ABSTRACT
A recombinant strain of Lactococcus lactis displaying a cell-surface anchored fibronectin binding protein A (FnBPA) from Staphylococcus aureus (LL-FnBPA) had been shown to be more efficient in delivering plasmid than its wild-type counterpart both in vitro and in vivo, and have the ability to orientate the immune response toward a Th2 profile in a context of a DNA vaccination. The aim of this work was to test whether this LL-FnBPA strain could shape the immune response after mucosal administration in mice. For this, we used a mouse model of human papilloma virus (HPV)-induced cancer and a L. lactis strain displaying at its cell surface both HPV-16-E7 antigen (LL-E7) and FnBPA (LL-E7+FnBPA). Our results revealed a more efficient systemic Th1 immune response with recombinant LL-E7+FnBPA. Furthermore, mice vaccinated with LL-E7+FnBPA were better protected when challenged with HPV-16-induced tumors. Altogether, the results suggest that FnBPA displays adjuvant properties when used in the context of mucosal delivery using L. lactis as a live vector.
Subject(s)
Adhesins, Bacterial/immunology , Cancer Vaccines/immunology , Lactococcus lactis , Papillomavirus E7 Proteins/immunology , Papillomavirus Infections/prevention & control , Animals , Caco-2 Cells , Cell Line, Tumor , Cell Surface Display Techniques , Female , Human papillomavirus 16 , Humans , Immunity, Cellular , Immunity, Humoral , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Plasmids , Staphylococcus aureus , T-Lymphocytes, Cytotoxic/immunology , Th1 Cells/immunologyABSTRACT
In recent years, recombinant lactic acid bacteria (LAB) have been successfully used as safe mucosal delivery vectors. Herein, we report on the development of a Stress-Inducible Controlled Expression (SICE) system in L. lactis for the production and delivery of proteins of health interest (both therapeutic and vaccine related) at mucosal surfaces. This system is episomal in nature and is composed of a vector carrying an expression cassette under the transcriptional control of a stress-inducible promoter. The functionality of the SICE system was validated in vivo using two different routes of administration: oral and intranasal, and in two different murine models of human pathologies: (i) a model of therapy against inflammatory bowel diseases (IBD) and (ii) a model of vaccination against human papillomavirus type-16 (HPV-16).
Subject(s)
Genetic Vectors , Inflammatory Bowel Diseases/drug therapy , Interleukin-10/administration & dosage , Interleukin-10/metabolism , Lactococcus lactis/genetics , Papillomavirus Infections/prevention & control , Papillomavirus Vaccines/administration & dosage , Administration, Oral , Administration, Rectal , Animals , Base Sequence , Disease Models, Animal , Female , Human papillomavirus 16/immunology , Humans , Interleukin-10/genetics , Interleukin-10/immunology , Lactococcus lactis/metabolism , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Mucous Membrane/metabolism , Organ Specificity , Papillomavirus Vaccines/genetics , Plasmids , Recombinant Proteins/genetics , Recombinant Proteins/therapeutic use , Reproducibility of Results , Stress, Physiological , Vaccines, SyntheticABSTRACT
Human papillomavirus (HPV) is the causative agent of cervical cancer (CxCa) and the most commonly sexually transmitted pathogen worldwide. HPV type 16 (HPV-16) E7 oncoprotein is constitutively produced in CxCa and considered as a good antigen candidate for the development of new therapeutic CxCa vaccines. Here, we report the use of non-genetically modified, E7-expressing lactic acid bacteria (LAB) by using the cell-binding domain from Lactobacillus casei A2 phage lysin as a cell wall anchor. The versatility of this system was validated by investigating E7 stability at the surface of Lactococcus lactis and L. casei, two major species of LAB. Moreover, we demonstrated the successful use of these LAB displaying E7 antigen as a mucosal live vaccine in mice. Altogether, these results show the feasibility of using non-genetically modified LAB for low-cost mucosal immunotherapy against HPV-related CxCa in humans.
