Progress on Listeria Monocytogenes as a Live Vaccine Vector
0
Citation
0
Reference
20
Related Paper
Abstract:
L.monocytogenes is a gram-positive,facultative intracellular bacterium that escapes the phagoly- sosome of host target cells,replicates in the cytosol,and efficiently presents both the class I MHC pathway of endogenous antigen and the classⅡpathway of exogenous antigen.The host's response to L. monocytogenes has been studied for more than 40 years.L.monocytogenes stimulates the innate immune re- sponse to produce cytokines that enhance antigen-presenting function and induce a Th1-type cytokine pro- file associated with cell-mediated immune responses.The natural route of infection by L.monocytogenes is at the mueosa upon oral ingestion,and targeted cells during infection include dendritic cells and macropha- ges.As a vector,foreign genes can be stably inserted into the L.monocytogenes genome and be expressed at high levels into the cytoplasm of host cells for processing and presentation by the major histocompatibility complex classⅠpathway.In this review,the development of methods to transform L.monocytogenes to ex- press and secrete foreign antigens,and the studies that demonstrate genetically engineered L. monocytogenes mutants as highly effective vectors for the induction of potent immune responses against vi- ral antigens and tumor cells were summarized.Keywords:
Intracellular parasite
Antigen processing
Cite
Intracellular parasite
Listeriolysin O
Cite
Citations (32)
IL-12 is a pivotal cytokine signal for the development of Th1-type cellular responses that are required for control of intracellular pathogens. We previously demonstrated that coinjection of IL-12 with heat-killed Listeria monocytogenes, which was not immunogenic when injected alone, elicited intense Ag-specific T cell responses that conferred protection against subsequent challenge with Listeria. Herein we describe the remarkable finding that a nonimmunogenic synthetic peptide corresponding to a dominant MHC class II (H-2k)-restricted listerial determinant, when coinjected i.p. with murine IL-12, elicited potent Ag-specific immune responses that conferred protective immunity against Listeria.
Intracellular parasite
Cellular immunity
Cite
Citations (22)
CTL*
Priming (agriculture)
Cite
Citations (211)
Vaccine strategies that utilize human DCs to enhance antitumor immunity have yet to realize their full potential. Approaches that optimally target a spectrum of antigens to DCs are urgently needed. Here we report the development of a platform for loading DCs with antigen. It is based on killed but metabolically active (KBMA) recombinant Listeria monocytogenes and facilitates both antigen delivery and maturation of human DCs. Highly attenuated KBMA L. monocytogenes were engineered to express an epitope of the melanoma-associated antigen MelanA/Mart-1 that is recognized by human CD8+ T cells when presented by the MHC class I molecule HLA-A*0201. The engineered KBMA L. monocytogenes induced human DC upregulation of costimulatory molecules and secretion of pro-Th1 cytokines and type I interferons, leading to effective priming of Mart-1–specific human CD8+ T cells and lysis of patient-derived melanoma cells. KBMA L. monocytogenes expressing full-length NY-ESO-1 protein, another melanoma-associated antigen, delivered the antigen for presentation by MHC class I and class II molecules independent of the MHC haplotype of the DC donor. A mouse therapeutic tumor model was used to show that KBMA L. monocytogenes efficiently targeted APCs in vivo to induce protective antitumor responses. Together, our data demonstrate that KBMA L. monocytogenes may be a powerful platform that can both deliver recombinant antigen to DCs for presentation and provide a potent DC-maturation stimulus, making it a potential cancer vaccine candidate.
Cancer Immunotherapy
Cite
Citations (35)
Replicating attenuated strains of intracellular bacteria like Salmonella typhimurium, Listeria monocytogenes or Mycobacterium bovis Bacille Calmette Guérin (BCG), and non-replicating virus-like-particles (VLP) consisting, for instance, of the VP1-surface component of polyoma virus offer great potential as heterologous carriers delivering foreign protein antigens for immune recognition. Moreover, attenuated S.typhimurium and L.monocytogenes strains hold also great promise as delivery vehicles for DNA vaccines. Polyoma virus-specific VLP consisting of VP1- pentamers are also of interest as carrier devices for eukaryotic expression plasmids. At first sight these different replicating and non-replicating types of vehicles have little in common, but from an immunological point of view viable bacteria and non-viable VLP are both well suited for evoking protective immune responses via several routes of vaccine administration. As these antigen carriers generate humoral and cell-mediated immunity, the heterologous antigens are not only targeted to appropriate pathways of major histocompatibility (MHC) class I and class II antigen processing and presentation, but also generate an adequate cytokine milieu for promoting antigen-specific responses. The most prominent advantage of these carrier devices is presented by their capacity to directly target antigenic proteins or DNA vaccines to immature dendritic cells (DC) along their maturation pathway. Mature DC are the key antigen presenting cell population which efficiently mediates antigen transport to organised lymphoid tissues for the initiation of T cell responses. In general, uptake of these diverse antigen delivery systems by antigen presenting cells (APC) finally lead to efficacious immune responses in the control of pathogenic microorganisms and tumours.
