<named-content content-type="genus-species">Brucella abortus</named-content> Infection of Placental Trophoblasts Triggers Endoplasmic Reticulum Stress-Mediated Cell Death and Fetal Loss via Type IV Secretion System-Dependent Activation of CHOP

ABSTRACT Subversion of endoplasmic reticulum (ER) function is a feature shared by multiple intracellular bacteria and viruses, and in many cases this disruption of cellular function activates pathways of the unfolded protein response (UPR). In the case of infection with Brucella abortus, the etiolog...

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Autores principales:	Mariana X. Byndloss, April Y. Tsai, Gregory T. Walker, Cheryl N. Miller, Briana M. Young, Bevin C. English, Núbia Seyffert, Tobias Kerrinnes, Maarten F. de Jong, Vidya L. Atluri, Maria G. Winter, Jean Celli, Renée M. Tsolis
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Brucella type IV secretion effector functions endoplasmic reticulum placenta trophoblast Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8f930186dae34fdd85cfc411dd999958
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spelling	oai:doaj.org-article:8f930186dae34fdd85cfc411dd9999582021-11-15T16:22:10Z<named-content content-type="genus-species">Brucella abortus</named-content> Infection of Placental Trophoblasts Triggers Endoplasmic Reticulum Stress-Mediated Cell Death and Fetal Loss via Type IV Secretion System-Dependent Activation of CHOP10.1128/mBio.01538-192150-7511https://doaj.org/article/8f930186dae34fdd85cfc411dd9999582019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01538-19https://doaj.org/toc/2150-7511ABSTRACT Subversion of endoplasmic reticulum (ER) function is a feature shared by multiple intracellular bacteria and viruses, and in many cases this disruption of cellular function activates pathways of the unfolded protein response (UPR). In the case of infection with Brucella abortus, the etiologic agent of brucellosis, the unfolded protein response in the infected placenta contributes to placentitis and abortion, leading to pathogen transmission. Here we show that B. abortus infection of pregnant mice led to death of infected placental trophoblasts in a manner that depended on the VirB type IV secretion system (T4SS) and its effector VceC. The trophoblast death program required the ER stress-induced transcription factor CHOP. While NOD1/NOD2 expression in macrophages contributed to ER stress-induced inflammation, these receptors did not play a role in trophoblast death. Both placentitis and abortion were independent of apoptosis-associated Speck-like protein containing a caspase activation and recruitment domain (ASC). These studies show that B. abortus uses its T4SS to induce cell-type-specific responses to ER stress in trophoblasts that trigger placental inflammation and abortion. Our results suggest further that in B. abortus the T4SS and its effectors are under selection as bacterial transmission factors. IMPORTANCE Brucella abortus infects the placenta of pregnant cows, where it replicates to high levels and triggers abortion of the calf. The aborted material is highly infectious and transmits infection to both cows and humans, but very little is known about how B. abortus causes abortion. By studying this infection in pregnant mice, we discovered that B. abortus kills trophoblasts, which are important cells for maintaining pregnancy. This killing required an injected bacterial protein (VceC) that triggered an endoplasmic reticulum (ER) stress response in the trophoblast. By inhibiting ER stress or infecting mice that lack CHOP, a protein induced by ER stress, we could prevent death of trophoblasts, reduce inflammation, and increase the viability of the pups. Our results suggest that B. abortus injects VceC into placental trophoblasts to promote its transmission by abortion.Mariana X. ByndlossApril Y. TsaiGregory T. WalkerCheryl N. MillerBriana M. YoungBevin C. EnglishNúbia SeyffertTobias KerrinnesMaarten F. de JongVidya L. AtluriMaria G. WinterJean CelliRenée M. TsolisAmerican Society for MicrobiologyarticleBrucellatype IV secretioneffector functionsendoplasmic reticulumplacentatrophoblastMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Brucella type IV secretion effector functions endoplasmic reticulum placenta trophoblast Microbiology QR1-502
spellingShingle	Brucella type IV secretion effector functions endoplasmic reticulum placenta trophoblast Microbiology QR1-502 Mariana X. Byndloss April Y. Tsai Gregory T. Walker Cheryl N. Miller Briana M. Young Bevin C. English Núbia Seyffert Tobias Kerrinnes Maarten F. de Jong Vidya L. Atluri Maria G. Winter Jean Celli Renée M. Tsolis <named-content content-type="genus-species">Brucella abortus</named-content> Infection of Placental Trophoblasts Triggers Endoplasmic Reticulum Stress-Mediated Cell Death and Fetal Loss via Type IV Secretion System-Dependent Activation of CHOP
