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Immunogenicity against Human Papillomavirus Type 16 Virus-Like Particles Is Strongly Enhanced by the PhoP^c Phenotype in Salmonella enterica Serovar Typhimurium

Department of Gynaecology, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne,¹ Department of Genetics and Microbiology, Centre Medical Universitaire, CH-1200 Geneva, Switzerland,² Department of Biology, Washington University, St. Louis, Missouri 63130³

Received 14 August 2003/ Returned for modification 25 September 2003/ Accepted 12 November 2003

Recombinant Salmonella strains have been widely used to deliver heterologous antigens and induce immune responses in vaccinated animals and humans. It remains to be established, however, how these bacteria mount an immune response; this has prevented the rational design of vaccines. Here we report for the first time that a particular genetic program, PhoP^c, is necessary for recombinant Salmonella strains to induce an antibody response to a heterologous antigen, the human papillomaviruses type 16 (HPV16) virus-like particle (VLP). The PhoP^c phenotype results from a point mutation in phoQ, the gene encoding the sensor component of a two-component regulatory system (PhoP-PhoQ) that controls the expression of a number of virulence factors in Salmonellae. To demonstrate that immunogenicity of the viral antigen expressed by the bacterial vector was dependent on the PhoP^c phenotype, we have expressed the phoQ mutant gene (phoQ24) in two differently attenuated Salmonella enterica serovar Typhimurium strains. Our data show extrachromosomal phoQ24 to be dominant over the chromosomal copy of the phoQ gene, conferring the PhoP^c phenotype on the recipient strains. In addition, activation of PhoPQ-regulated genes by the plasmid-encoded PhoQ24 did not alter bacterial survival and conferred immunogenicity to the HPV16 VLP expressed in the two S. enterica serovar Typhimurium backgrounds, inducing the production of HPV-specific antibodies in mice. This strongly suggests that at least one of the PhoP-regulated genes is necessary for mounting an efficient antibody response to HPV16 VLP. This finding sets the stage for further development of a Salmonella-based vaccine against HPV infection and cervical cancer.

Editor: B. B. Finlay

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