Brucellosis is a bacterial zoonotic disease affecting several mammalian species that is transmitted to humans by direct or indirect contact with infected animals or their products. In cattle, brucellosis is almost invariably caused by Brucella abortus. Live, attenuated Brucella vaccines are commonly used to prevent illness in cattle, but can cause abortions in pregnant animals. It is, therefore, desirable to design an effective and safer vaccine against Brucella. We have used specific Brucella antigens that induce immunity and protection against B. abortus. A novel recombinant multi-epitope DNA vaccine specific for brucellosis was developed. To design the vaccine construct, we employed bioinformatics tools to predict epitopes present in Cu–Zn superoxide dismutase and in the open reading frames of the genomic island-3 (BAB1_0260, BAB1_0270, BAB1_0273, and BAB1_0278) of Brucella. We successfully designed a multi-epitope DNA plasmid vaccine chimera that encodes and expresses 21 epitopes. This DNA vaccine induced a specific humoral and cellular immune response in BALB/c mice. It induced a typical T-helper 1 response, eliciting production of immunoglobulin G2a and IFN-γ particularly associated with the Th1 cell subset of CD4+ T cells. The production of IL-4, an indicator of Th2 activation, was not detected in splenocytes. Therefore, it is reasonable to suggest that the vaccine induced a predominantly Th1 response. The vaccine induced a statistically significant level of protection in BALB/c mice when challenged with B. abortus 2308. This is the first use of an in silico strategy to a design a multi-epitope DNA vaccine against B. abortus.
NUAK1 is an AMPK-related kinase located in the cytosol and the nucleus, whose expression associates with tumor malignancy and poor patient prognosis in several cancers. Accordingly, NUAK1 was associated with metastasis because it promotes cell migration and invasion in different cancer cells. Besides, NUAK1 supports cancer cell survival under metabolic stress and maintains ATP levels in hepatocarcinoma cells, suggesting a role in energy metabolism in cancer. However, the underlying mechanism for this metabolic function, as well as its link to NUAK1 subcellular localization, is unclear. We demonstrated that cytosolic NUAK1 increases ATP levels, which associates with increased mitochondrial respiration, supporting that cytosolic NUAK1 is involved in mitochondrial function regulation in cancer cells. NUAK1 inhibition led to the formation of "donut-like" structures, providing evidence of NUAK1-dependent mitochondrial morphology regulation. Additionally, our results indicated that cytosolic NUAK1 increases the glycolytic capacity of cancer cells under mitochondrial inhibition. Nuclear NUAK1 seems to be involved in the metabolic switch to glycolysis. Altogether, our results suggest that cytosolic NUAK1 participates in mitochondrial ATP production and the maintenance of proper glycolysis in cancer cells. Our current studies support the role of NUAK1 in bioenergetics, mitochondrial homeostasis, glycolysis and metabolic capacities. They suggest different metabolic outcomes depending on its subcellular localization. The identified roles of NUAK1 in cancer metabolism provide a potential mechanism relevant for tumor progression and its association with poor patient prognosis in several cancers. Further studies could shed light on the molecular mechanisms involved in the identified metabolic NUAK1 functions.
As an alternative brucellosis prevention method, we evaluated the immunogenicity induced by new multivalent DNA vaccines in BALB/c mice. We constructed the vaccines by fusion of BAB1_0273 and/or BAB1_0278 open reading frames (ORFs) from genomic island 3 (GI-3) and the Brucella abortus 2308 sodC gene with a link based on prolines and alanines (pV273-sod, pV278-sod, and pV273-278-sod, resp.). Results show that immunization with all tested multivalent DNA vaccines induced a specific humoral and cellular immune response. These novel multivalent vaccines significantly increased the production of IgM, IgG, and IgG2a antibodies as well as IFN-γ levels and the lymphoproliferative response of splenocytes. Although immunization with these multivalent vaccines induced a typical T-helper 1- (Th1-) dominated immune response, such immunogenicity conferred low protection levels in mice challenged with the B. abortus 2308 pathogenic strain. Our results demonstrated that the expression of BAB1_0273 and/or BABl_0278 antigens conjugated to SOD protein can polarize mice immunity to a Th1-type phenotype, conferring low levels of protection.
Salmonella Enteritidis is the main cause of foodborne salmonellosis worldwide. The limited effectiveness of current interventions against this pathogen has been the main incentive to develop new methods for the efficient control of this infection. To investigate the use of DNA vaccines against S. Enteritidis in humans, immune responses stimulated by two plasmids containing the genes designated SEN1002, located in the pathogenicity island SPI-19 and encoding a Hcp protein involved in transport mechanisms, and SEN1395, located in the genomic island ΦSE14 and encoding a protein of a new superfamily of lysozymes, were evaluated. Humoral and cellular responses following intranasal immunization of two groups of BALB/c mice with the plasmids pV1002 and pV1395 plus adjuvant were evaluated and it was observed that the IgG2a/IgG1 ratios were sixfold higher than control groups. Both plasmids stimulated specific secretory IgA production. Increased proliferation of lymphocytes and IFN-γ production were detected in both experimental groups. DNA-vaccinated mice developed protective immunity against a virulent strain of S. Enteritidis, with nearly 2 logs of protection level compared to the negative control values in the spleen. Therefore, DNA vaccines are efficient at stimulating cellular and humoral immune responses at systemic and mucosal levels.
The lymphatic vasculature is a unidirectional network of lymphatic endothelial cells, whose main role is to maintain fluid homeostasis along with the absorption of dietary fat in the gastrointestinal organs and management and coordination of immune cell trafficking into lymph nodes during homeostasis and under inflammatory conditions. In homeostatic conditions, immune cells, such as dendritic cells, macrophages, or T cells can enter into the lymphatic vasculature and move easily through the lymph reaching secondary lymph nodes where immune cell activation or peripheral tolerance can be modulated. However, under inflammatory conditions such as pathogen infection, increased permeabilization of lymphatic vessels allows faster immune cell migration into inflamed tissues following a chemokine gradient, facilitating pathogen clearance and the resolution of inflammation. Interestingly, since the re‐discovery of lymphatic vasculature in the central nervous system, known as the meningeal lymphatic vasculature, the role of these lymphatics as a key player in several neurological disorders has been described, with emphasis on the neurodegenerative process. Alternatively, less has been discussed about meningeal lymphatics and its role in neuroinflammation. In this review, we discuss current knowledge about the anatomy and function of the meningeal lymphatic vasculature and specifically analyze its contribution to different neuroinflammatory processes, highlighting the potential therapeutic target of meningeal lymphatic vasculature in these pathological conditions.
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