Conversion of RpoS<sup>−</sup> Attenuated <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhi Vaccine Strains to RpoS<sup>+</sup> Improves Their Resistance to Host Defense Barriers

ABSTRACT The vast majority of live attenuated typhoid vaccines are constructed from the Salmonella enterica serovar Typhi strain Ty2, which is devoid of a functioning alternative sigma factor, RpoS, due to the presence of a frameshift mutation. RpoS is a specialized sigma factor that plays an import...

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Autores principales:	Whittney N. Burda, Karen E. Brenneman, Amanda Gonzales, Roy Curtiss
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	RASV RpoS S. Typhi vaccines Salmonella recombinant Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c1993bec9cbd489da77b1ebb59e7ebb9
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spelling	oai:doaj.org-article:c1993bec9cbd489da77b1ebb59e7ebb92021-11-15T15:22:01ZConversion of RpoS<sup>−</sup> Attenuated <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhi Vaccine Strains to RpoS<sup>+</sup> Improves Their Resistance to Host Defense Barriers10.1128/mSphere.00006-182379-5042https://doaj.org/article/c1993bec9cbd489da77b1ebb59e7ebb92018-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00006-18https://doaj.org/toc/2379-5042ABSTRACT The vast majority of live attenuated typhoid vaccines are constructed from the Salmonella enterica serovar Typhi strain Ty2, which is devoid of a functioning alternative sigma factor, RpoS, due to the presence of a frameshift mutation. RpoS is a specialized sigma factor that plays an important role in the general stress response of a number of Gram-negative organisms, including Salmonella. Previous studies have demonstrated that this sigma factor is necessary for survival following exposure to acid, hydrogen peroxide, nutrient-limiting conditions, and starvation. In addition, studies with Salmonella enterica serovar Typhimurium and the mouse model of typhoid fever have shown that RpoS is important in colonization and survival within the infected murine host. We converted 4 clinically studied candidate typhoid vaccine strains derived from Ty2 [CVD908-htrA, Ty800, and χ9639(pYA3493)] and the licensed live typhoid vaccine Ty21a (also derived from Ty2) to RpoS+ and compared their abilities to withstand environmental stresses that may be encountered within the host to those of the RpoS− parent strains. The results of our study indicate that strains that contain a functional RpoS were better able to survive following stress and that they would be ideal for further development as safe, effective vaccines to prevent S. Typhi infections or as vectors in recombinant attenuated Salmonella vaccines (RASVs) designed to protect against other infectious disease agents in humans. The S. Typhi strains constructed and described here will be made freely available upon request, as will the suicide vector used to convert rpoS mutants to RpoS+. IMPORTANCE Recombinant attenuated Salmonella vaccines (RASVs) represent a unique prevention strategy to combating infectious disease because they utilize the ability of Salmonella to invade and colonize deep effector lymphoid tissues and deliver hetero- and homologous derived antigens at the lowest immunizing dose. Our recent clinical trial in human volunteers indicated that an RpoS+ derivative of Ty2 was better at inducing immune responses than its RpoS− counterpart. In this study, we demonstrate that a functional RpoS allele is beneficial for developing effective live attenuated vaccines against S. Typhi or in using S. Typhi as a recombinant attenuated vaccine vector to deliver other protective antigens.Whittney N. BurdaKaren E. BrennemanAmanda GonzalesRoy CurtissAmerican Society for MicrobiologyarticleRASVRpoSS. Typhi vaccinesSalmonellarecombinantMicrobiologyQR1-502ENmSphere, Vol 3, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	RASV RpoS S. Typhi vaccines Salmonella recombinant Microbiology QR1-502
spellingShingle	RASV RpoS S. Typhi vaccines Salmonella recombinant Microbiology QR1-502 Whittney N. Burda Karen E. Brenneman Amanda Gonzales Roy Curtiss Conversion of RpoS<sup>−</sup> Attenuated <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhi Vaccine Strains to RpoS<sup>+</sup> Improves Their Resistance to Host Defense Barriers
