Toxoplasma gondii rhoptry kinase rop16 activates stat3 and stat6 resulting in cytokine inhibition and arginase-1-dependent growth control

Barbara A. Butcher, Barbara A. Fox, Leah M. Rommereim, Sung Guk Kim, Kirk J. Maurer, Felix Yarovinsky, De'Broski R. Herbert, David J. Bzik, Eric Y. Denkers

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

The ROP16 kinase of Toxoplasma gondii is injected into the host cell cytosol where it activates signal transducer and activator of transcription (STAT)-3 and STAT6. Here, we generated a ROP16 deletion mutant on a Type I parasite strain background, as well as a control complementation mutant with restored ROP16 expression. We investigated the biological role of the ROP16 molecule during T. gondii infection. Infection of mouse bone marrow-derived macrophages with rop16-deleted (ΔROP16) parasites resulted in increased amounts of IL-12p40 production relative to the ROP16-positive RH parental strain. High level IL-12p40 production in ΔROP16 infection was dependent on the host cell adaptor molecule MyD88, but surprisingly was independent of any previously recognized T. gondii triggered pathway linking to MyD88 (TLR2, TLR4, TLR9, TLR11, IL-1ß and IL-18). In addition, ROP16 was found to mediate the suppressive effects of Toxoplasma on LPS-induced cytokine synthesis in macrophages and on IFN-γ-induced nitric oxide production by astrocytes and microglial cells. Furthermore, ROP16 triggered synthesis of host cell arginase-1 in a STAT6-dependent manner. In fibroblasts and macrophages, failure to induce arginase-1 by ΔROP16 tachyzoites resulted in resistance to starvation conditions of limiting arginine, an essential amino acid for replication and virulence of this parasite. ΔROP16 tachyzoites that failed to induce host cell arginase-1 displayed increased replication and dissemination during in vivo infection. We conclude that encounter between Toxoplasma ROP16 and the host cell STAT signaling cascade has pleiotropic downstream effects that act in multiple and complex ways to direct the course of infection.

Original languageEnglish (US)
Article numbere1002236
JournalPLoS Pathogens
Volume7
Issue number9
DOIs
StatePublished - Sep 2011

Fingerprint

Arginase
Toxoplasma
Phosphotransferases
Cytokines
Growth
Interleukin-12 Subunit p40
Parasites
Macrophages
Infection
STAT3 Transcription Factor
Interleukin-18
Essential Amino Acids
Toxoplasmosis
Starvation
Transducers
Interleukin-1
Astrocytes
Cytosol
Virulence
Arginine

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Butcher, B. A., Fox, B. A., Rommereim, L. M., Kim, S. G., Maurer, K. J., Yarovinsky, F., ... Denkers, E. Y. (2011). Toxoplasma gondii rhoptry kinase rop16 activates stat3 and stat6 resulting in cytokine inhibition and arginase-1-dependent growth control. PLoS Pathogens, 7(9), [e1002236]. https://doi.org/10.1371/journal.ppat.1002236

Toxoplasma gondii rhoptry kinase rop16 activates stat3 and stat6 resulting in cytokine inhibition and arginase-1-dependent growth control. / Butcher, Barbara A.; Fox, Barbara A.; Rommereim, Leah M.; Kim, Sung Guk; Maurer, Kirk J.; Yarovinsky, Felix; Herbert, De'Broski R.; Bzik, David J.; Denkers, Eric Y.

In: PLoS Pathogens, Vol. 7, No. 9, e1002236, 09.2011.

Research output: Contribution to journalArticle

Butcher, BA, Fox, BA, Rommereim, LM, Kim, SG, Maurer, KJ, Yarovinsky, F, Herbert, DBR, Bzik, DJ & Denkers, EY 2011, 'Toxoplasma gondii rhoptry kinase rop16 activates stat3 and stat6 resulting in cytokine inhibition and arginase-1-dependent growth control', PLoS Pathogens, vol. 7, no. 9, e1002236. https://doi.org/10.1371/journal.ppat.1002236
Butcher, Barbara A. ; Fox, Barbara A. ; Rommereim, Leah M. ; Kim, Sung Guk ; Maurer, Kirk J. ; Yarovinsky, Felix ; Herbert, De'Broski R. ; Bzik, David J. ; Denkers, Eric Y. / Toxoplasma gondii rhoptry kinase rop16 activates stat3 and stat6 resulting in cytokine inhibition and arginase-1-dependent growth control. In: PLoS Pathogens. 2011 ; Vol. 7, No. 9.
@article{1cc13f5bbab34786bdfeb8462274f991,
title = "Toxoplasma gondii rhoptry kinase rop16 activates stat3 and stat6 resulting in cytokine inhibition and arginase-1-dependent growth control",
abstract = "The ROP16 kinase of Toxoplasma gondii is injected into the host cell cytosol where it activates signal transducer and activator of transcription (STAT)-3 and STAT6. Here, we generated a ROP16 deletion mutant on a Type I parasite strain background, as well as a control complementation mutant with restored ROP16 expression. We investigated the biological role of the ROP16 molecule during T. gondii infection. Infection of mouse bone marrow-derived macrophages with rop16-deleted (ΔROP16) parasites resulted in increased amounts of IL-12p40 production relative to the ROP16-positive RH parental strain. High level IL-12p40 production in ΔROP16 infection was dependent on the host cell adaptor molecule MyD88, but surprisingly was independent of any previously recognized T. gondii triggered pathway linking to MyD88 (TLR2, TLR4, TLR9, TLR11, IL-1{\ss} and IL-18). In addition, ROP16 was found to mediate the suppressive effects of Toxoplasma on LPS-induced cytokine synthesis in macrophages and on IFN-γ-induced nitric oxide production by astrocytes and microglial cells. Furthermore, ROP16 triggered synthesis of host cell arginase-1 in a STAT6-dependent manner. In fibroblasts and macrophages, failure to induce arginase-1 by ΔROP16 tachyzoites resulted in resistance to starvation conditions of limiting arginine, an essential amino acid for replication and virulence of this parasite. ΔROP16 tachyzoites that failed to induce host cell arginase-1 displayed increased replication and dissemination during in vivo infection. We conclude that encounter between Toxoplasma ROP16 and the host cell STAT signaling cascade has pleiotropic downstream effects that act in multiple and complex ways to direct the course of infection.",
author = "Butcher, {Barbara A.} and Fox, {Barbara A.} and Rommereim, {Leah M.} and Kim, {Sung Guk} and Maurer, {Kirk J.} and Felix Yarovinsky and Herbert, {De'Broski R.} and Bzik, {David J.} and Denkers, {Eric Y.}",
year = "2011",
month = "9",
doi = "10.1371/journal.ppat.1002236",
language = "English (US)",
volume = "7",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "9",

