Human Innate Immunity to <named-content content-type="genus-species">Toxoplasma gondii</named-content> Is Mediated by Host Caspase-1 and ASC and Parasite GRA15

ABSTRACT Interleukin-1β (IL-1β) functions as a key regulator of inflammation and innate immunity. The protozoan parasite Toxoplasma gondii actively infects human blood monocytes and induces the production of IL-1β; however, the host and parasite factors that mediate IL-1β production during T. gond...

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Autores principales:	Lanny Gov, Alborz Karimzadeh, Norikiyo Ueno, Melissa B. Lodoen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bb2321ddd215458e9dc1b4d5617f9a66
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spelling	oai:doaj.org-article:bb2321ddd215458e9dc1b4d5617f9a662021-11-15T15:43:09ZHuman Innate Immunity to <named-content content-type="genus-species">Toxoplasma gondii</named-content> Is Mediated by Host Caspase-1 and ASC and Parasite GRA1510.1128/mBio.00255-132150-7511https://doaj.org/article/bb2321ddd215458e9dc1b4d5617f9a662013-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00255-13https://doaj.org/toc/2150-7511ABSTRACT Interleukin-1β (IL-1β) functions as a key regulator of inflammation and innate immunity. The protozoan parasite Toxoplasma gondii actively infects human blood monocytes and induces the production of IL-1β; however, the host and parasite factors that mediate IL-1β production during T. gondii infection are poorly understood. We report that T. gondii induces IL-1β transcript, processing/cleavage, and release from infected primary human monocytes and THP-1 cells. Treating monocytes with the caspase-1 inhibitor Ac-YVAD-CMK reduced IL-1β release, suggesting a role for the inflammasome in T. gondii-induced IL-1β production. This was confirmed by performing short hairpin RNA (shRNA) knockdown of caspase-1 and of the inflammasome adaptor protein ASC. IL-1β induction required active parasite invasion of monocytes, since heat-killed or mycalolide B-treated parasites did not induce IL-1β. Among the type I, II, and III strains of T. gondii, the type II strain induced substantially more IL-1β mRNA and protein release than did the type I and III strains. Since IL-1β transcript is known to be induced downstream of NF-κB signaling, we investigated a role for the GRA15 protein, which induces sustained NF-κB signaling in a parasite strain-specific manner. By infecting human monocytes with a GRA15-knockout type II strain and a type I strain stably expressing type II GRA15, we determined that GRA15 is responsible for IL-1β induction during T. gondii infection of human monocytes. This research defines a pathway driving human innate immunity by describing a role for the classical inflammasome components caspase-1 and ASC and the parasite GRA15 protein in T. gondii-induced IL-1β production. IMPORTANCE Monocytes are immune cells that protect against infection by increasing inflammation and antimicrobial activities in the body. Upon infection with the parasitic pathogen Toxoplasma gondii, human monocytes release interleukin-1β (IL-1β), a “master regulator” of inflammation, which amplifies immune responses. Although inflammatory responses are critical for host defense against infection, excessive inflammation can result in tissue damage and pathology. This delicate balance underscores the importance of understanding the mechanisms that regulate IL-1β during infection. We have investigated the molecular pathway by which T. gondii induces the synthesis and release of IL-1β in human monocytes. We found that specific proteins in the parasite and the host cell coordinate to induce IL-1β production. This research is significant because it contributes to a greater understanding of human innate immunity to infection and IL-1β regulation, thereby enhancing our potential to modulate inflammation in the body.Lanny GovAlborz KarimzadehNorikiyo UenoMelissa B. LodoenAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 4 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Lanny Gov Alborz Karimzadeh Norikiyo Ueno Melissa B. Lodoen Human Innate Immunity to <named-content content-type="genus-species">Toxoplasma gondii</named-content> Is Mediated by Host Caspase-1 and ASC and Parasite GRA15
