TY - JOUR
T1 - Tgif2k-b is an eif2a kinase in toxoplasma gondii that responds to oxidative stress and optimizes pathogenicity
AU - Augusto, Leonardo
AU - Martynowicz, Jennifer
AU - Amin, Parth H.
AU - Carlson, Kenneth R.
AU - Wek, Ronald C.
AU - Sullivan, William J.
N1 - Funding Information:
R.C.W. has received grant support from Eli Lilly and Company and is a scientific advisor to HiberCell. The other authors declare no conflicts of interest.
Funding Information:
This research was supported by a research grant from the National Institutes of Health (AI124723 to W.J.S. and R.C.W.). This research was also supported in part by Lilly Endowment, Inc., through its support for the Indiana University Pervasive Technology Institute, and in part by the Indiana METACyt Initiative. The Indiana METACyt Initiative at IU was also supported in part by Lilly Endowment, Inc. This material is based upon work supported by the National Science Foundation under grant no. CNS-0521433.
Publisher Copyright:
© 2021 Augusto et al.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Toxoplasma gondii is an obligate intracellular parasite that persists in its vertebrate hosts in the form of dormant tissue cysts, which facilitate transmission through predation. The parasite must strike a balance that allows it to disseminate throughout its host without killing it, which requires the ability to properly counter host cell defenses. For example, oxidative stress encountered by Toxoplasma is sug-gested to impair parasite replication and dissemination. However, the strategies by which Toxoplasma mitigates oxidative stress are not yet clear. Among eukaryotes, environmental stresses induce the integrated stress response via phosphorylation of a translation initiation factor, eukaryotic initiation factor 2 (eIF2). Here, we show that the Toxoplasma eIF2 kinase TgIF2K-B is activated in response to oxidative stress and affords protection. Knockout of the TgIF2K-B gene, Dtgif2k-b, disrupted parasite responses to oxidative stresses and enhanced replication, diminishing the ability of the parasite to differentiate into tissue cysts. In addition, parasites lacking TgIF2K-B exhibited resistance to activated macrophages and showed greater virulence in an in vivo model of infection. Our results establish that TgIF2K-B is essential for Toxoplasma responses to oxidative stress, which are important for the parasite’s ability to establish persistent infection in its host. IMPORTANCE Toxoplasma gondii is a single-celled parasite that infects nucleated cells of warm-blooded vertebrates, including one-third of the human population. The parasites are not cleared by the immune response and persist in the host by converting into a latent tissue cyst form. Development of tissue cysts can be triggered by cellular stresses, which activate a family of TgIF2 kinases to phosphorylate the eukaryotic translation initiation factor TgIF2a. Here, we establish that the TgIF2 kinase TgIF2K-B is activated by oxidative stress and is critical for maintaining oxidative balance in the parasite. Depletion of TgIF2K-B alters gene expression, leading to accelerated growth and a diminished ability to convert into tissue cysts. This study establishes that TgIF2K-B is essential for the parasite’s oxidative stress response and its ability to persist in the host as a latent infection.
AB - Toxoplasma gondii is an obligate intracellular parasite that persists in its vertebrate hosts in the form of dormant tissue cysts, which facilitate transmission through predation. The parasite must strike a balance that allows it to disseminate throughout its host without killing it, which requires the ability to properly counter host cell defenses. For example, oxidative stress encountered by Toxoplasma is sug-gested to impair parasite replication and dissemination. However, the strategies by which Toxoplasma mitigates oxidative stress are not yet clear. Among eukaryotes, environmental stresses induce the integrated stress response via phosphorylation of a translation initiation factor, eukaryotic initiation factor 2 (eIF2). Here, we show that the Toxoplasma eIF2 kinase TgIF2K-B is activated in response to oxidative stress and affords protection. Knockout of the TgIF2K-B gene, Dtgif2k-b, disrupted parasite responses to oxidative stresses and enhanced replication, diminishing the ability of the parasite to differentiate into tissue cysts. In addition, parasites lacking TgIF2K-B exhibited resistance to activated macrophages and showed greater virulence in an in vivo model of infection. Our results establish that TgIF2K-B is essential for Toxoplasma responses to oxidative stress, which are important for the parasite’s ability to establish persistent infection in its host. IMPORTANCE Toxoplasma gondii is a single-celled parasite that infects nucleated cells of warm-blooded vertebrates, including one-third of the human population. The parasites are not cleared by the immune response and persist in the host by converting into a latent tissue cyst form. Development of tissue cysts can be triggered by cellular stresses, which activate a family of TgIF2 kinases to phosphorylate the eukaryotic translation initiation factor TgIF2a. Here, we establish that the TgIF2 kinase TgIF2K-B is activated by oxidative stress and is critical for maintaining oxidative balance in the parasite. Depletion of TgIF2K-B alters gene expression, leading to accelerated growth and a diminished ability to convert into tissue cysts. This study establishes that TgIF2K-B is essential for the parasite’s oxidative stress response and its ability to persist in the host as a latent infection.
KW - Apicomplexa
KW - Differentiation
KW - Oxidative stress
KW - Parasites
KW - Stress response
KW - Toxoplasma
KW - Translation
KW - Translational control
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UR - http://www.scopus.com/inward/citedby.url?scp=85099862478&partnerID=8YFLogxK
U2 - 10.1128/mBio.03160-20
DO - 10.1128/mBio.03160-20
M3 - Article
C2 - 33500345
AN - SCOPUS:85099862478
SN - 2161-2129
VL - 12
SP - 1
EP - 14
JO - mBio
JF - mBio
IS - 1
M1 - e03160-20
ER -