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Mucosal Vaccination with Lactococcus lactis-Secreting Surface Immunological Protein Induces Humoral and Cellular Immune Protection against Group B Streptococcus in a Murine Model
(2020)
Diego A. Diaz-Dinamarca
;
Carlos Hernandez
;
Daniel F. Escobar
;
Daniel A. Soto
;
Guillermo A. Muñoz
<jats:p>Group B Streptococcus (GBS) is the primary etiological agent of sepsis and meningitis in newborns and is associated with premature birth and stillbirth. The development of a licensed vaccine is one of the pending challenges for the World Health Organization. Previously, we showed that oral immunization with surface immune protein (SIP) decreases vaginal colonization of GBS and generates functional opsonizing antibodies, which was determined by opsonophagocytic assays (OPA) in vitro. We also showed that the protein has an adjuvant vaccine profile. Therefore, an oral vaccine based on SIP may be an attractive alternative to employ in the development of new vaccines against GBS. Lactococcus lactis is a highlighted oral vaccine probiotic inducer of the mucosal immune response. This bacterium could serve as an antigen-delivering vehicle for the development of an edible vaccine and has been used in clinical trials. In this study, we showed that an oral vaccine with a recombinant L. lactis strain secreting SIP from GBS (rL. lactis-SIP) can induce protective humoral and cellular immunity in an experimental model of GBS vaginal colonization in C57BL/6 mice. Mice immunized with rL. lactis-SIP were protected against clinical symptoms and bacterial colonization after GBS vaginal colonization. Our rL. lactis-SIP vaccine also induces an increase of immunoglobulin G (IgG) and immunoglobulin A (IgA) specifically against SIP. The adoptive transfer of serum from vaccinated mice to naïve mice generated protection against GBS vaginal colonization. Moreover, the rL. lactis-SIP strain induces the activation of SIP-specific T cells, which could decrease GBS vaginal colonization and generate protective antibodies when transferred to other mice. Our experimental observations strongly support the notion that rL. lactis-SIP induces protective humoral and cellular immunity and could be considered as a novel alternative in the development of vaccines for GBS.</jats:p>
9Scopus© Citations 22
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Time-dependent LPS exposure commands MSC immunoplasticity through TLR4 activation leading to opposite therapeutic outcome in EAE
(2020)
Mónica Kurte
;
Ana María Vega-Letter
;
Patricia Luz-Crawford
;
Farida Djouad
;
Danièle Noël
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Mesenchymal stem cells (MSCs) have been recognized for their regenerative and anti-inflammatory capacity which makes them very attractive to cell therapy, especially those ones to treat inflammatory and autoimmune disease. Two different immune-phenotypes have been described for MSCs depending on which Toll-like receptor (TLR) is activated. MSC1 is endowed with a pro-inflammatory phenotype following TLR4 activation with LPS. On the other hand, anti-inflammatory MSC2 is induced by the activation of TLR3 with Poly(I:C). High immunoplasticity of MSCs is a matter of concern in cell-based therapies. In this study, we investigated whether a single stimulus can induce both types of MSCs through a differential activation of TLR4 with LPS.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>MSCs were activated with LPS following a short exposure of 1-h (MSCs-LPS1h) or long-time exposure for 48 h (MSCs-LPS48h), and then, we evaluated the biological response in vitro, the immunosuppressive capacity of MSCs in vitro, and the therapeutic potential of MSCs in an experimental autoimmune encephalomyelitis (EAE) mouse model.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Our results showed that 1-h LPS exposure induced a MSC1 phenotype. Indeed, MSCs-LPS1h expressed low levels of NO/iNOS and decreased immunosuppressive capacity in vitro without therapeutic effect in the EAE model. In contrast, MSCs-LPS48h achieved a MSC2-like phenotype with significant increase in the immunosuppressive capacity on T cell proliferation in vitro, together with an improved in the therapeutic effect and higher Treg, compared to unstimulated MSCs. Furthermore, we determine through the MSCs-TLR4KO that the expression of TLR4 receptor is essential for MSCs’ suppressive activity since TLR4 deletion was associated with a diminished suppressive effect in vitro and a loss of therapeutic effect in vivo.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>We demonstrate that MSCs display a high immunoplasticity commanded by a single stimulus, where LPS exposure time regulated the MSC suppressive effect leading into either an enhanced or an impairment therapeutic activity. Our results underscore the importance of phenotype conversion probably related to the TLR4 expression and activation, in the design of future clinical protocols to treat patients with inflammatory and autoimmune diseases.</jats:p> </jats:sec>
