PPE Surface Proteins Are Required for Heme Utilization by <italic toggle="yes">Mycobacterium tuberculosis</italic>

ABSTRACT Iron is essential for replication of Mycobacterium tuberculosis, but iron is efficiently sequestered in the human host during infection. Heme constitutes the largest iron reservoir in the human body and is utilized by many bacterial pathogens as an iron source. While heme acquisition is wel...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Avishek Mitra, Alexander Speer, Kan Lin, Sabine Ehrt, Michael Niederweis
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6292d8eaa5544b939a06b55c8f002dcc
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:6292d8eaa5544b939a06b55c8f002dcc
record_format	dspace
spelling	oai:doaj.org-article:6292d8eaa5544b939a06b55c8f002dcc2021-11-15T15:51:07ZPPE Surface Proteins Are Required for Heme Utilization by <italic toggle="yes">Mycobacterium tuberculosis</italic>10.1128/mBio.01720-162150-7511https://doaj.org/article/6292d8eaa5544b939a06b55c8f002dcc2017-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01720-16https://doaj.org/toc/2150-7511ABSTRACT Iron is essential for replication of Mycobacterium tuberculosis, but iron is efficiently sequestered in the human host during infection. Heme constitutes the largest iron reservoir in the human body and is utilized by many bacterial pathogens as an iron source. While heme acquisition is well studied in other bacterial pathogens, little is known in M. tuberculosis. To identify proteins involved in heme utilization by M. tuberculosis, a transposon mutant library was screened for resistance to the toxic heme analog gallium(III)-porphyrin (Ga-PIX). Inactivation of the ppe36, ppe62, and rv0265c genes resulted in resistance to Ga-PIX. Growth experiments using isogenic M. tuberculosis deletion mutants showed that PPE36 is essential for heme utilization by M. tuberculosis, while the functions of PPE62 and Rv0265c are partially redundant. None of the genes restored growth of the heterologous M. tuberculosis mutants, indicating that the proteins encoded by the genes have separate functions. PPE36, PPE62, and Rv0265c bind heme as shown by surface plasmon resonance spectroscopy and are associated with membranes. Both PPE36 and PPE62 proteins are cell surface accessible, while the Rv0265c protein is probably located in the periplasm. PPE36 and PPE62 are, to our knowledge, the first proline-proline-glutamate (PPE) proteins of M. tuberculosis that bind small molecules and are involved in nutrient acquisition. The absence of a virulence defect of the ppe36 deletion mutant indicates that the different iron acquisition pathways of M. tuberculosis may substitute for each other during growth and persistence in mice. The emerging model of heme utilization by M. tuberculosis as derived from this study is substantially different from those of other bacteria. IMPORTANCE Tuberculosis is caused by Mycobacterium tuberculosis and is a devastating disease affecting eight million people each year. Iron is an essential nutrient for replication of M. tuberculosis in the human host. More than 70% of iron in the human body is bound in heme. Not surprisingly, many bacterial pathogens, including M. tuberculosis, are able to acquire iron from heme. However, the mechanism of heme uptake by M. tuberculosis is poorly understood. We have identified two novel surface proteins that bind heme and are required for heme utilization by M. tuberculosis. These findings constitute a major advancement of our understanding of iron acquisition by M. tuberculosis and show that M. tuberculosis has evolved heme uptake systems different from the paradigms established by other bacteria.Avishek MitraAlexander SpeerKan LinSabine EhrtMichael NiederweisAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 8, Iss 1 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Avishek Mitra Alexander Speer Kan Lin Sabine Ehrt Michael Niederweis PPE Surface Proteins Are Required for Heme Utilization by <italic toggle="yes">Mycobacterium tuberculosis</italic>
description	ABSTRACT Iron is essential for replication of Mycobacterium tuberculosis, but iron is efficiently sequestered in the human host during infection. Heme constitutes the largest iron reservoir in the human body and is utilized by many bacterial pathogens as an iron source. While heme acquisition is well studied in other bacterial pathogens, little is known in M. tuberculosis. To identify proteins involved in heme utilization by M. tuberculosis, a transposon mutant library was screened for resistance to the toxic heme analog gallium(III)-porphyrin (Ga-PIX). Inactivation of the ppe36, ppe62, and rv0265c genes resulted in resistance to Ga-PIX. Growth experiments using isogenic M. tuberculosis deletion mutants showed that PPE36 is essential for heme utilization by M. tuberculosis, while the functions of PPE62 and Rv0265c are partially redundant. None of the genes restored growth of the heterologous M. tuberculosis mutants, indicating that the proteins encoded by the genes have separate functions. PPE36, PPE62, and Rv0265c bind heme as shown by surface plasmon resonance spectroscopy and are associated with membranes. Both PPE36 and PPE62 proteins are cell surface accessible, while the Rv0265c protein is probably located in the periplasm. PPE36 and PPE62 are, to our knowledge, the first proline-proline-glutamate (PPE) proteins of M. tuberculosis that bind small molecules and are involved in nutrient acquisition. The absence of a virulence defect of the ppe36 deletion mutant indicates that the different iron acquisition pathways of M. tuberculosis may substitute for each other during growth and persistence in mice. The emerging model of heme utilization by M. tuberculosis as derived from this study is substantially different from those of other bacteria. IMPORTANCE Tuberculosis is caused by Mycobacterium tuberculosis and is a devastating disease affecting eight million people each year. Iron is an essential nutrient for replication of M. tuberculosis in the human host. More than 70% of iron in the human body is bound in heme. Not surprisingly, many bacterial pathogens, including M. tuberculosis, are able to acquire iron from heme. However, the mechanism of heme uptake by M. tuberculosis is poorly understood. We have identified two novel surface proteins that bind heme and are required for heme utilization by M. tuberculosis. These findings constitute a major advancement of our understanding of iron acquisition by M. tuberculosis and show that M. tuberculosis has evolved heme uptake systems different from the paradigms established by other bacteria.
format	article
author	Avishek Mitra Alexander Speer Kan Lin Sabine Ehrt Michael Niederweis
author_facet	Avishek Mitra Alexander Speer Kan Lin Sabine Ehrt Michael Niederweis
author_sort	Avishek Mitra
title	PPE Surface Proteins Are Required for Heme Utilization by <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_short	PPE Surface Proteins Are Required for Heme Utilization by <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_full	PPE Surface Proteins Are Required for Heme Utilization by <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_fullStr	PPE Surface Proteins Are Required for Heme Utilization by <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_full_unstemmed	PPE Surface Proteins Are Required for Heme Utilization by <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_sort	ppe surface proteins are required for heme utilization by <italic toggle="yes">mycobacterium tuberculosis</italic>
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/6292d8eaa5544b939a06b55c8f002dcc
work_keys_str_mv	AT avishekmitra ppesurfaceproteinsarerequiredforhemeutilizationbyitalictoggleyesmycobacteriumtuberculosisitalic AT alexanderspeer ppesurfaceproteinsarerequiredforhemeutilizationbyitalictoggleyesmycobacteriumtuberculosisitalic AT kanlin ppesurfaceproteinsarerequiredforhemeutilizationbyitalictoggleyesmycobacteriumtuberculosisitalic AT sabineehrt ppesurfaceproteinsarerequiredforhemeutilizationbyitalictoggleyesmycobacteriumtuberculosisitalic AT michaelniederweis ppesurfaceproteinsarerequiredforhemeutilizationbyitalictoggleyesmycobacteriumtuberculosisitalic
_version_	1718427401230221312

PPE Surface Proteins Are Required for Heme Utilization by <italic toggle="yes">Mycobacterium tuberculosis</italic>

Ejemplares similares