AUTHOR=Li Pei , Liu Qing , Luo Hongyan , Liang Kang , Yi Jie , Luo Ying , Hu Yunlong , Han Yue , Kong Qingke 

TITLE=O-Serotype Conversion in Salmonella Typhimurium Induces Protective Immune Responses against Invasive Non-Typhoidal Salmonella Infections

JOURNAL=Frontiers in Immunology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.01647

DOI=10.3389/fimmu.2017.01647

ISSN=1664-3224

ABSTRACT=<p><italic>Salmonella</italic> infections remain a big problem worldwide, causing enteric fever by <italic>Salmonella</italic> Typhi (or Paratyphi) or self-limiting gastroenteritis by non-typhoidal <italic>Salmonella</italic> (NTS) in healthy individuals. NTS may become invasive and cause septicemia in elderly or immuno-compromised individuals, leading to high mortality and morbidity. No vaccines are currently available for preventing NTS infection in human. As these invasive NTS are restricted to several O-antigen serogroups including B1, D1, C1, and C2, O-antigen polysaccharide is believed to be a good target for vaccine development. In this study, a strategy of O-serotype conversion was investigated to develop live attenuated <italic>S</italic>. Typhimurium vaccines against the major serovars of NTS infections. The immunodominant O4 serotype of <italic>S</italic>. Typhimurium was converted into O9, O7, and O8 serotypes through unmarked chromosomal deletion–insertion mutations. O-serotype conversion was confirmed by LPS silver staining and western blotting. All O-serotype conversion mutations were successfully introduced into the live attenuated <italic>S</italic>. Typhimurium vaccine S738 (Δ<italic>crp</italic> Δ<italic>cya</italic>) to evaluate their immunogenicity in mice model. The vaccine candidates induced high amounts of heterologous O-polysaccharide-specific functional IgG responses. Vaccinated mice survived a challenge of 100 times the 50% lethality dose (LD<sub>50</sub>) of wild-type <italic>S</italic>. Typhimurium. Protective efficacy against heterologous virulent <italic>Salmonella</italic> challenges was highly O-serotype related. Furthermore, broad-spectrum protection against <italic>S</italic>. Typhimurium, <italic>S</italic>. Enteritidis, and <italic>S</italic>. Choleraesuis was observed by co-vaccination of O9 and O7 O-serotype-converted vaccine candidates. This study highlights the strategy of expressing heterologous O-polysaccharides <italic>via</italic> genetic engineering in developing live attenuated <italic>S</italic>. Typhimurium vaccines against NTS infections.</p>