7Scopus© Citations 60
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Surface Immunogenic Protein of Streptococcus Group B is an Agonist of Toll-Like Receptors 2 and 4 and a Potential Immune Adjuvant
(2020)
Diego A. Diaz-Dinamarca
;
Ricardo A. Manzo
;
Daniel A. Soto
;
María José Avendaño-Valenzuela
;
Diego N. Bastias
<jats:p>Vaccine-induced protection against pathogens, especially subunit-based vaccines, are related to antigen properties but mainly in their ability to stimulate the immune system by the use of an adjuvant. Modern vaccines are formulated with a high level of antigen purity, where an efficient adjuvant is necessary. In this context, the use of protein Toll-Like Receptor (TLR) agonists as vaccine adjuvants has been highlighted because of their optimal immunogenicity and minimal toxicity. The Surface Immunogenic Protein (SIP) from Group B Streptococcus (GBS) has gained importance as a new potential protein-based vaccine. Recently, we reported that recombinant SIP (rSIP) expressed by E. coli and purified by High Performance Liquid Chromatography (HPLC) alone induces a protective humoral immune response. In this study, we present the immunomodulatory properties of rSIP as a protein-based adjuvant, as an agonist of TLR. To this end, we showed that C57BL/6 bone marrow-derived dendritic cells pulsed by rSIP resulted in enhanced CD40, CD80, CD86, and Major Histocompatibility Complex (MHC) class II as well as increased secretion proinflammatory cytokines Interleukin (IL)-6, Interferon (IFN)-γ, Tumor Necrosis Factor (TNF)-α, and IL-10. Next, we investigated the in vivo effect of rSIP in the absence or presence of ovalbumin (OVA) on antigen-specific antibody secretion in C57BL/6 mice. Immunization with rSIP plus OVA showed that anti-OVA IgG2a and IgG1a increased significantly compared with OVA alone in C57BL/6 mice. Also, the immunization of rSIP plus OVA generates increased serum cytokines levels characterized by IL-12p70, IL-10, IL-4, and IFN-γ. Interestingly, we observed that rSIP stimulate Toll Like Receptor (TLR)2 and TLR4, individually expressed by Human embryonic kidney (HEK) 293-derived TLR reporter cells. These findings suggest that rSIP is a new potential protein TLR agonist adjuvant and may be employed in the development of new vaccines.</jats:p>
7Scopus© Citations 8
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Epanorin, a lichen secondary metabolite, inhibits proliferation of MCF-7 breast cancer cells.
(2019)
Juan Palacios-Moreno
;
Cecilia Rubio
;
Wanda Quilhot
;
M. Fernanda Cavieres
;
Eduardo de la Peña
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Epanorin (EP) is a secondary metabolite of the <jats:italic>Acarospora</jats:italic> lichenic species. EP has been found in lichenic extracts with antimicrobial activity, and UV-absorption properties have been described for closely related molecules; however, its antiproliferative activity in cancer cells has not yet been explored. It has been hypothesized that EP inhibits cancer cell growth. MCF-7 breast cancer cells, normal fibroblasts, and the non-transformed HEK-293 cell line were exposed to increasing concentrations of EP, and proliferation was assessed by the sulforhodamine-B assay.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>MCF-7 cells exposed to EP were examined for cell cycle progression using flow cytometry, and DNA fragmentation was examined using the TUNEL assay. In addition, EP’s mutagenic activity was assessed using the <jats:italic>Salmonella typhimurium</jats:italic> reverse mutation assay. The data showed that EP inhibits proliferation of MCF-7 cells, and it induces cell cycle arrest in G0/G1 through a DNA fragmentation-independent mechanism. Furthermore, EP’s lack of overt cytotoxicity in the normal cell line HEK-293 and human fibroblasts in cell culture is supported by the absence of mutagenic activity of EP.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>EP emerges as a suitable molecule for further studies as a potential antineoplastic agent.</jats:p> </jats:sec>
Scopus© Citations 7 20

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