Salmonella Synthesizing 1-Monophosphorylated Lipopolysaccharide Exhibits Low Endotoxic Activity while Retaining Its Immunogenicity

• Published in: The Journal of immunology (1950) 2011-07, Vol.187 (1), p.412-423
• Main Authors: Kong, Qingke, Six, David A., Roland, Kenneth L., Liu, Qing, Gu, Lillian, Reynolds, C. Michael, Wang, Xiaoyuan, Raetz, Christian R. H., Curtiss, Roy
• Format: Article
• Language: English
• Subjects: Francisella tularensis; Salmonella; Streptococcus pneumoniae
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1100339

The development of safe live, attenuated Salmonella vaccines may be facilitated by detoxification of its LPS. Recent characterization of the lipid A 1-phosphatase, LpxE, from Francisella tularensis allowed us to construct recombinant, plasmid-free strains of Salmonella that produce predominantly 1-dephosphorylated lipid A, similar to the adjuvant approved for human use. Complete lipid A 1-dephosphorylation was also confirmed under low pH, low Mg2+ culture conditions, which induce lipid A modifications. lpxE expression in Salmonella reduced its virulence in mice by five orders of magnitude. Moreover, mice inoculated with these detoxified strains were protected against wild-type challenge. Candidate Salmonella vaccine strains synthesizing pneumococcal surface protein A (PspA) were also confirmed to possess nearly complete lipid A 1-dephosphorylation. After inoculation by the LpxE/PspA strains, mice produced robust levels of anti-PspA Abs and showed significantly improved survival against challenge with wild-type Streptococcus pneumoniae WU2 compared with vector-only–immunized mice, validating Salmonella synthesizing 1-dephosphorylated lipid A as an Ag-delivery system.