<named-content content-type="genus-species">Ehrlichia chaffeensis</named-content> TRP120 Activates Canonical Notch Signaling To Downregulate TLR2/4 Expression and Promote Intracellular Survival

ABSTRACT Ehrlichia chaffeensis preferentially targets mononuclear phagocytes and survives through a strategy of subverting innate immune defenses, but the mechanisms are unknown. We have shown E. chaffeensis type 1 secreted tandem repeat protein (TRP) effectors are involved in diverse molecular path...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Taslima T. Lina, Paige S. Dunphy, Tian Luo, Jere W. McBride
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a3a41c4f93ec4b9f9e3f5f7d348d0abb
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:a3a41c4f93ec4b9f9e3f5f7d348d0abb
record_format	dspace
spelling	oai:doaj.org-article:a3a41c4f93ec4b9f9e3f5f7d348d0abb2021-11-15T15:50:18Z<named-content content-type="genus-species">Ehrlichia chaffeensis</named-content> TRP120 Activates Canonical Notch Signaling To Downregulate TLR2/4 Expression and Promote Intracellular Survival10.1128/mBio.00672-162150-7511https://doaj.org/article/a3a41c4f93ec4b9f9e3f5f7d348d0abb2016-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00672-16https://doaj.org/toc/2150-7511ABSTRACT Ehrlichia chaffeensis preferentially targets mononuclear phagocytes and survives through a strategy of subverting innate immune defenses, but the mechanisms are unknown. We have shown E. chaffeensis type 1 secreted tandem repeat protein (TRP) effectors are involved in diverse molecular pathogen-host interactions, such as the TRP120 interaction with the Notch receptor-cleaving metalloprotease ADAM17. In the present study, we demonstrate E. chaffeensis, via the TRP120 effector, activates the canonical Notch signaling pathway to promote intracellular survival. We found that nuclear translocation of the transcriptionally active Notch intracellular domain (NICD) occurs in response to E. chaffeensis or recombinant TRP120, resulting in upregulation of Notch signaling pathway components and target genes notch1, adam17, hes, and hey. Significant differences in canonical Notch signaling gene expression levels (>40%) were observed during early and late stages of infection, indicating activation of the Notch pathway. We linked Notch pathway activation specifically to the TRP120 effector, which directly interacts with the Notch metalloprotease ADAM17. Using pharmacological inhibitors and small interfering RNAs (siRNAs) against γ-secretase enzyme, Notch transcription factor complex, Notch1, and ADAM17, we demonstrated that Notch signaling is required for ehrlichial survival. We studied the downstream effects and found that E. chaffeensis TRP120-mediated activation of the Notch pathway causes inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) pathways required for PU.1 and subsequent Toll-like receptor 2/4 (TLR2/4) expression. This investigation reveals a novel mechanism whereby E. chaffeensis exploits the Notch pathway to evade the host innate immune response for intracellular survival. IMPORTANCE E. chaffeensis is an obligately intracellular bacterium and the etiologic agent of human monocytotropic ehrlichiosis (HME), an emerging life-threatening tick-borne zoonosis. Mechanisms by which E. chaffeensis establishes intracellular infection and avoids innate host defenses are not understood, but functionally relevant host-pathogen interactions with type 1 secreted TRP effectors are essential for the ehrlichial cellular reprogramming strategy. This study provides further insight into the molecular strategies used by obligately intracellular pathogens such as E. chaffeensis, which have small genomes and a limited number of effector proteins and exploit evolutionarily conserved host cell programs such as Notch signaling to promote infection and intracellular survival.Taslima T. LinaPaige S. DunphyTian LuoJere W. McBrideAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 4 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Taslima T. Lina Paige S. Dunphy Tian Luo Jere W. McBride <named-content content-type="genus-species">Ehrlichia chaffeensis</named-content> TRP120 Activates Canonical Notch Signaling To Downregulate TLR2/4 Expression and Promote Intracellular Survival
