Immunogenicity against Human Papillomavirus Type 16 Virus-Like Particles Is Strongly Enhanced by the PhoPcPhenotype inSalmonella entericaSerovar Typhimurium

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Abstract
RecombinantSalmonellastrains 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, PhoPc, is necessary for recombinantSalmonellastrains to induce an antibody response to a heterologous antigen, the human papillomaviruses type 16 (HPV16) virus-like particle (VLP). The PhoPcphenotype results from a point mutation inphoQ, 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 PhoPcphenotype, we have expressed thephoQmutant gene (phoQ24) in two differently attenuatedSalmonella entericaserovar Typhimurium strains. Our data show extrachromosomalphoQ24to be dominant over the chromosomal copy of thephoQgene, conferring the PhoPcphenotype 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 twoS. entericaserovar 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 aSalmonella-based vaccine against HPV infection and cervical cancer.

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