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Infection and Immunity, March 2009, p. 1071-1082, Vol. 77, No. 3
0019-9567/09/$08.00+0 doi:10.1128/IAI.00693-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Salmonella enterica Serovar Typhimurium Strains with Regulated Delayed Attenuation In Vivo
Roy Curtiss III,1*
Soo-Young Wanda,1
Bronwyn M. Gunn,1,
Xin Zhang,2,
Steven A. Tinge,3
Vidya Ananthnarayan,1
Hua Mo,1
Shifeng Wang,1 and
Wei Kong1
Center for Infectious Diseases and Vaccinology, Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, Arizona 85287-5401,1 Department of Biology, Washington University, St. Louis, Missouri 63130,2 Avant Immunotherapeutics, Inc., 8620 Pennell Drive, Overland, Missouri 631143
Received 2 June 2008/ Returned for modification 31 July 2008/ Accepted 8 December 2008
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 PBAD 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.
* Corresponding author. Mailing address: Biodesign Institute, Arizona State University, P.O. Box 875401, Tempe, AZ 85287-5401. Phone: (480) 727-0445. Fax: (480) 727-0466. E-mail: rcurtiss{at}asu.edu
Published ahead of print on 22 December 2008.
Present address: Department of Microbiology, University of North Carolina, Chapel Hill, NC.
Present address: Department of Pathology, Washington University, St. Louis, MO 63108.
Infection and Immunity, March 2009, p. 1071-1082, Vol. 77, No. 3
0019-9567/09/$08.00+0 doi:10.1128/IAI.00693-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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