting the parasitophorous vacuole membrane (PVM) in murine cells. The polymorphic pseudokinase ROP5 determines strain differences in virulence through an unknown mechanism. Here we report that ROP18 can only inhibit accumulation of the IRGs on the PVM of strains that also express virulent ROP5 alleles. In contrast, specific ROP5 alleles can reduce IRG coating even in the absence of ROP18 expression and can directly interact with one or more IRGs. We further show that the allelic combination of ROP18 and ROP5 also determines IRG evasion and virulence of strains belonging to other lineages besides types I, II and III. However, neither ROP18 nor ROP5 markedly affect survival in IFNγ-activated human cells, which lack the multitude of IRGs present in murine cells. These findings suggest that ROP18 and ROP5 have specifically evolved to block the IRGs and are unlikely to have effects in species that do not have the IRG system, such as humans.

【 授权许可】

CC BY