Abstract
Toxoplasma gondii is an intracellular pathogen that exerts its virulence through inhibiting host’s innate immune responses, which is mainly related to the type II interferon (IFN-γ) response. IFN-γ inducible tripartite motif 21 (TRIM21), an E3 ligase, plays an important role in anti-infection responses against the intracellular pathogens including bacteria, virus, and parasite. We found that T. gondii virulence factor ROP18 of the type I RH strain (TgROP18I) interacted with human TRIM21, and promoted the latter’s phosphorylation, which subsequently accelerated TRIM21 degradation through lysosomal pathway. Furthermore, TRIM21 protein level was found to be upregulated during RH and CEP strains of T. gondii infection. TRIM21 knocking down reduced the ubiquitin labeling on the parasitophorous vacuole membrane (PVM) [which led to parasitophorous vacuole (PV) acidification and death of CEP tachyzoites], and relieved the inhibition of CEP proliferation induced by IFN-γ in human foreskin fibroblast (HFF) cells which was consistent with the result of TRIM21 overexpression. On the other hand, TRIM21 overexpression enhanced the inhibition of CEP proliferation, and inhibited the binding of IκB-α with p65 to activate the IFN-γ-inducible NF-κB pathway, which might be resulted by TRIM21-IκB-α interaction. In brief, our research identified that in human cells, IFN-γ-inducible TRIM21 functioned in the innate immune responses against type III T. gondii infection; however, TgROP18I promoted TRIM21 phosphorylation, leading to TRIM21 degradation for immune escape in type I strain infection.
Highlights
Toxoplasma gondii is an obligate intracellular protozoon, and about 30% of the world population is serum positive with its antibodies (Montoya and Liesenfeld, 2004)
We found that the kinase dead mutant ROP18-KD still interacted with tripartite motif 21 (TRIM21) (Figure 1B)
These results suggested that TRIM21 interacted with TgROP18I via its PRY-SPRY domain
Summary
Toxoplasma gondii is an obligate intracellular protozoon, and about 30% of the world population is serum positive with its antibodies (Montoya and Liesenfeld, 2004). T. gondii rhoptries discharge many effectors to the host cytoplasm and the parasitophorous vacuole (PV) to modulate the homeostasis between the host cell and the parasite (Bradley et al, 2005; Boothroyd and Dubremetz, 2008; Hakimi et al, 2017). Among these effectors, TgROP18I is considered to be a key determinant related to the high mortality phenotype of type I strains (Saeij et al, 2006; Taylor et al, 2006). The transcription of genes related to host immune system can be upregulated by IFN-γ treatment (Platanias, 2005); T. gondii can manipulate some of these genes’ transcription in infected cells to maintain its replication (Platanias, 2005; Kim et al, 2007)
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