Control of <italic toggle="yes">gdhR</italic> Expression in <italic toggle="yes">Neisseria gonorrhoeae</italic> via Autoregulation and a Master Repressor (MtrR) of a Drug Efflux Pump Operon

ABSTRACT The MtrCDE efflux pump of Neisseria gonorrhoeae contributes to gonococcal resistance to a number of antibiotics used previously or currently in treatment of gonorrhea, as well as to host-derived antimicrobials that participate in innate defense. Overexpression of the MtrCDE efflux pump incr...

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Autores principales:	Corinne E. Rouquette-Loughlin, Yaramah M. Zalucki, Vijaya L. Dhulipala, Jacqueline T. Balthazar, Raúl G. Doyle, Robert A. Nicholas, Afrin A. Begum, Erica L. Raterman, Ann E. Jerse, William M. Shafer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	gonococci transcription efflux pumps physiology Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/78a52acdff2b4e739aa56bb2bf870f78
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spelling	oai:doaj.org-article:78a52acdff2b4e739aa56bb2bf870f782021-11-15T15:51:00ZControl of <italic toggle="yes">gdhR</italic> Expression in <italic toggle="yes">Neisseria gonorrhoeae</italic> via Autoregulation and a Master Repressor (MtrR) of a Drug Efflux Pump Operon10.1128/mBio.00449-172150-7511https://doaj.org/article/78a52acdff2b4e739aa56bb2bf870f782017-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00449-17https://doaj.org/toc/2150-7511ABSTRACT The MtrCDE efflux pump of Neisseria gonorrhoeae contributes to gonococcal resistance to a number of antibiotics used previously or currently in treatment of gonorrhea, as well as to host-derived antimicrobials that participate in innate defense. Overexpression of the MtrCDE efflux pump increases gonococcal survival and fitness during experimental lower genital tract infection of female mice. Transcription of mtrCDE can be repressed by the DNA-binding protein MtrR, which also acts as a global regulator of genes involved in important metabolic, physiologic, or regulatory processes. Here, we investigated whether a gene downstream of mtrCDE, previously annotated gdhR in Neisseria meningitidis, is a target for regulation by MtrR. In meningococci, GdhR serves as a regulator of genes involved in glucose catabolism, amino acid transport, and biosynthesis, including gdhA, which encodes an l-glutamate dehydrogenase and is located next to gdhR but is transcriptionally divergent. We report here that in N. gonorrhoeae, expression of gdhR is subject to autoregulation by GdhR and direct repression by MtrR. Importantly, loss of GdhR significantly increased gonococcal fitness compared to a complemented mutant strain during experimental murine infection. Interestingly, loss of GdhR did not influence expression of gdhA, as reported for meningococci. This variance is most likely due to differences in promoter localization and utilization between gonococci and meningococci. We propose that transcriptional control of gonococcal genes through the action of MtrR and GdhR contributes to fitness of N. gonorrhoeae during infection. IMPORTANCE The pathogenic Neisseria species are strict human pathogens that can cause a sexually transmitted infection (N. gonorrhoeae) or meningitis or fulminant septicemia (N. meningitidis). Although they share considerable genetic information, little attention has been directed to comparing transcriptional regulatory systems that modulate expression of their conserved genes. We hypothesized that transcriptional regulatory differences exist between these two pathogens, and we used the gdh locus as a model to test this idea. For this purpose, we studied two conserved genes (gdhR and gdhA) within the locus. Despite general conservation of the gdh locus in gonococci and meningococci, differences exist in noncoding sequences that correspond to promoter elements or potential sites for interacting with DNA-binding proteins, such as GdhR and MtrR. Our results indicate that implications drawn from studying regulation of conserved genes in one pathogen are not necessarily translatable to a genetically related pathogen.Corinne E. Rouquette-LoughlinYaramah M. ZaluckiVijaya L. DhulipalaJacqueline T. BalthazarRaúl G. DoyleRobert A. NicholasAfrin A. BegumErica L. RatermanAnn E. JerseWilliam M. ShaferAmerican Society for Microbiologyarticlegonococcitranscriptionefflux pumpsphysiologyMicrobiologyQR1-502ENmBio, Vol 8, Iss 2 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	gonococci transcription efflux pumps physiology Microbiology QR1-502
spellingShingle	gonococci transcription efflux pumps physiology Microbiology QR1-502 Corinne E. Rouquette-Loughlin Yaramah M. Zalucki Vijaya L. Dhulipala Jacqueline T. Balthazar Raúl G. Doyle Robert A. Nicholas Afrin A. Begum Erica L. Raterman Ann E. Jerse William M. Shafer Control of <italic toggle="yes">gdhR</italic> Expression in <italic toggle="yes">Neisseria gonorrhoeae</italic> via Autoregulation and a Master Repressor (MtrR) of a Drug Efflux Pump Operon
