A Conserved Streptococcal Virulence Regulator Controls the Expression of a Distinct Class of M-Like Proteins

ABSTRACT Streptococcus equi subspecies zooepidemicus (SEZ) are group C streptococci that are important pathogens of economically valuable animals such as horses and pigs. Here, we found that many SEZ isolates bind to a monoclonal antibody that recognizes poly-N-acetylglucosamine (PNAG), a polymer th...

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Autores principales:	Jonathan D. D’Gama, Zhe Ma, Hailong Zhang, Xu Liu, Hongjie Fan, Ellen Ruth A. Morris, Noah D. Cohen, Colette Cywes-Bentley, Gerald B. Pier, Matthew K. Waldor
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	M protein Streptococcus equi Streptococcus zooepidemicus whole-genome sequencing group A streptococcus streptococcal pathogenesis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c1b66c529c354a83a71e7fd051d76409
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spelling	oai:doaj.org-article:c1b66c529c354a83a71e7fd051d764092021-11-15T15:59:41ZA Conserved Streptococcal Virulence Regulator Controls the Expression of a Distinct Class of M-Like Proteins10.1128/mBio.02500-192150-7511https://doaj.org/article/c1b66c529c354a83a71e7fd051d764092019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02500-19https://doaj.org/toc/2150-7511ABSTRACT Streptococcus equi subspecies zooepidemicus (SEZ) are group C streptococci that are important pathogens of economically valuable animals such as horses and pigs. Here, we found that many SEZ isolates bind to a monoclonal antibody that recognizes poly-N-acetylglucosamine (PNAG), a polymer that is found as a surface capsule-like structure on diverse microbes. A fluorescence-activated cell sorting-based transposon insertion sequencing (Tn-seq) screen, coupled with whole-genome sequencing, was used to search for genes for PNAG biosynthesis. Surprisingly, mutations in a gene encoding an M-like protein, szM, and the adjacent transcription factor, designated sezV, rendered strains PNAG negative. SezV was required for szM expression and transcriptome analysis showed that SezV has a small regulon. SEZ strains with inactivating mutations in either sezV or szM were highly attenuated in a mouse model of infection. Comparative genomic analyses revealed that linked sezV and szM homologues are present in all SEZ, S. equi subspecies equi (SEE), and M18 group A streptococcal (GAS) genomes in the database, but not in other streptococci. The antibody to PNAG bound to a wide range of SEZ, SEE, and M18 GAS strains. Immunochemical studies suggest that the SzM protein may be decorated with a PNAG-like oligosaccharide although an intact oligosaccharide substituent could not be isolated. Collectively, our findings suggest that the szM and sezV loci define a subtype of virulent streptococci and that an antibody to PNAG may have therapeutic applications in animal and human diseases caused by streptococci bearing SzM-like proteins. IMPORTANCE M proteins are surface-anchored virulence factors in group A streptococci, human pathogens. Here, we identified an M-like protein, SzM, and its positive regulator, SezV, in Streptococcus equi subspecies zooepidemicus (SEZ), an important group of pathogens for domesticated animals, including horses and pigs. SzM and SezV homologues were found in the genomes of all SEZ and S. equi subspecies equi and M18 group A streptococcal strains analyzed but not in other streptococci. Mutant SEZ strains lacking either sezV or szM were highly attenuated in a mouse model of infection. Collectively, our findings suggest that SezV-related regulators and the linked SzM family of M-like proteins define a new subset of virulent streptococci.Jonathan D. D’GamaZhe MaHailong ZhangXu LiuHongjie FanEllen Ruth A. MorrisNoah D. CohenColette Cywes-BentleyGerald B. PierMatthew K. WaldorAmerican Society for MicrobiologyarticleM proteinStreptococcus equiStreptococcus zooepidemicuswhole-genome sequencinggroup A streptococcusstreptococcal pathogenesisMicrobiologyQR1-502ENmBio, Vol 10, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	M protein Streptococcus equi Streptococcus zooepidemicus whole-genome sequencing group A streptococcus streptococcal pathogenesis Microbiology QR1-502