Antigen processing
Cite
Citations (42)
Intracellular parasite
Naked DNA
Cite
Citations (4)
Listeria infection
Cite
Citations (12)
The development of T cell-based subunit protein vaccines against diseases such as tuberculosis and malaria remains a challenge for immunologists. Here, we have identified a nanoemulsion adjuvant, Adjuplex (ADJ), which enhanced dendritic cell (DC) cross-presentation and elicited effective memory T cell-based immunity to Listeria monocytogenes. We further evaluated whether cross-presentation induced by ADJ can be combined with the immunomodulatory effects of Toll-like receptor (TLR) agonists (CpG or glucopyranosyl lipid adjuvant [GLA]) to evoke systemic CD8 T cell-based immunity to L. monocytogenes. Mechanistically, vaccination with ADJ, alone or in combination with CpG or GLA, augmented activation and antigen uptake by CD103+ migratory and CD8α+ resident DCs and upregulated CD69 expression on B and T lymphocytes in vaccine-draining lymph nodes. By engaging basic leucine zipper ATF-like transcription factor 3-dependent cross-presenting DCs, ADJ potently elicited effector CD8 T cells that differentiated into granzyme B-expressing CD27LO effector-like memory CD8 T cells, which provided effective immunity to L. monocytogenes in the spleen and liver. CpG or GLA alone did not elicit effector-like memory CD8 T cells and induced moderate protection in the spleen but not in the liver. Surprisingly, combining CpG or GLA with ADJ reduced the number of ADJ-induced memory CD8 T cells and compromised protective immunity to L. monocytogenes, especially in the liver. Taken together, the data presented in this study provide a glimpse of protective CD8 T cell memory differentiation induced by a nanoemulsion adjuvant and demonstrate the unexpected negative effects of TLR signaling on the magnitude of CD8 T cell memory and protective immunity to L. monocytogenes, a model intracellular pathogen.
Cite
Citations (3)
Abstract Listeria monocytogenes has been proposed as a carrier to elicit major histocompatibility complex class‐I restricted immune responses able to protect against tumor challenge. In this study the properties of the attenuated L. monocytogenes Δmpl2 mutant has been evaluated in vivo against a highly aggressive mouse fibrosarcoma which expresses β‐galactosidase (β‐gal) as a tumor‐associated antigen (TAA). Immunization with the vaccine prototypes resulted in both elicitation of specific antibodies and generation of cytotoxic lymphocytes (CTL). Oral vaccination protected 55–64% of the immunized animals from tumor take ( p < 0.01) and strongly reduced the average size of the tumor in the other 34–45% ( p < 0.01). Vaccinated mice developed a long‐lasting response, which resulted in 100% protection from a subsequent tumor challenge. Substitution of the whole TAA by its CTL‐defined immunodominant epitope resulted in 43% protection, suggesting a contribution of the humoral response to the observed antitumor effect. No statistically significant differences were observed in the antitumor response when mice were immunized with strains expressing the immunodominant TAA epitope in the context of carrier proteins which were either exported or restricted to the bacterial cytoplasm. This suggests that the topology of the recombinant antigen does not play a major role in the outcome of the protective response.
CTL*
Cite
Citations (52)
CD8+ T cells (TCD8+) can mediate protective immunity to intracellular pathogens and tumours. Viruses generate strong TCD8+ responses and, therefore, represent attractive vectors for generating vaccines aimed at producing TCD8+-mediated protective immunity. This review will examine the immunological properties of viruses that make them good candidates as vaccine vectors, as well as the manipulations of both vector and antigen that may be required to produce an effective vaccine. The areas addressed include virus infection of dendritic cells in vivo, stimulation of the innate immune response via intracellular and extracellular pattern recognition receptors, the effect of antigenic form on the pathways of antigen presentation and the requirement for elimination of viral genes that target various aspects of the innate and adaptive immune response.
Cite
Citations (26)