ABSTRACT
Attenuated enteropathogenic yersiniae that translocate heterologous antigens into the cytosol of antigen presenting cells via their type three secretion system (TTSS) are considered promising candidates for the development of live oral vaccine carrier strains that induce CD8 T cell responses. Wild type Yersinia enterocolitica of serotype O:8 however efficiently suppresses the immune response of the host by translocating effector proteins called Yersinia outer proteins (Yops) into the cytosol of immune cells. We therefore tested immunogenicity, protective efficacy, and virulence ofyop mutants that translocate the model antigen Listeriolysin (LLO) of Listeria monocytogenes in a mouse model. A deltayopP mutant-based vaccine carrier strain induced the highest numbers of LLO91-99-specific CD8 T cells and effectively protected mice against a lethal challenge with Listeria whereas deltayopPT, deltayopPV(K42Q), and deltayopPO mutants of Y. enterocolitica induced fewer CD8 T cells and conferred only partial protection. The deltayopPH, deltayopPE, deltayopPM, and deltayopPQ mutants induced the weakest CD8 T cell response and did not significantly protect mice against Listeria presumably due to the strong attenuation of these strains in the mouse model. Even though a Y. enterocolitica strain WA-C(pTTSS), which translocated only LLO (but not Yops), induced superior MHC class I-restricted antigen presentation in DC compared to the deltayopP mutants in vitro, this strain was not able to significantly colonize mouse tissue or to induce CD8 T cell responses in vivo. The success in designing a Yersinia oral vaccine carrier is therefore dependent to a great extent on the subtle balance between immunogenicity and attenuation.
Subject(s)
Bacterial Proteins/immunology , Bacterial Vaccines/immunology , Listeria monocytogenes/immunology , Listeriosis/prevention & control , Yersinia enterocolitica/immunology , Animals , Antigen Presentation , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Female , Gene Knockout Techniques , Listeriosis/immunology , Mice , Mice, Inbred BALB C , Vaccines, Attenuated/immunology , Yersinia enterocolitica/geneticsABSTRACT
Attenuated enteropathogenic Yersinia strains are attractive candidates for the development of oral live carrier vaccines. Yersiniae colonize the small intestine and invade lymphoid tissue of the terminal ileum where they replicate extracellularly. Yersiniae can be engineered to secrete or translocate heterologous antigens into the cytosol of antigen-presenting cells by their type 3 secretion system (T3SS). This results in the induction of both cellular and humoral immune responses to heterologous antigens of viral, bacterial and parasitic origin. In this review, we summarize the progress in developing Yersinia-based vaccine carrier strains by mutating the T3SS effector proteins of Yersinia called Yops (Yersinia outer proteins) to both attenuate the strains and to modulate the T-cell response.