spellingShingle	M protein Streptococcus equi Streptococcus zooepidemicus whole-genome sequencing group A streptococcus streptococcal pathogenesis Microbiology QR1-502 Jonathan D. D’Gama Zhe Ma Hailong Zhang Xu Liu Hongjie Fan Ellen Ruth A. Morris Noah D. Cohen Colette Cywes-Bentley Gerald B. Pier Matthew K. Waldor A Conserved Streptococcal Virulence Regulator Controls the Expression of a Distinct Class of M-Like Proteins
description	ABSTRACT Streptococcus equi subspecies zooepidemicus (SEZ) are group C streptococci that are important pathogens of economically valuable animals such as horses and pigs. Here, we found that many SEZ isolates bind to a monoclonal antibody that recognizes poly-N-acetylglucosamine (PNAG), a polymer that is found as a surface capsule-like structure on diverse microbes. A fluorescence-activated cell sorting-based transposon insertion sequencing (Tn-seq) screen, coupled with whole-genome sequencing, was used to search for genes for PNAG biosynthesis. Surprisingly, mutations in a gene encoding an M-like protein, szM, and the adjacent transcription factor, designated sezV, rendered strains PNAG negative. SezV was required for szM expression and transcriptome analysis showed that SezV has a small regulon. SEZ strains with inactivating mutations in either sezV or szM were highly attenuated in a mouse model of infection. Comparative genomic analyses revealed that linked sezV and szM homologues are present in all SEZ, S. equi subspecies equi (SEE), and M18 group A streptococcal (GAS) genomes in the database, but not in other streptococci. The antibody to PNAG bound to a wide range of SEZ, SEE, and M18 GAS strains. Immunochemical studies suggest that the SzM protein may be decorated with a PNAG-like oligosaccharide although an intact oligosaccharide substituent could not be isolated. Collectively, our findings suggest that the szM and sezV loci define a subtype of virulent streptococci and that an antibody to PNAG may have therapeutic applications in animal and human diseases caused by streptococci bearing SzM-like proteins. IMPORTANCE M proteins are surface-anchored virulence factors in group A streptococci, human pathogens. Here, we identified an M-like protein, SzM, and its positive regulator, SezV, in Streptococcus equi subspecies zooepidemicus (SEZ), an important group of pathogens for domesticated animals, including horses and pigs. SzM and SezV homologues were found in the genomes of all SEZ and S. equi subspecies equi and M18 group A streptococcal strains analyzed but not in other streptococci. Mutant SEZ strains lacking either sezV or szM were highly attenuated in a mouse model of infection. Collectively, our findings suggest that SezV-related regulators and the linked SzM family of M-like proteins define a new subset of virulent streptococci.
format	article
author	Jonathan D. D’Gama Zhe Ma Hailong Zhang Xu Liu Hongjie Fan Ellen Ruth A. Morris Noah D. Cohen Colette Cywes-Bentley Gerald B. Pier Matthew K. Waldor
author_facet	Jonathan D. D’Gama Zhe Ma Hailong Zhang Xu Liu Hongjie Fan Ellen Ruth A. Morris Noah D. Cohen Colette Cywes-Bentley Gerald B. Pier Matthew K. Waldor
author_sort	Jonathan D. D’Gama
title	A Conserved Streptococcal Virulence Regulator Controls the Expression of a Distinct Class of M-Like Proteins
title_short	A Conserved Streptococcal Virulence Regulator Controls the Expression of a Distinct Class of M-Like Proteins
title_full	A Conserved Streptococcal Virulence Regulator Controls the Expression of a Distinct Class of M-Like Proteins
title_fullStr	A Conserved Streptococcal Virulence Regulator Controls the Expression of a Distinct Class of M-Like Proteins
title_full_unstemmed	A Conserved Streptococcal Virulence Regulator Controls the Expression of a Distinct Class of M-Like Proteins
title_sort	conserved streptococcal virulence regulator controls the expression of a distinct class of m-like proteins
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/c1b66c529c354a83a71e7fd051d76409
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A Conserved Streptococcal Virulence Regulator Controls the Expression of a Distinct Class of M-Like Proteins

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