Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway

ABSTRACT The reverse transsulfuration pathway is the major route for the metabolism of sulfur-containing amino acids. The role of this metabolic pathway in macrophage response and function is unknown. We show that the enzyme cystathionine γ-lyase (CTH) is induced in macrophages infected with pathoge...

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Autores principales:	Alain P. Gobert, Yvonne L. Latour, Mohammad Asim, Jordan L. Finley, Thomas G. Verriere, Daniel P. Barry, Ginger L. Milne, Paula B. Luis, Claus Schneider, Emilio S. Rivera, Kristie Lindsey-Rose, Kevin L. Schey, Alberto G. Delgado, Johanna C. Sierra, M. Blanca Piazuelo, Keith T. Wilson
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Helicobacter pylori immune evasion immunometabolism innate immunity macrophages pathogenic bacteria Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/db50a92f548d4b85beae15ff68935760
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spelling	oai:doaj.org-article:db50a92f548d4b85beae15ff689357602021-11-15T15:59:41ZBacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway10.1128/mBio.02174-192150-7511https://doaj.org/article/db50a92f548d4b85beae15ff689357602019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02174-19https://doaj.org/toc/2150-7511ABSTRACT The reverse transsulfuration pathway is the major route for the metabolism of sulfur-containing amino acids. The role of this metabolic pathway in macrophage response and function is unknown. We show that the enzyme cystathionine γ-lyase (CTH) is induced in macrophages infected with pathogenic bacteria through signaling involving phosphatidylinositol 3-kinase (PI3K)/MTOR and the transcription factor SP1. This results in the synthesis of cystathionine, which facilitates the survival of pathogens within myeloid cells. Our data demonstrate that the expression of CTH leads to defective macrophage activation by (i) dysregulation of polyamine metabolism by depletion of S-adenosylmethionine, resulting in immunosuppressive putrescine accumulation and inhibition of spermidine and spermine synthesis, and (ii) increased histone H3K9, H3K27, and H3K36 di/trimethylation, which is associated with gene expression silencing. Thus, CTH is a pivotal enzyme of the innate immune response that disrupts host defense. The induction of the reverse transsulfuration pathway by bacterial pathogens can be considered an unrecognized mechanism for immune escape. IMPORTANCE Macrophages are professional immune cells that ingest and kill microbes. In this study, we show that different pathogenic bacteria induce the expression of cystathionine γ-lyase (CTH) in macrophages. This enzyme is involved in a metabolic pathway called the reverse transsulfuration pathway, which leads to the production of numerous metabolites, including cystathionine. Phagocytized bacteria use cystathionine to better survive in macrophages. In addition, the induction of CTH results in dysregulation of the metabolism of polyamines, which in turn dampens the proinflammatory response of macrophages. In conclusion, pathogenic bacteria can evade the host immune response by inducing CTH in macrophages.Alain P. GobertYvonne L. LatourMohammad AsimJordan L. FinleyThomas G. VerriereDaniel P. BarryGinger L. MilnePaula B. LuisClaus SchneiderEmilio S. RiveraKristie Lindsey-RoseKevin L. ScheyAlberto G. DelgadoJohanna C. SierraM. Blanca PiazueloKeith T. WilsonAmerican Society for MicrobiologyarticleHelicobacter pyloriimmune evasionimmunometabolisminnate immunitymacrophagespathogenic bacteriaMicrobiologyQR1-502ENmBio, Vol 10, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Helicobacter pylori immune evasion immunometabolism innate immunity macrophages pathogenic bacteria Microbiology QR1-502
spellingShingle	Helicobacter pylori immune evasion immunometabolism innate immunity macrophages pathogenic bacteria Microbiology QR1-502 Alain P. Gobert Yvonne L. Latour Mohammad Asim Jordan L. Finley Thomas G. Verriere Daniel P. Barry Ginger L. Milne Paula B. Luis Claus Schneider Emilio S. Rivera Kristie Lindsey-Rose Kevin L. Schey Alberto G. Delgado Johanna C. Sierra M. Blanca Piazuelo Keith T. Wilson Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway
description	ABSTRACT The reverse transsulfuration pathway is the major route for the metabolism of sulfur-containing amino acids. The role of this metabolic pathway in macrophage response and function is unknown. We show that the enzyme cystathionine γ-lyase (CTH) is induced in macrophages infected with pathogenic bacteria through signaling involving phosphatidylinositol 3-kinase (PI3K)/MTOR and the transcription factor SP1. This results in the synthesis of cystathionine, which facilitates the survival of pathogens within myeloid cells. Our data demonstrate that the expression of CTH leads to defective macrophage activation by (i) dysregulation of polyamine metabolism by depletion of S-adenosylmethionine, resulting in immunosuppressive putrescine accumulation and inhibition of spermidine and spermine synthesis, and (ii) increased histone H3K9, H3K27, and H3K36 di/trimethylation, which is associated with gene expression silencing. Thus, CTH is a pivotal enzyme of the innate immune response that disrupts host defense. The induction of the reverse transsulfuration pathway by bacterial pathogens can be considered an unrecognized mechanism for immune escape. IMPORTANCE Macrophages are professional immune cells that ingest and kill microbes. In this study, we show that different pathogenic bacteria induce the expression of cystathionine γ-lyase (CTH) in macrophages. This enzyme is involved in a metabolic pathway called the reverse transsulfuration pathway, which leads to the production of numerous metabolites, including cystathionine. Phagocytized bacteria use cystathionine to better survive in macrophages. In addition, the induction of CTH results in dysregulation of the metabolism of polyamines, which in turn dampens the proinflammatory response of macrophages. In conclusion, pathogenic bacteria can evade the host immune response by inducing CTH in macrophages.
format	article
author	Alain P. Gobert Yvonne L. Latour Mohammad Asim Jordan L. Finley Thomas G. Verriere Daniel P. Barry Ginger L. Milne Paula B. Luis Claus Schneider Emilio S. Rivera Kristie Lindsey-Rose Kevin L. Schey Alberto G. Delgado Johanna C. Sierra M. Blanca Piazuelo Keith T. Wilson
author_facet	Alain P. Gobert Yvonne L. Latour Mohammad Asim Jordan L. Finley Thomas G. Verriere Daniel P. Barry Ginger L. Milne Paula B. Luis Claus Schneider Emilio S. Rivera Kristie Lindsey-Rose Kevin L. Schey Alberto G. Delgado Johanna C. Sierra M. Blanca Piazuelo Keith T. Wilson
author_sort	Alain P. Gobert
title	Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway
title_short	Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway
title_full	Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway
title_fullStr	Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway
title_full_unstemmed	Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway
title_sort	bacterial pathogens hijack the innate immune response by activation of the reverse transsulfuration pathway
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/db50a92f548d4b85beae15ff68935760
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Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway

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