description	ABSTRACT Ehrlichia chaffeensis preferentially targets mononuclear phagocytes and survives through a strategy of subverting innate immune defenses, but the mechanisms are unknown. We have shown E. chaffeensis type 1 secreted tandem repeat protein (TRP) effectors are involved in diverse molecular pathogen-host interactions, such as the TRP120 interaction with the Notch receptor-cleaving metalloprotease ADAM17. In the present study, we demonstrate E. chaffeensis, via the TRP120 effector, activates the canonical Notch signaling pathway to promote intracellular survival. We found that nuclear translocation of the transcriptionally active Notch intracellular domain (NICD) occurs in response to E. chaffeensis or recombinant TRP120, resulting in upregulation of Notch signaling pathway components and target genes notch1, adam17, hes, and hey. Significant differences in canonical Notch signaling gene expression levels (>40%) were observed during early and late stages of infection, indicating activation of the Notch pathway. We linked Notch pathway activation specifically to the TRP120 effector, which directly interacts with the Notch metalloprotease ADAM17. Using pharmacological inhibitors and small interfering RNAs (siRNAs) against γ-secretase enzyme, Notch transcription factor complex, Notch1, and ADAM17, we demonstrated that Notch signaling is required for ehrlichial survival. We studied the downstream effects and found that E. chaffeensis TRP120-mediated activation of the Notch pathway causes inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) pathways required for PU.1 and subsequent Toll-like receptor 2/4 (TLR2/4) expression. This investigation reveals a novel mechanism whereby E. chaffeensis exploits the Notch pathway to evade the host innate immune response for intracellular survival. IMPORTANCE E. chaffeensis is an obligately intracellular bacterium and the etiologic agent of human monocytotropic ehrlichiosis (HME), an emerging life-threatening tick-borne zoonosis. Mechanisms by which E. chaffeensis establishes intracellular infection and avoids innate host defenses are not understood, but functionally relevant host-pathogen interactions with type 1 secreted TRP effectors are essential for the ehrlichial cellular reprogramming strategy. This study provides further insight into the molecular strategies used by obligately intracellular pathogens such as E. chaffeensis, which have small genomes and a limited number of effector proteins and exploit evolutionarily conserved host cell programs such as Notch signaling to promote infection and intracellular survival.
format	article
author	Taslima T. Lina Paige S. Dunphy Tian Luo Jere W. McBride
author_facet	Taslima T. Lina Paige S. Dunphy Tian Luo Jere W. McBride
author_sort	Taslima T. Lina
title	<named-content content-type="genus-species">Ehrlichia chaffeensis</named-content> TRP120 Activates Canonical Notch Signaling To Downregulate TLR2/4 Expression and Promote Intracellular Survival
title_short	<named-content content-type="genus-species">Ehrlichia chaffeensis</named-content> TRP120 Activates Canonical Notch Signaling To Downregulate TLR2/4 Expression and Promote Intracellular Survival
title_full	<named-content content-type="genus-species">Ehrlichia chaffeensis</named-content> TRP120 Activates Canonical Notch Signaling To Downregulate TLR2/4 Expression and Promote Intracellular Survival
title_fullStr	<named-content content-type="genus-species">Ehrlichia chaffeensis</named-content> TRP120 Activates Canonical Notch Signaling To Downregulate TLR2/4 Expression and Promote Intracellular Survival
title_full_unstemmed	<named-content content-type="genus-species">Ehrlichia chaffeensis</named-content> TRP120 Activates Canonical Notch Signaling To Downregulate TLR2/4 Expression and Promote Intracellular Survival
title_sort	<named-content content-type="genus-species">ehrlichia chaffeensis</named-content> trp120 activates canonical notch signaling to downregulate tlr2/4 expression and promote intracellular survival
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/a3a41c4f93ec4b9f9e3f5f7d348d0abb
work_keys_str_mv	AT taslimatlina namedcontentcontenttypegenusspeciesehrlichiachaffeensisnamedcontenttrp120activatescanonicalnotchsignalingtodownregulatetlr24expressionandpromoteintracellularsurvival AT paigesdunphy namedcontentcontenttypegenusspeciesehrlichiachaffeensisnamedcontenttrp120activatescanonicalnotchsignalingtodownregulatetlr24expressionandpromoteintracellularsurvival AT tianluo namedcontentcontenttypegenusspeciesehrlichiachaffeensisnamedcontenttrp120activatescanonicalnotchsignalingtodownregulatetlr24expressionandpromoteintracellularsurvival AT jerewmcbride namedcontentcontenttypegenusspeciesehrlichiachaffeensisnamedcontenttrp120activatescanonicalnotchsignalingtodownregulatetlr24expressionandpromoteintracellularsurvival
_version_	1718427417796673536

<named-content content-type="genus-species">Ehrlichia chaffeensis</named-content> TRP120 Activates Canonical Notch Signaling To Downregulate TLR2/4 Expression and Promote Intracellular Survival

Ejemplares similares