Cleaved CD95L perturbs in vitro macrophages responses to Toxoplasma gondii

Ellen A. Tiffney; Janine L. Coombes; Patrick Legembre; Robin J. Flynn

doi:10.1016/j.micinf.2022.104952

Cleaved CD95L perturbs in vitro macrophages responses to Toxoplasma gondii

Ellen A. Tiffney, Janine L. Coombes, Patrick Legembre, Robin J. Flynn

Research, Innovation & Graduate Studies

Research output: Contribution to journal › Article › peer-review

Abstract

Toxoplasma gondii infects approximately 1–2 billion people, and manipulation of the macrophage response is critical to host and parasite survival. A cleaved (cl)-CD95L form can promote cellular migration and we have previously shown that cl-CD95L aggravates inflammation and pathology in systemic lupus erythematosus (SLE). Findings have shown that CD95L is upregulated during human infection, therefore we examined the effect of cl-CD95L on the macrophage response to T. gondii. We find that cl-CD95L promotes parasite replication in macrophages, associated with increased arginase-1 levels, mediated by signal transducer and activator of transcription (STAT)6. Inhibition of both arginase-1 and STAT6 reversed the effects of cl-CD95L. Phospho-kinase array showed that cl-CD95L alters Janus Kinases (JAK)/STAT, mammalian target of rapamycin (mTOR), and Src kinase signals. By triggering changes in JAK/STAT cl-CD95L may limit anti-parasite effectors.

Original language	English
Article number	104952
Pages (from-to)	104952
Journal	Microbes and Infection
Volume	24
Issue number	5
DOIs	https://doi.org/10.1016/j.micinf.2022.104952
Publication status	Published - 01 Jul 2022

Keywords

Arginase
CD95L
Cleaved CD95L
JAK/STAT
Macrophage
Toxoplasma gondii
Toxoplasma
Janus Kinases
Fas Ligand Protein/metabolism
Macrophages/parasitology
Humans

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.micinf.2022.104952

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title = "Cleaved CD95L perturbs in vitro macrophages responses to Toxoplasma gondii",

abstract = "Toxoplasma gondii infects approximately 1–2 billion people, and manipulation of the macrophage response is critical to host and parasite survival. A cleaved (cl)-CD95L form can promote cellular migration and we have previously shown that cl-CD95L aggravates inflammation and pathology in systemic lupus erythematosus (SLE). Findings have shown that CD95L is upregulated during human infection, therefore we examined the effect of cl-CD95L on the macrophage response to T. gondii. We find that cl-CD95L promotes parasite replication in macrophages, associated with increased arginase-1 levels, mediated by signal transducer and activator of transcription (STAT)6. Inhibition of both arginase-1 and STAT6 reversed the effects of cl-CD95L. Phospho-kinase array showed that cl-CD95L alters Janus Kinases (JAK)/STAT, mammalian target of rapamycin (mTOR), and Src kinase signals. By triggering changes in JAK/STAT cl-CD95L may limit anti-parasite effectors.",

keywords = "Arginase, CD95L, Cleaved CD95L, JAK/STAT, Macrophage, Toxoplasma gondii, Toxoplasma, Janus Kinases, Fas Ligand Protein/metabolism, Macrophages/parasitology, Humans",

author = "Tiffney, {Ellen A.} and Coombes, {Janine L.} and Patrick Legembre and Flynn, {Robin J.}",

note = "Funding Information: We would like to thank Catherine Hartley for her technical assistance and the staff at University of Liverpool Biomedical Services Unit. EAT was supported in part through a Wellcome Trust ISSF award to RJF. Publisher Copyright: {\textcopyright} 2022 Institut Pasteur",

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T1 - Cleaved CD95L perturbs in vitro macrophages responses to Toxoplasma gondii

AU - Tiffney, Ellen A.

AU - Coombes, Janine L.

AU - Legembre, Patrick

AU - Flynn, Robin J.

N1 - Funding Information: We would like to thank Catherine Hartley for her technical assistance and the staff at University of Liverpool Biomedical Services Unit. EAT was supported in part through a Wellcome Trust ISSF award to RJF. Publisher Copyright: © 2022 Institut Pasteur

PY - 2022/7/1

Y1 - 2022/7/1

N2 - Toxoplasma gondii infects approximately 1–2 billion people, and manipulation of the macrophage response is critical to host and parasite survival. A cleaved (cl)-CD95L form can promote cellular migration and we have previously shown that cl-CD95L aggravates inflammation and pathology in systemic lupus erythematosus (SLE). Findings have shown that CD95L is upregulated during human infection, therefore we examined the effect of cl-CD95L on the macrophage response to T. gondii. We find that cl-CD95L promotes parasite replication in macrophages, associated with increased arginase-1 levels, mediated by signal transducer and activator of transcription (STAT)6. Inhibition of both arginase-1 and STAT6 reversed the effects of cl-CD95L. Phospho-kinase array showed that cl-CD95L alters Janus Kinases (JAK)/STAT, mammalian target of rapamycin (mTOR), and Src kinase signals. By triggering changes in JAK/STAT cl-CD95L may limit anti-parasite effectors.

AB - Toxoplasma gondii infects approximately 1–2 billion people, and manipulation of the macrophage response is critical to host and parasite survival. A cleaved (cl)-CD95L form can promote cellular migration and we have previously shown that cl-CD95L aggravates inflammation and pathology in systemic lupus erythematosus (SLE). Findings have shown that CD95L is upregulated during human infection, therefore we examined the effect of cl-CD95L on the macrophage response to T. gondii. We find that cl-CD95L promotes parasite replication in macrophages, associated with increased arginase-1 levels, mediated by signal transducer and activator of transcription (STAT)6. Inhibition of both arginase-1 and STAT6 reversed the effects of cl-CD95L. Phospho-kinase array showed that cl-CD95L alters Janus Kinases (JAK)/STAT, mammalian target of rapamycin (mTOR), and Src kinase signals. By triggering changes in JAK/STAT cl-CD95L may limit anti-parasite effectors.

KW - Arginase

KW - CD95L

KW - Cleaved CD95L

KW - JAK/STAT

KW - Macrophage

KW - Toxoplasma gondii

KW - Toxoplasma

KW - Janus Kinases

KW - Fas Ligand Protein/metabolism

KW - Macrophages/parasitology

KW - Humans

UR - https://doi.org/10.1016/j.micinf.2022.104952

U2 - 10.1016/j.micinf.2022.104952

DO - 10.1016/j.micinf.2022.104952

M3 - Article

C2 - 35240289

SN - 1286-4579

VL - 24

SP - 104952

JO - Microbes and Infection

JF - Microbes and Infection

IS - 5

M1 - 104952

ER -

Cleaved CD95L perturbs in vitro macrophages responses to Toxoplasma gondii

Abstract

Keywords

UN SDGs

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