Deletion of an immune evasion gene, steD , from a live Salmonella enterica serovar Typhimurium vaccine improves vaccine responses in aged mice.

Autor:	Allen JC; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States.; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States., Natta SS; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States.; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States., Nasrin S; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States.; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States., Toapanta FR; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States.; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States., Tennant SM; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States.; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Jun 07; Vol. 15, pp. 1376734. Date of Electronic Publication: 2024 Jun 07 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1376734
Abstrakt:	Introduction: Non-typhoidal Salmonella (NTS) generally causes self-limiting gastroenteritis. However, older adults (≥65 years) can experience more severe outcomes from NTS infection. We have previously shown that a live attenuated S . Typhimurium vaccine, CVD 1926 (I77 Δ guaBA Δ clpP Δ pipA Δ htrA ), was immunogenic in adult but not aged mice. Here we describe modification of CVD 1926 through deletion of steD , a Salmonella effector responsible for host immune escape, which we hypothesized would increase immunogenicity in aged mice. Methods: Mel Juso and/or mutuDC cells were infected with S . Typhimurium I77, CVD 1926, and their respective steD mutants, and the MHC-II levels were evaluated. Aged (18-month-old) C57BL/6 mice received two doses of PBS, CVD 1926, or CVD 1926 Δ steD perorally (10 9 CFU) and the number of FliC-specific CD4 + T cells were determined. Lastly, aged C57BL/6 mice received three doses of PBS, CVD 1926, or CVD 1926 Δ steD perorally (10 9 CFU) and then were challenged perorally with wild-type S . Typhimurium SL1344 (10 8 CFU). These animals were also evaluated for antibody responses. Results: MHC-II induction was higher in cells treated with steD mutants, compared to their respective parental strains. Compared to PBS-vaccinated mice, CVD 1926 Δ steD elicited significantly more FliC-specific CD4 + T cells in the Peyer's Patches. There were no significant differences in FliC-specific CD4 + T cells in the Peyer's patches or spleen of CVD 1926- versus PBS-immunized mice. CVD 1926 and CVD 1926 Δ steD induced similar serum and fecal anti-core and O polysaccharide antibody titers after three doses. After two immunizations, the proportion of seroconverters for CVD 1926 Δ steD was 83% (10/12) compared to 42% (5/12) for CVD 1926. Compared to PBS-immunized mice, mice immunized with CVD 1926 Δ steD had significantly lower S . Typhimurium counts in the spleen, cecum, and small intestine upon challenge. In contrast, there were no differences in bacterial loads in the tissues of PBS-vaccinated and CVD 1926-immunized animals. Conclusion: These data suggest that the steD deletion enhanced the immunogenicity of our live attenuated S . Typhimurium vaccine. Deletion of immune evasion genes could be a potential strategy to improve the immunogenicity of live attenuated vaccines in older adults. Competing Interests: ST is a holder of the following patents that describe development of NTS vaccines: US patent 9,050,283, “Broad spectrum vaccine against non-typhoidal Salmonella”; US patent 9,011,871, “Broad spectrum vaccine against typhoidal and non-typhoidal Salmonella disease”; and European Patent Number 2387417, “Broad spectrum vaccine against non-typhoidal Salmonella”. JC, FT and ST are inventors for “Composition and methods for making a Salmonella Immune Modulation (SIM) vaccine” (patent pending). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Allen, Natta, Nasrin, Toapanta and Tennant.)
Databáze:	MEDLINE
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