Brucella abortus Infection of Placental Trophoblasts Triggers Endoplasmic Reticulum Stress-Mediated Cell Death and Fetal Loss via Type IV Secretion System-Dependent Activation of CHOP

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, Renee M Tsolis

Research output: Contribution to journalArticle

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.IMPORTANCEBrucella 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.

Original languageEnglish (US)
JournalmBio
Volume10
Issue number4
DOIs
StatePublished - Jul 23 2019

Fingerprint

Brucella abortus
Endoplasmic Reticulum Stress
Trophoblasts
Cell Death
Infection
Unfolded Protein Response
Inflammation
Placenta
Transcription Factor CHOP
Infectious Disease Transmission
Bacterial Proteins
Brucellosis
Type IV Secretion Systems
Endoplasmic Reticulum
Proteins
Macrophages
Apoptosis
Viruses
Bacteria
Pregnancy

Keywords

  • Brucella
  • effector functions
  • endoplasmic reticulum
  • placenta
  • trophoblast
  • type IV secretion

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Brucella abortus Infection of Placental Trophoblasts Triggers Endoplasmic Reticulum Stress-Mediated Cell Death and Fetal Loss via Type IV Secretion System-Dependent Activation of CHOP. / Byndloss, Mariana X.; Tsai, April Y.; Walker, Gregory T.; Miller, Cheryl N.; Young, Briana M.; English, Bevin C.; Seyffert, Núbia; Kerrinnes, Tobias; de Jong, Maarten F.; Atluri, Vidya L.; Winter, Maria G.; Celli, Jean; Tsolis, Renee M.

In: mBio, Vol. 10, No. 4, 23.07.2019.

Research output: Contribution to journalArticle

Byndloss, MX, Tsai, AY, Walker, GT, Miller, CN, Young, BM, English, BC, Seyffert, N, Kerrinnes, T, de Jong, MF, Atluri, VL, Winter, MG, Celli, J & Tsolis, RM 2019, 'Brucella abortus Infection of Placental Trophoblasts Triggers Endoplasmic Reticulum Stress-Mediated Cell Death and Fetal Loss via Type IV Secretion System-Dependent Activation of CHOP', mBio, vol. 10, no. 4. https://doi.org/10.1128/mBio.01538-19
Byndloss, Mariana X. ; Tsai, April Y. ; Walker, Gregory T. ; Miller, Cheryl N. ; Young, Briana M. ; English, Bevin C. ; Seyffert, Núbia ; Kerrinnes, Tobias ; de Jong, Maarten F. ; Atluri, Vidya L. ; Winter, Maria G. ; Celli, Jean ; Tsolis, Renee M. / Brucella abortus Infection of Placental Trophoblasts Triggers Endoplasmic Reticulum Stress-Mediated Cell Death and Fetal Loss via Type IV Secretion System-Dependent Activation of CHOP. In: mBio. 2019 ; Vol. 10, No. 4.
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AU - Seyffert, Núbia

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AU - de Jong, Maarten F.

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