The secreted kinase ROP17 promotes Toxoplasma gondii dissemination by hijacking monocyte tissue migration

TY - JOUR

T1 - The secreted kinase ROP17 promotes Toxoplasma gondii dissemination by hijacking monocyte tissue migration

AU - Drewry, Lisa L.

AU - Jones, Nathaniel G.

AU - Wang, Quiling

AU - Onken, Michael D.

AU - Miller, Mark J.

AU - Sibley, L. David

PY - 2019/7/22

Y1 - 2019/7/22

N2 - The protozoan parasite Toxoplasma gondii is thought to exploit monocyte trafficking to facilitate dissemination across endothelial barriers such as the blood–brain barrier. Here, we analysed the migration of parasitized monocytes in model endothelial and interstitial environments. We report that infection enhanced monocyte locomotion on the surface of endothelial cells, but profoundly inhibited monocyte transmigration across endothelial barriers. By contrast, infection robustly increased monocyte and macrophage migration through collagen-rich tissues in a Rho–ROCK-dependent manner consistent with integrin-independent interstitial migration. We further demonstrated that the secreted T. gondii protein kinase ROP17 was required for enhanced tissue migration. In vivo, ROP17-deficient parasites failed to upregulate monocyte tissue migration and exhibited an early dissemination delay, leading to prolonged mouse survival. Our findings indicate that the parasite-induced changes in monocyte motility primarily facilitate the transport of T. gondii through tissues and promote systemic dissemination, rather than shuttle parasites across the blood–brain barrier via extravasation.

AB - The protozoan parasite Toxoplasma gondii is thought to exploit monocyte trafficking to facilitate dissemination across endothelial barriers such as the blood–brain barrier. Here, we analysed the migration of parasitized monocytes in model endothelial and interstitial environments. We report that infection enhanced monocyte locomotion on the surface of endothelial cells, but profoundly inhibited monocyte transmigration across endothelial barriers. By contrast, infection robustly increased monocyte and macrophage migration through collagen-rich tissues in a Rho–ROCK-dependent manner consistent with integrin-independent interstitial migration. We further demonstrated that the secreted T. gondii protein kinase ROP17 was required for enhanced tissue migration. In vivo, ROP17-deficient parasites failed to upregulate monocyte tissue migration and exhibited an early dissemination delay, leading to prolonged mouse survival. Our findings indicate that the parasite-induced changes in monocyte motility primarily facilitate the transport of T. gondii through tissues and promote systemic dissemination, rather than shuttle parasites across the blood–brain barrier via extravasation.

UR - http://www.scopus.com/inward/record.url?scp=85068777262&partnerID=8YFLogxK

U2 - 10.1038/s41564-019-0504-8

DO - 10.1038/s41564-019-0504-8

M3 - Article

C2 - 31332383

SN - 2058-5276

VL - 4

SP - 1951

EP - 1963

JO - Nature Microbiology

JF - Nature Microbiology

IS - 11

ER -