description	ABSTRACT Interleukin-1β (IL-1β) functions as a key regulator of inflammation and innate immunity. The protozoan parasite Toxoplasma gondii actively infects human blood monocytes and induces the production of IL-1β; however, the host and parasite factors that mediate IL-1β production during T. gondii infection are poorly understood. We report that T. gondii induces IL-1β transcript, processing/cleavage, and release from infected primary human monocytes and THP-1 cells. Treating monocytes with the caspase-1 inhibitor Ac-YVAD-CMK reduced IL-1β release, suggesting a role for the inflammasome in T. gondii-induced IL-1β production. This was confirmed by performing short hairpin RNA (shRNA) knockdown of caspase-1 and of the inflammasome adaptor protein ASC. IL-1β induction required active parasite invasion of monocytes, since heat-killed or mycalolide B-treated parasites did not induce IL-1β. Among the type I, II, and III strains of T. gondii, the type II strain induced substantially more IL-1β mRNA and protein release than did the type I and III strains. Since IL-1β transcript is known to be induced downstream of NF-κB signaling, we investigated a role for the GRA15 protein, which induces sustained NF-κB signaling in a parasite strain-specific manner. By infecting human monocytes with a GRA15-knockout type II strain and a type I strain stably expressing type II GRA15, we determined that GRA15 is responsible for IL-1β induction during T. gondii infection of human monocytes. This research defines a pathway driving human innate immunity by describing a role for the classical inflammasome components caspase-1 and ASC and the parasite GRA15 protein in T. gondii-induced IL-1β production. IMPORTANCE Monocytes are immune cells that protect against infection by increasing inflammation and antimicrobial activities in the body. Upon infection with the parasitic pathogen Toxoplasma gondii, human monocytes release interleukin-1β (IL-1β), a “master regulator” of inflammation, which amplifies immune responses. Although inflammatory responses are critical for host defense against infection, excessive inflammation can result in tissue damage and pathology. This delicate balance underscores the importance of understanding the mechanisms that regulate IL-1β during infection. We have investigated the molecular pathway by which T. gondii induces the synthesis and release of IL-1β in human monocytes. We found that specific proteins in the parasite and the host cell coordinate to induce IL-1β production. This research is significant because it contributes to a greater understanding of human innate immunity to infection and IL-1β regulation, thereby enhancing our potential to modulate inflammation in the body.
format	article
author	Lanny Gov Alborz Karimzadeh Norikiyo Ueno Melissa B. Lodoen
author_facet	Lanny Gov Alborz Karimzadeh Norikiyo Ueno Melissa B. Lodoen
author_sort	Lanny Gov
title	Human Innate Immunity to <named-content content-type="genus-species">Toxoplasma gondii</named-content> Is Mediated by Host Caspase-1 and ASC and Parasite GRA15
title_short	Human Innate Immunity to <named-content content-type="genus-species">Toxoplasma gondii</named-content> Is Mediated by Host Caspase-1 and ASC and Parasite GRA15
title_full	Human Innate Immunity to <named-content content-type="genus-species">Toxoplasma gondii</named-content> Is Mediated by Host Caspase-1 and ASC and Parasite GRA15
title_fullStr	Human Innate Immunity to <named-content content-type="genus-species">Toxoplasma gondii</named-content> Is Mediated by Host Caspase-1 and ASC and Parasite GRA15
title_full_unstemmed	Human Innate Immunity to <named-content content-type="genus-species">Toxoplasma gondii</named-content> Is Mediated by Host Caspase-1 and ASC and Parasite GRA15
title_sort	human innate immunity to <named-content content-type="genus-species">toxoplasma gondii</named-content> is mediated by host caspase-1 and asc and parasite gra15
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/bb2321ddd215458e9dc1b4d5617f9a66
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Human Innate Immunity to <named-content content-type="genus-species">Toxoplasma gondii</named-content> Is Mediated by Host Caspase-1 and ASC and Parasite GRA15

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