Intracellular <named-content content-type="genus-species">Staphylococcus aureus</named-content> Modulates Host Central Carbon Metabolism To Activate Autophagy

ABSTRACT Staphylococcus aureus is a facultative intracellular pathogen that invades and replicates within many types of phagocytic and nonphagocytic cells. During intracellular infection, S. aureus is capable of subverting xenophagy and escaping to the cytosol of the host cell. Furthermore, drug-ind...

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Autores principales:	Natalia Bravo-Santano, James K. Ellis, Luis M. Mateos, Yolanda Calle, Hector C. Keun, Volker Behrends, Michal Letek
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Staphylococcus aureus autophagy host cell intracellular pathogen metabolism Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/13bebf22c6074de1b1dabba86f7211aa
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spelling	oai:doaj.org-article:13bebf22c6074de1b1dabba86f7211aa2021-11-15T15:25:50ZIntracellular <named-content content-type="genus-species">Staphylococcus aureus</named-content> Modulates Host Central Carbon Metabolism To Activate Autophagy10.1128/mSphere.00374-182379-5042https://doaj.org/article/13bebf22c6074de1b1dabba86f7211aa2018-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00374-18https://doaj.org/toc/2379-5042ABSTRACT Staphylococcus aureus is a facultative intracellular pathogen that invades and replicates within many types of phagocytic and nonphagocytic cells. During intracellular infection, S. aureus is capable of subverting xenophagy and escaping to the cytosol of the host cell. Furthermore, drug-induced autophagy facilitates the intracellular replication of S. aureus, but the reasons behind this are unclear. Here, we have studied the host central carbon metabolism during S. aureus intracellular infection. We found extensive metabolic rerouting and detected several distinct metabolic changes that suggested starvation-induced autophagic flux in infected cells. These changes included increased uptake but lower intracellular levels of glucose and low abundance of several essential amino acids, as well as markedly upregulated glutaminolysis. Furthermore, we show that AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinase (ERK) phosphorylation levels are significantly increased in infected cells. Interestingly, while autophagy was activated in response to S. aureus invasion, most of the autophagosomes detected in infected cells did not contain bacteria, suggesting that S. aureus induces the autophagic flux during cell invasion for energy generation and nutrient scavenging. Accordingly, AMPK inhibition halted S. aureus intracellular proliferation. IMPORTANCE Staphylococcus aureus escapes from immune recognition by invading a wide range of human cells. Once the pathogen becomes intracellular, the most important last resort antibiotics are not effective. Therefore, novel anti-infective therapies against intracellular S. aureus are urgently needed. Here, we have studied the physiological changes induced in the host cells by S. aureus during its intracellular proliferation. This is important, because the pathogen exploits the host cell’s metabolism for its own proliferation. We find that S. aureus severely depletes glucose and amino acid pools, which leads to increased breakdown of glutamine by the host cell in an attempt to meet its own metabolic needs. All of these metabolic changes activate autophagy in the host cell for nutrient scavenging and energy generation. The metabolic activation of autophagy could be used by the pathogen to sustain its own intracellular survival, making it an attractive target for novel anti-infectives.Natalia Bravo-SantanoJames K. EllisLuis M. MateosYolanda CalleHector C. KeunVolker BehrendsMichal LetekAmerican Society for MicrobiologyarticleStaphylococcus aureusautophagyhost cellintracellular pathogenmetabolismMicrobiologyQR1-502ENmSphere, Vol 3, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Staphylococcus aureus autophagy host cell intracellular pathogen metabolism Microbiology QR1-502
spellingShingle	Staphylococcus aureus autophagy host cell intracellular pathogen metabolism Microbiology QR1-502 Natalia Bravo-Santano James K. Ellis Luis M. Mateos Yolanda Calle Hector C. Keun Volker Behrends Michal Letek Intracellular <named-content content-type="genus-species">Staphylococcus aureus</named-content> Modulates Host Central Carbon Metabolism To Activate Autophagy
description	ABSTRACT Staphylococcus aureus is a facultative intracellular pathogen that invades and replicates within many types of phagocytic and nonphagocytic cells. During intracellular infection, S. aureus is capable of subverting xenophagy and escaping to the cytosol of the host cell. Furthermore, drug-induced autophagy facilitates the intracellular replication of S. aureus, but the reasons behind this are unclear. Here, we have studied the host central carbon metabolism during S. aureus intracellular infection. We found extensive metabolic rerouting and detected several distinct metabolic changes that suggested starvation-induced autophagic flux in infected cells. These changes included increased uptake but lower intracellular levels of glucose and low abundance of several essential amino acids, as well as markedly upregulated glutaminolysis. Furthermore, we show that AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinase (ERK) phosphorylation levels are significantly increased in infected cells. Interestingly, while autophagy was activated in response to S. aureus invasion, most of the autophagosomes detected in infected cells did not contain bacteria, suggesting that S. aureus induces the autophagic flux during cell invasion for energy generation and nutrient scavenging. Accordingly, AMPK inhibition halted S. aureus intracellular proliferation. IMPORTANCE Staphylococcus aureus escapes from immune recognition by invading a wide range of human cells. Once the pathogen becomes intracellular, the most important last resort antibiotics are not effective. Therefore, novel anti-infective therapies against intracellular S. aureus are urgently needed. Here, we have studied the physiological changes induced in the host cells by S. aureus during its intracellular proliferation. This is important, because the pathogen exploits the host cell’s metabolism for its own proliferation. We find that S. aureus severely depletes glucose and amino acid pools, which leads to increased breakdown of glutamine by the host cell in an attempt to meet its own metabolic needs. All of these metabolic changes activate autophagy in the host cell for nutrient scavenging and energy generation. The metabolic activation of autophagy could be used by the pathogen to sustain its own intracellular survival, making it an attractive target for novel anti-infectives.
format	article
author	Natalia Bravo-Santano James K. Ellis Luis M. Mateos Yolanda Calle Hector C. Keun Volker Behrends Michal Letek
author_facet	Natalia Bravo-Santano James K. Ellis Luis M. Mateos Yolanda Calle Hector C. Keun Volker Behrends Michal Letek
author_sort	Natalia Bravo-Santano
title	Intracellular <named-content content-type="genus-species">Staphylococcus aureus</named-content> Modulates Host Central Carbon Metabolism To Activate Autophagy
title_short	Intracellular <named-content content-type="genus-species">Staphylococcus aureus</named-content> Modulates Host Central Carbon Metabolism To Activate Autophagy
title_full	Intracellular <named-content content-type="genus-species">Staphylococcus aureus</named-content> Modulates Host Central Carbon Metabolism To Activate Autophagy
title_fullStr	Intracellular <named-content content-type="genus-species">Staphylococcus aureus</named-content> Modulates Host Central Carbon Metabolism To Activate Autophagy
title_full_unstemmed	Intracellular <named-content content-type="genus-species">Staphylococcus aureus</named-content> Modulates Host Central Carbon Metabolism To Activate Autophagy
title_sort	intracellular <named-content content-type="genus-species">staphylococcus aureus</named-content> modulates host central carbon metabolism to activate autophagy
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/13bebf22c6074de1b1dabba86f7211aa
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Intracellular <named-content content-type="genus-species">Staphylococcus aureus</named-content> Modulates Host Central Carbon Metabolism To Activate Autophagy

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