Salmonella enterica serovar typhimurium strains with regulated delayed attenuation in vivo

Roy Curtiss, Soo Young Wanda, Bronwyn M. Gunn, Xin Zhang, Steven A. Tinge, Vidya Ananthnarayan, Hua Mo, Shifeng Wang, Wei Kong

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

Recombinant bacterial vaccines must be fully attenuated for animal or human hosts to avoid inducing disease symptoms while exhibiting a high degree of immunogenicity. Unfortunately, many well-studied means for attenuating Salmonella render strains more susceptible to host defense stresses encountered following oral vaccination than wild-type virulent strains and/or impair their ability to effectively colonize the gut-associated and internal lymphoid tissues. This thus impairs the ability of recombinant vaccines to serve as factories to produce recombinant antigens to induce the desired protective immunity. To address these problems, we designed strains that display features of wild-type virulent strains of Salmonella at the time of immunization to enable strains first to effectively colonize lymphoid tissues and then to exhibit a regulated delayed attenuation in vivo to preclude inducing disease symptoms. We recently described one means to achieve this based on a reversible smooth-rough synthesis of lipopolysaccharide O antigen. We report here a second means to achieve regulated delayed attenuation in vivo that is based on the substitution of a tightly regulated araC P BAD cassette for the promoters of the fur, crp, phoPQ, and rpoS genes such that expression of these genes is dependent on arabinose provided during growth. Thus, following colonization of lymphoid tissues, the Fur, Crp, PhoPQ, and/or RpoS proteins cease to be synthesized due to the absence of arabinose such that attenuation is gradually manifest in vivo to preclude induction of diseases symptoms. Means for achieving regulated delayed attenuation can be combined with other mutations, which together may yield safe efficacious recombinant attenuated Salmonella vaccines.

Original languageEnglish (US)
Pages (from-to)1071-1082
Number of pages12
JournalInfection and Immunity
Volume77
Issue number3
DOIs
StatePublished - Mar 2009

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Synthetic Vaccines
Salmonella enterica
Lymphoid Tissue
Arabinose
Salmonella
Salmonella Vaccines
Bacterial Vaccines
O Antigens
Attenuated Vaccines
Lipopolysaccharides
Immunity
Immunization
Vaccination
Gene Expression
Antigens
Mutation
Growth
Genes
Serogroup
Proteins

ASJC Scopus subject areas

  • Immunology
  • Microbiology
  • Parasitology
  • Infectious Diseases

Cite this

Curtiss, R., Wanda, S. Y., Gunn, B. M., Zhang, X., Tinge, S. A., Ananthnarayan, V., ... Kong, W. (2009). Salmonella enterica serovar typhimurium strains with regulated delayed attenuation in vivo. Infection and Immunity, 77(3), 1071-1082. https://doi.org/10.1128/IAI.00693-08

Salmonella enterica serovar typhimurium strains with regulated delayed attenuation in vivo. / Curtiss, Roy; Wanda, Soo Young; Gunn, Bronwyn M.; Zhang, Xin; Tinge, Steven A.; Ananthnarayan, Vidya; Mo, Hua; Wang, Shifeng; Kong, Wei.

In: Infection and Immunity, Vol. 77, No. 3, 03.2009, p. 1071-1082.

Research output: Contribution to journalArticle

Curtiss, R, Wanda, SY, Gunn, BM, Zhang, X, Tinge, SA, Ananthnarayan, V, Mo, H, Wang, S & Kong, W 2009, 'Salmonella enterica serovar typhimurium strains with regulated delayed attenuation in vivo', Infection and Immunity, vol. 77, no. 3, pp. 1071-1082. https://doi.org/10.1128/IAI.00693-08
Curtiss R, Wanda SY, Gunn BM, Zhang X, Tinge SA, Ananthnarayan V et al. Salmonella enterica serovar typhimurium strains with regulated delayed attenuation in vivo. Infection and Immunity. 2009 Mar;77(3):1071-1082. https://doi.org/10.1128/IAI.00693-08
Curtiss, Roy ; Wanda, Soo Young ; Gunn, Bronwyn M. ; Zhang, Xin ; Tinge, Steven A. ; Ananthnarayan, Vidya ; Mo, Hua ; Wang, Shifeng ; Kong, Wei. / Salmonella enterica serovar typhimurium strains with regulated delayed attenuation in vivo. In: Infection and Immunity. 2009 ; Vol. 77, No. 3. pp. 1071-1082.
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