description	ABSTRACT Subversion of endoplasmic reticulum (ER) function is a feature shared by multiple intracellular bacteria and viruses, and in many cases this disruption of cellular function activates pathways of the unfolded protein response (UPR). In the case of infection with Brucella abortus, the etiologic agent of brucellosis, the unfolded protein response in the infected placenta contributes to placentitis and abortion, leading to pathogen transmission. Here we show that B. abortus infection of pregnant mice led to death of infected placental trophoblasts in a manner that depended on the VirB type IV secretion system (T4SS) and its effector VceC. The trophoblast death program required the ER stress-induced transcription factor CHOP. While NOD1/NOD2 expression in macrophages contributed to ER stress-induced inflammation, these receptors did not play a role in trophoblast death. Both placentitis and abortion were independent of apoptosis-associated Speck-like protein containing a caspase activation and recruitment domain (ASC). These studies show that B. abortus uses its T4SS to induce cell-type-specific responses to ER stress in trophoblasts that trigger placental inflammation and abortion. Our results suggest further that in B. abortus the T4SS and its effectors are under selection as bacterial transmission factors. IMPORTANCE Brucella abortus infects the placenta of pregnant cows, where it replicates to high levels and triggers abortion of the calf. The aborted material is highly infectious and transmits infection to both cows and humans, but very little is known about how B. abortus causes abortion. By studying this infection in pregnant mice, we discovered that B. abortus kills trophoblasts, which are important cells for maintaining pregnancy. This killing required an injected bacterial protein (VceC) that triggered an endoplasmic reticulum (ER) stress response in the trophoblast. By inhibiting ER stress or infecting mice that lack CHOP, a protein induced by ER stress, we could prevent death of trophoblasts, reduce inflammation, and increase the viability of the pups. Our results suggest that B. abortus injects VceC into placental trophoblasts to promote its transmission by abortion.
format	article
author	Mariana X. Byndloss April Y. Tsai Gregory T. Walker Cheryl N. Miller Briana M. Young Bevin C. English Núbia Seyffert Tobias Kerrinnes Maarten F. de Jong Vidya L. Atluri Maria G. Winter Jean Celli Renée M. Tsolis
author_facet	Mariana X. Byndloss April Y. Tsai Gregory T. Walker Cheryl N. Miller Briana M. Young Bevin C. English Núbia Seyffert Tobias Kerrinnes Maarten F. de Jong Vidya L. Atluri Maria G. Winter Jean Celli Renée M. Tsolis
author_sort	Mariana X. Byndloss
title	<named-content content-type="genus-species">Brucella abortus</named-content> Infection of Placental Trophoblasts Triggers Endoplasmic Reticulum Stress-Mediated Cell Death and Fetal Loss via Type IV Secretion System-Dependent Activation of CHOP
title_short	<named-content content-type="genus-species">Brucella abortus</named-content> Infection of Placental Trophoblasts Triggers Endoplasmic Reticulum Stress-Mediated Cell Death and Fetal Loss via Type IV Secretion System-Dependent Activation of CHOP
title_full	<named-content content-type="genus-species">Brucella abortus</named-content> Infection of Placental Trophoblasts Triggers Endoplasmic Reticulum Stress-Mediated Cell Death and Fetal Loss via Type IV Secretion System-Dependent Activation of CHOP
title_fullStr	<named-content content-type="genus-species">Brucella abortus</named-content> Infection of Placental Trophoblasts Triggers Endoplasmic Reticulum Stress-Mediated Cell Death and Fetal Loss via Type IV Secretion System-Dependent Activation of CHOP
title_full_unstemmed	<named-content content-type="genus-species">Brucella abortus</named-content> Infection of Placental Trophoblasts Triggers Endoplasmic Reticulum Stress-Mediated Cell Death and Fetal Loss via Type IV Secretion System-Dependent Activation of CHOP
title_sort	<named-content content-type="genus-species">brucella abortus</named-content> infection of placental trophoblasts triggers endoplasmic reticulum stress-mediated cell death and fetal loss via type iv secretion system-dependent activation of chop
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/8f930186dae34fdd85cfc411dd999958
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<named-content content-type="genus-species">Brucella abortus</named-content> Infection of Placental Trophoblasts Triggers Endoplasmic Reticulum Stress-Mediated Cell Death and Fetal Loss via Type IV Secretion System-Dependent Activation of CHOP

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