5 years ago

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

The use of recombinant attenuated Salmonella vaccine (RASV) strains is a promising strategy to present heterologous antigens to the mammalian immune system to induce both cellular and humoral immune responses. However, studies on RASV development differ in where heterologous antigens are expressed and localised within the bacterium and it is unclear how antigen localisation modulates the immune response. Previously, we exploited the plasmid-encoded toxin (Pet) autotransporter system for accumulation of heterologous antigens in the cell culture supernatant. Here, 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 antigen (SL3261/sec). Using these RASVs, the relationship between antigen localisation and immunogenicity in infected C57BL/6 mice was systematically compared. Using purified antigen and specific tetramers we show that mice infected with the SL3261/surf or SL3261/sec strains generated high numbers of Th1 CD4(+) ESAT-6(+) splenic T cells compared to mice infected with SL3261/cyto. While all mice induced ESAT-6-specific antibody responses when infected with SL3261/surf or SL3261/sec, peak total serum IgG antibody titres were reached more rapidly in mice that received SL3261/sec. Thus, how antigen is localised after production within the bacteria has a more marked effect on the antibody response rather than the CD4(+) T cell response, which might influence the chosen strategy to localise recombinant antigen in RASVs.

Publisher URL: http://doi.org/10.1128/IAI.00593-17

DOI: 10.1128/IAI.00593-17

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