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Parasite secreted products modulate STAT6-dependent and -independent transcription in macrophages

ABSTRACT: Toxoplasma gondii is an obligate intracellular protozoan parasite which, upon invasion of host cells, injects virulence factors that are known to induce dramatic alterations in host cell signaling. Although much work has been directed at understanding the impact of specific secreted proteins on host cell function, dissecting the host response to injected virulence factors has been complicated by the fact that injection is rapidly followed by invasion, establishment of a parasitophorous vacuole in the host cell cytoplasm, secretion of parasite proteins from other specialized organelles, and remodeling of the host cell cytoskeleton Here, we describe the global macrophage transcriptional response to secreted proteins and show that injection of rhoptry contents alone is sufficient to trigger a dramatic host cells response. We further define modules of genes that are regulated in a parasite strain-specific manner by activation of the host transcription factor, STAT6. Our approach leverages transgenic parasites that express mCherry and inject Cre-recombinase along with normal virulence factors into the cytoplasm of host cells. Primary macrophages were recovered from transgenic reporter mice (Ai6) that express the ZsGreen1 fluorochrome when exposed to cre recombinase, allowing for the identification of a unique population of cells into which T. gondii injects virulence factors but does not infect (uninfected-injected, or U-I). Transcriptional profiling of these U-I cells compared to infected cells or uninfected controls from the same cultures was carried out, using bone marrow derived macrophages (BMDM) from either WT or STAT6-/- mice. This data allows us to interrogate the outcomes T. gondii induced STAT signaling in both infected and U-I cell populations, and to resolve effects of injected virulence factors, like ROP16, from those changes induced by infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE55892 | GEO | 2019/03/01

REPOSITORIES: GEO

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Project description:Toxoplasma gondii is a globally distributed obligate intracellular parasite which can cause zoonotic toxoplasmosis with great harms. The average death time of mice that infected with Toxoplasma gondii RH strain tachyzoites recovered from the liquid nitrogen was shortened after multiple generations. It has been reported that the parasite is in a state of static virulence during cryopreservation and the virulence of the protozoan parasite can be enhanced after continuous passages in hosts under laboratory conditions. However, no research has been conducted to elucidate its biological mechanism. Herein, we sequenced the T. gondii transcriptome using RNA-Seq technology and performed de novo assembly to investigated the virulence factors expression changes by comparing gene expression profiles between incipiently recovered and completely resuscitated tachyzoites. Transcriptome analysis identified 1,951 differentially expressed transcripts in infected liver, of which 1,752 were significantly downregulated and 199 upregulated. We identified many differentially expressed proteins and genes, including serine/threonine kinase, calnexin, myosin and microtubule-associated protein which have previously been reported to be either involved in cell adhesion, parasite gliding or participate in cell invasion. The great majority of the virulence factors including microneme proteins, rhoptry proteins and dense granule proteins were upregulated in fully recovered tachyzoites. The enhanced virulence of recovered Toxoplasma gondii RH strain from the liquid nitrogen is associated with the up-regulated expression of MICs, ROPs and GRAs. Our data will facilitate future genomic research and in-depth annotation of Toxoplasma gondii RH strain genomes. This study provides a profile of the candidate genes that are suspected to be involved with virulence enhancement of recovered Toxoplasma gondii RH strain tachyzoites. Many further studies should be carried out to confirm the function of the candidate genes. Moreover, the preliminary identification of genes and pathways exhibiting differential expression in complete resuscitation stage may further our general understanding of virulence enhancement in this parasite.

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Parasite secreted products modulate STAT6-dependent and -independent transcription in macrophages

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