2 research outputs found
A bacterium from the human microbiota as a vaccine vector. Efficient priming of the murine immune system by vaginal delivery of recombinant Streptococcus gordonii
No full textThe ability to prime the immune system against an antigen, and to rapidly recall this response upon antigen reencounter is a fundamental characteristic of the adaptive immune response. The association of an antigen recognized by the immune system in a certain tissue, with the same antigen encountered at a later timepoint in a different tissue, is of primary importance to obtain a systemic and effective immune response and is the foundation behind the utilization of vaccines. The study of vaccine delivery platforms that may activate the immune system in such a manner is therefore of primary importance in the effort to design novel vaccine formulation and prime-boost strategies.
The aim of the present work was to study the in vivo priming effect induced by a recombinant Streptococcus gordonii vaccine vector expressing a heterologous antigen and delivered to the vaginal tract, a unique mucosal tissue.
To study the priming effect induced by the recombinant Streptococcus gordonii, we employed a prime-boost strategy and compared the cellular an humoral immune response towards the soluble antigen between recombinant- and WT-immunized mice. Using this model, we show that vaginal immunization with the recombinant Streptococcus gordonii elicited systemic production of antigen-specific antibodies, shifted the IgG subclasses profile, led to an increase in plasma cells in the lymph nodes, a higher number of antigen-specific antibody-secreting cells in the spleen and modulated the cytokine expression profile of splenocytes. The longevity of the priming effect induced by the recombinant vector was also analyzed by comparing three and six months boosting schedules. We found that the priming is boostable with a similar efficacy for at least six months (Chapter 3). These data demonstrate that vaginal priming with the recombinant S. gordonii vector results in a systemic activation of both cellular and humoral immune compartments, and that this priming effect is long-lived without significant immune waning.
In this study, we also assessed the transcriptomic response of splenocytes from S. gordonii-immunized mice towards the antigen. We observed differences in immune pathways between recombinant- and WT-immunized mice, and also between the three- and six-months boosted groups (Chapter 4). In addition, we observed a gene signature correlated with antigen-specific IgG titers. These findings suggest that the immune system’s encounter with the antigen on the surface of the recombinant S. gordonii in the vaginal tract results in a differential immune activation in in response to the antigen.
This work contributes to the knowledge on the capability of recombinant live vaccine vectors delivered mucosally to prime and modulate the immune response, and has important implications in the design of innovative vaccination strategies
Astrocyte immunometabolic regulation of the tumour microenvironment drives glioblastoma pathogenicity
No full textAbstract
Malignant brain tumours are the cause of a disproportionate level of morbidity and mortality among cancer patients, an unfortunate statistic that has remained constant for decades. Despite considerable advances in the molecular characterization of these tumours, targeting the cancer cells has yet to produce significant advances in treatment. An alternative strategy is to target cells in the glioblastoma microenvironment, such as tumour-associated astrocytes. Astrocytes control multiple processes in health and disease, ranging from maintaining the brain’s metabolic homeostasis, to modulating neuroinflammation. However, their role in glioblastoma pathogenicity is not well understood. Here we report that depletion of reactive astrocytes regresses glioblastoma and prolongs mouse survival. Analysis of the tumour-associated astrocyte translatome revealed astrocytes initiate transcriptional programmes that shape the immune and metabolic compartments in the glioma microenvironment. Specifically, their expression of CCL2 and CSF1 governs the recruitment of tumour-associated macrophages and promotes a pro-tumourigenic macrophage phenotype. Concomitantly, we demonstrate that astrocyte-derived cholesterol is key to glioma cell survival, and that targeting astrocytic cholesterol efflux, via ABCA1, halts tumour progression. In summary, astrocytes control glioblastoma pathogenicity by reprogramming the immunological properties of the tumour microenvironment and supporting the non-oncogenic metabolic dependency of glioblastoma on cholesterol. These findings suggest that targeting astrocyte immunometabolic signalling may be useful in treating this uniformly lethal brain tumour.</jats:p