description	ABSTRACT The MtrCDE efflux pump of Neisseria gonorrhoeae contributes to gonococcal resistance to a number of antibiotics used previously or currently in treatment of gonorrhea, as well as to host-derived antimicrobials that participate in innate defense. Overexpression of the MtrCDE efflux pump increases gonococcal survival and fitness during experimental lower genital tract infection of female mice. Transcription of mtrCDE can be repressed by the DNA-binding protein MtrR, which also acts as a global regulator of genes involved in important metabolic, physiologic, or regulatory processes. Here, we investigated whether a gene downstream of mtrCDE, previously annotated gdhR in Neisseria meningitidis, is a target for regulation by MtrR. In meningococci, GdhR serves as a regulator of genes involved in glucose catabolism, amino acid transport, and biosynthesis, including gdhA, which encodes an l-glutamate dehydrogenase and is located next to gdhR but is transcriptionally divergent. We report here that in N. gonorrhoeae, expression of gdhR is subject to autoregulation by GdhR and direct repression by MtrR. Importantly, loss of GdhR significantly increased gonococcal fitness compared to a complemented mutant strain during experimental murine infection. Interestingly, loss of GdhR did not influence expression of gdhA, as reported for meningococci. This variance is most likely due to differences in promoter localization and utilization between gonococci and meningococci. We propose that transcriptional control of gonococcal genes through the action of MtrR and GdhR contributes to fitness of N. gonorrhoeae during infection. IMPORTANCE The pathogenic Neisseria species are strict human pathogens that can cause a sexually transmitted infection (N. gonorrhoeae) or meningitis or fulminant septicemia (N. meningitidis). Although they share considerable genetic information, little attention has been directed to comparing transcriptional regulatory systems that modulate expression of their conserved genes. We hypothesized that transcriptional regulatory differences exist between these two pathogens, and we used the gdh locus as a model to test this idea. For this purpose, we studied two conserved genes (gdhR and gdhA) within the locus. Despite general conservation of the gdh locus in gonococci and meningococci, differences exist in noncoding sequences that correspond to promoter elements or potential sites for interacting with DNA-binding proteins, such as GdhR and MtrR. Our results indicate that implications drawn from studying regulation of conserved genes in one pathogen are not necessarily translatable to a genetically related pathogen.
format	article
author	Corinne E. Rouquette-Loughlin Yaramah M. Zalucki Vijaya L. Dhulipala Jacqueline T. Balthazar Raúl G. Doyle Robert A. Nicholas Afrin A. Begum Erica L. Raterman Ann E. Jerse William M. Shafer
author_facet	Corinne E. Rouquette-Loughlin Yaramah M. Zalucki Vijaya L. Dhulipala Jacqueline T. Balthazar Raúl G. Doyle Robert A. Nicholas Afrin A. Begum Erica L. Raterman Ann E. Jerse William M. Shafer
author_sort	Corinne E. Rouquette-Loughlin
title	Control of <italic toggle="yes">gdhR</italic> Expression in <italic toggle="yes">Neisseria gonorrhoeae</italic> via Autoregulation and a Master Repressor (MtrR) of a Drug Efflux Pump Operon
title_short	Control of <italic toggle="yes">gdhR</italic> Expression in <italic toggle="yes">Neisseria gonorrhoeae</italic> via Autoregulation and a Master Repressor (MtrR) of a Drug Efflux Pump Operon
title_full	Control of <italic toggle="yes">gdhR</italic> Expression in <italic toggle="yes">Neisseria gonorrhoeae</italic> via Autoregulation and a Master Repressor (MtrR) of a Drug Efflux Pump Operon
title_fullStr	Control of <italic toggle="yes">gdhR</italic> Expression in <italic toggle="yes">Neisseria gonorrhoeae</italic> via Autoregulation and a Master Repressor (MtrR) of a Drug Efflux Pump Operon
title_full_unstemmed	Control of <italic toggle="yes">gdhR</italic> Expression in <italic toggle="yes">Neisseria gonorrhoeae</italic> via Autoregulation and a Master Repressor (MtrR) of a Drug Efflux Pump Operon
title_sort	control of <italic toggle="yes">gdhr</italic> expression in <italic toggle="yes">neisseria gonorrhoeae</italic> via autoregulation and a master repressor (mtrr) of a drug efflux pump operon
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/78a52acdff2b4e739aa56bb2bf870f78
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Control of <italic toggle="yes">gdhR</italic> Expression in <italic toggle="yes">Neisseria gonorrhoeae</italic> via Autoregulation and a Master Repressor (MtrR) of a Drug Efflux Pump Operon

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