description	ABSTRACT The vast majority of live attenuated typhoid vaccines are constructed from the Salmonella enterica serovar Typhi strain Ty2, which is devoid of a functioning alternative sigma factor, RpoS, due to the presence of a frameshift mutation. RpoS is a specialized sigma factor that plays an important role in the general stress response of a number of Gram-negative organisms, including Salmonella. Previous studies have demonstrated that this sigma factor is necessary for survival following exposure to acid, hydrogen peroxide, nutrient-limiting conditions, and starvation. In addition, studies with Salmonella enterica serovar Typhimurium and the mouse model of typhoid fever have shown that RpoS is important in colonization and survival within the infected murine host. We converted 4 clinically studied candidate typhoid vaccine strains derived from Ty2 [CVD908-htrA, Ty800, and χ9639(pYA3493)] and the licensed live typhoid vaccine Ty21a (also derived from Ty2) to RpoS+ and compared their abilities to withstand environmental stresses that may be encountered within the host to those of the RpoS− parent strains. The results of our study indicate that strains that contain a functional RpoS were better able to survive following stress and that they would be ideal for further development as safe, effective vaccines to prevent S. Typhi infections or as vectors in recombinant attenuated Salmonella vaccines (RASVs) designed to protect against other infectious disease agents in humans. The S. Typhi strains constructed and described here will be made freely available upon request, as will the suicide vector used to convert rpoS mutants to RpoS+. IMPORTANCE Recombinant attenuated Salmonella vaccines (RASVs) represent a unique prevention strategy to combating infectious disease because they utilize the ability of Salmonella to invade and colonize deep effector lymphoid tissues and deliver hetero- and homologous derived antigens at the lowest immunizing dose. Our recent clinical trial in human volunteers indicated that an RpoS+ derivative of Ty2 was better at inducing immune responses than its RpoS− counterpart. In this study, we demonstrate that a functional RpoS allele is beneficial for developing effective live attenuated vaccines against S. Typhi or in using S. Typhi as a recombinant attenuated vaccine vector to deliver other protective antigens.
format	article
author	Whittney N. Burda Karen E. Brenneman Amanda Gonzales Roy Curtiss
author_facet	Whittney N. Burda Karen E. Brenneman Amanda Gonzales Roy Curtiss
author_sort	Whittney N. Burda
title	Conversion of RpoS<sup>−</sup> Attenuated <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhi Vaccine Strains to RpoS<sup>+</sup> Improves Their Resistance to Host Defense Barriers
title_short	Conversion of RpoS<sup>−</sup> Attenuated <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhi Vaccine Strains to RpoS<sup>+</sup> Improves Their Resistance to Host Defense Barriers
title_full	Conversion of RpoS<sup>−</sup> Attenuated <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhi Vaccine Strains to RpoS<sup>+</sup> Improves Their Resistance to Host Defense Barriers
title_fullStr	Conversion of RpoS<sup>−</sup> Attenuated <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhi Vaccine Strains to RpoS<sup>+</sup> Improves Their Resistance to Host Defense Barriers
title_full_unstemmed	Conversion of RpoS<sup>−</sup> Attenuated <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhi Vaccine Strains to RpoS<sup>+</sup> Improves Their Resistance to Host Defense Barriers
title_sort	conversion of rpos<sup>−</sup> attenuated <named-content content-type="genus-species">salmonella enterica</named-content> serovar typhi vaccine strains to rpos<sup>+</sup> improves their resistance to host defense barriers
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/c1993bec9cbd489da77b1ebb59e7ebb9
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Conversion of RpoS<sup>−</sup> Attenuated <named-content content-type="genus-species">Salmonella enterica</named-content> Serovar Typhi Vaccine Strains to RpoS<sup>+</sup> Improves Their Resistance to Host Defense Barriers

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