}

TY - JOUR

T1 - Toxoplasma gondii rhoptry kinase rop16 activates stat3 and stat6 resulting in cytokine inhibition and arginase-1-dependent growth control

AU - Butcher, Barbara A.

AU - Fox, Barbara A.

AU - Rommereim, Leah M.

AU - Kim, Sung Guk

AU - Maurer, Kirk J.

AU - Yarovinsky, Felix

AU - Herbert, De'Broski R.

AU - Bzik, David J.

AU - Denkers, Eric Y.

PY - 2011/9

Y1 - 2011/9

N2 - The ROP16 kinase of Toxoplasma gondii is injected into the host cell cytosol where it activates signal transducer and activator of transcription (STAT)-3 and STAT6. Here, we generated a ROP16 deletion mutant on a Type I parasite strain background, as well as a control complementation mutant with restored ROP16 expression. We investigated the biological role of the ROP16 molecule during T. gondii infection. Infection of mouse bone marrow-derived macrophages with rop16-deleted (ΔROP16) parasites resulted in increased amounts of IL-12p40 production relative to the ROP16-positive RH parental strain. High level IL-12p40 production in ΔROP16 infection was dependent on the host cell adaptor molecule MyD88, but surprisingly was independent of any previously recognized T. gondii triggered pathway linking to MyD88 (TLR2, TLR4, TLR9, TLR11, IL-1ß and IL-18). In addition, ROP16 was found to mediate the suppressive effects of Toxoplasma on LPS-induced cytokine synthesis in macrophages and on IFN-γ-induced nitric oxide production by astrocytes and microglial cells. Furthermore, ROP16 triggered synthesis of host cell arginase-1 in a STAT6-dependent manner. In fibroblasts and macrophages, failure to induce arginase-1 by ΔROP16 tachyzoites resulted in resistance to starvation conditions of limiting arginine, an essential amino acid for replication and virulence of this parasite. ΔROP16 tachyzoites that failed to induce host cell arginase-1 displayed increased replication and dissemination during in vivo infection. We conclude that encounter between Toxoplasma ROP16 and the host cell STAT signaling cascade has pleiotropic downstream effects that act in multiple and complex ways to direct the course of infection.

AB - The ROP16 kinase of Toxoplasma gondii is injected into the host cell cytosol where it activates signal transducer and activator of transcription (STAT)-3 and STAT6. Here, we generated a ROP16 deletion mutant on a Type I parasite strain background, as well as a control complementation mutant with restored ROP16 expression. We investigated the biological role of the ROP16 molecule during T. gondii infection. Infection of mouse bone marrow-derived macrophages with rop16-deleted (ΔROP16) parasites resulted in increased amounts of IL-12p40 production relative to the ROP16-positive RH parental strain. High level IL-12p40 production in ΔROP16 infection was dependent on the host cell adaptor molecule MyD88, but surprisingly was independent of any previously recognized T. gondii triggered pathway linking to MyD88 (TLR2, TLR4, TLR9, TLR11, IL-1ß and IL-18). In addition, ROP16 was found to mediate the suppressive effects of Toxoplasma on LPS-induced cytokine synthesis in macrophages and on IFN-γ-induced nitric oxide production by astrocytes and microglial cells. Furthermore, ROP16 triggered synthesis of host cell arginase-1 in a STAT6-dependent manner. In fibroblasts and macrophages, failure to induce arginase-1 by ΔROP16 tachyzoites resulted in resistance to starvation conditions of limiting arginine, an essential amino acid for replication and virulence of this parasite. ΔROP16 tachyzoites that failed to induce host cell arginase-1 displayed increased replication and dissemination during in vivo infection. We conclude that encounter between Toxoplasma ROP16 and the host cell STAT signaling cascade has pleiotropic downstream effects that act in multiple and complex ways to direct the course of infection.

UR - http://www.scopus.com/inward/record.url?scp=80053460958&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053460958&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1002236

DO - 10.1371/journal.ppat.1002236

M3 - Article

VL - 7

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 9

M1 - e1002236

ER -