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

mBio

Ellen Ruth A. Morris¹  Noah D. Cohen¹  Hailong Zhang²  Jonathan D. D’Gama²  Matthew K. Waldor²  Gerald B. Pier²  Colette Cywes-Bentley²  Xu Liu²  Zhe Ma³  Hongjie Fan⁴ 

[1] Department of Large Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, College Station, Texas, USA;Department of Microbiology, Harvard Medical School, Boston, Massachusetts, USA;Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts, USA;MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China;

关键词: M protein;    Streptococcus equi;    Streptococcus zooepidemicus;    whole-genome sequencing;    group A streptococcus;    streptococcal pathogenesis;   

DOI  :  10.1128/mBio.02500-19

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown