Antigen localization influences the magnitude and kinetics of endogenous adaptive immune response to recombinant Salmonella vaccines

Yanina R. Sevastsyanovich*, David R. Withers, Claire L. Marriott, Faye C. Morris, Timothy J. Wells, Douglas F. Browning, Irene Beriotto, Ewan Ross, Hossam Omar Ali, Catherine A. Wardius, Adam F. Cunningham, Ian R. Henderson, Amanda E. Rossiter

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

The use of recombinant attenuated Salmonella vaccine (RASV) strains is a promising strategy for presenting heterologous antigens to the mammalian immune system to induce both cellular and humoral immune responses. However, studies on RASV development differ on where heterologous antigens are expressed and localized within the bacterium, and it is unclear how antigen localization modulates the immune response. Previously, we exploited the plasmid-encoded toxin (Pet) autotransporter system for accumulation of heterologous antigens in cell culture supernatant. In the present study, this Pet system was used to express early secretory antigen 6 (ESAT-6), an immunodominant and diagnostic antigen from Mycobacterium tuberculosis, in Salmonella enterica serovar Typhimurium strain SL3261. Three strains were generated, whereby ESAT-6 was expressed as a cytoplasmic (SL3261/cyto), surface-bound (SL3261/surf), or secreted (SL3261/sec) antigen. Using these RASVs, the relationship between antigen localization and immunogenicity in infected C57BL/6 mice was systematically examined. Using purified antigen and specific tetramers, we showed that mice infected with the SL3261/surf or SL3261/sec strain generated large numbers of Th1 CD4+ ESAT-6+ splenic T cells compared to those of mice infected with SL3261/cyto. While all mice showed ESAT-6-specific antibody responses when infected with SL3261/surf or SL3261/sec, peak total serum IgG antibody titers were reached more rapidly in mice that received SL3261/sec. Thus, how antigen is localized after production within bacteria has a more marked effect on the antibody response than on the CD4+ T cell response, which might influence the chosen strategy to localize recombinant antigen in RASVs.

Original languageEnglish
Article numbere00593-17
JournalInfection and Immunity
Volume85
Issue number12
DOIs
Publication statusPublished - 17 Nov 2017

Bibliographical note

© Crown copyright 2017.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords

  • Autotransporter proteins
  • Salmonella
  • Vaccines

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