Gasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo

Abstract Burkholderia cenocepacia (B. cenocepacia) is an opportunistic bacterium; causing severe life threatening systemic infections in immunocompromised individuals including cystic fibrosis patients. The lack of gasdermin D (GSDMD) protects mice against endotoxin lipopolysaccharide (LPS) shock. O...

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Autores principales:	Shady Estfanous, Kathrin Krause, Midhun N. K. Anne, Mostafa Eltobgy, Kyle Caution, Arwa Abu Khweek, Kaitlin Hamilton, Asmaa Badr, Kylene Daily, Cierra Carafice, Daniel Baetzhold, Xiaoli Zhang, Tianliang Li, Haitao Wen, Mikhail A. Gavrilin, Hesham Haffez, Sameh Soror, Amal O. Amer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dfc42d70a6394957ad2316ed4514e290
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spelling	oai:doaj.org-article:dfc42d70a6394957ad2316ed4514e2902021-12-02T14:12:46ZGasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo10.1038/s41598-020-79201-52045-2322https://doaj.org/article/dfc42d70a6394957ad2316ed4514e2902021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79201-5https://doaj.org/toc/2045-2322Abstract Burkholderia cenocepacia (B. cenocepacia) is an opportunistic bacterium; causing severe life threatening systemic infections in immunocompromised individuals including cystic fibrosis patients. The lack of gasdermin D (GSDMD) protects mice against endotoxin lipopolysaccharide (LPS) shock. On the other hand, GSDMD promotes mice survival in response to certain bacterial infections. However, the role of GSDMD during B. cenocepacia infection is not yet determined. Our in vitro study shows that GSDMD restricts B. cenocepacia replication within macrophages independent of its role in cell death through promoting mitochondrial reactive oxygen species (mROS) production. mROS is known to stimulate autophagy, hence, the inhibition of mROS or the absence of GSDMD during B. cenocepacia infections reduces autophagy which plays a critical role in the restriction of the pathogen. GSDMD promotes inflammation in response to B. cenocepacia through mediating the release of inflammasome dependent cytokine (IL-1β) and an independent one (CXCL1) (KC). Additionally, different B. cenocepacia secretory systems (T3SS, T4SS, and T6SS) contribute to inflammasome activation together with bacterial survival within macrophages. In vivo study confirmed the in vitro findings and showed that GSDMD restricts B. cenocepacia infection and dissemination and stimulates autophagy in response to B. cenocepacia. Nevertheless, GSDMD promotes lung inflammation and necrosis in response to B. cenocepacia without altering mice survival. This study describes the double-edged functions of GSDMD in response to B. cenocepacia infection and shows the importance of GSDMD-mediated mROS in restriction of B. cenocepacia.Shady EstfanousKathrin KrauseMidhun N. K. AnneMostafa EltobgyKyle CautionArwa Abu KhweekKaitlin HamiltonAsmaa BadrKylene DailyCierra CaraficeDaniel BaetzholdXiaoli ZhangTianliang LiHaitao WenMikhail A. GavrilinHesham HaffezSameh SororAmal O. AmerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-20 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shady Estfanous Kathrin Krause Midhun N. K. Anne Mostafa Eltobgy Kyle Caution Arwa Abu Khweek Kaitlin Hamilton Asmaa Badr Kylene Daily Cierra Carafice Daniel Baetzhold Xiaoli Zhang Tianliang Li Haitao Wen Mikhail A. Gavrilin Hesham Haffez Sameh Soror Amal O. Amer Gasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo
description	Abstract Burkholderia cenocepacia (B. cenocepacia) is an opportunistic bacterium; causing severe life threatening systemic infections in immunocompromised individuals including cystic fibrosis patients. The lack of gasdermin D (GSDMD) protects mice against endotoxin lipopolysaccharide (LPS) shock. On the other hand, GSDMD promotes mice survival in response to certain bacterial infections. However, the role of GSDMD during B. cenocepacia infection is not yet determined. Our in vitro study shows that GSDMD restricts B. cenocepacia replication within macrophages independent of its role in cell death through promoting mitochondrial reactive oxygen species (mROS) production. mROS is known to stimulate autophagy, hence, the inhibition of mROS or the absence of GSDMD during B. cenocepacia infections reduces autophagy which plays a critical role in the restriction of the pathogen. GSDMD promotes inflammation in response to B. cenocepacia through mediating the release of inflammasome dependent cytokine (IL-1β) and an independent one (CXCL1) (KC). Additionally, different B. cenocepacia secretory systems (T3SS, T4SS, and T6SS) contribute to inflammasome activation together with bacterial survival within macrophages. In vivo study confirmed the in vitro findings and showed that GSDMD restricts B. cenocepacia infection and dissemination and stimulates autophagy in response to B. cenocepacia. Nevertheless, GSDMD promotes lung inflammation and necrosis in response to B. cenocepacia without altering mice survival. This study describes the double-edged functions of GSDMD in response to B. cenocepacia infection and shows the importance of GSDMD-mediated mROS in restriction of B. cenocepacia.
format	article
author	Shady Estfanous Kathrin Krause Midhun N. K. Anne Mostafa Eltobgy Kyle Caution Arwa Abu Khweek Kaitlin Hamilton Asmaa Badr Kylene Daily Cierra Carafice Daniel Baetzhold Xiaoli Zhang Tianliang Li Haitao Wen Mikhail A. Gavrilin Hesham Haffez Sameh Soror Amal O. Amer
author_facet	Shady Estfanous Kathrin Krause Midhun N. K. Anne Mostafa Eltobgy Kyle Caution Arwa Abu Khweek Kaitlin Hamilton Asmaa Badr Kylene Daily Cierra Carafice Daniel Baetzhold Xiaoli Zhang Tianliang Li Haitao Wen Mikhail A. Gavrilin Hesham Haffez Sameh Soror Amal O. Amer
author_sort	Shady Estfanous
title	Gasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo
title_short	Gasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo
title_full	Gasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo
title_fullStr	Gasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo
title_full_unstemmed	Gasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo
title_sort	gasdermin d restricts burkholderia cenocepacia infection in vitro and in vivo
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/dfc42d70a6394957ad2316ed4514e290
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Gasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo

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