Juan Ignacio Aguiló
University of Zaragoza
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Publication
Featured researches published by Juan Ignacio Aguiló.
Vaccine | 2013
Ainhoa Arbués; Juan Ignacio Aguiló; Jesús Gonzalo-Asensio; Dessislava Marinova; Santiago Uranga; Eugenia Puentes; Conchita Fernandez; Alberto Parra; P. J. Cardona; C. Vilaplana; Vicente Ausina; Ann Williams; Simon O. Clark; Wladimir Malaga; Christophe Guilhot; Brigitte Gicquel; Carlos Martín
The development of a new tuberculosis vaccine is an urgent need due to the failure of the current vaccine, BCG, to protect against the respiratory form of the disease. MTBVAC is an attenuated Mycobacterium tuberculosis vaccine candidate genetically engineered to fulfil the Geneva consensus requirements to enter human clinical trials. We selected a M. tuberculosis clinical isolate to generate two independent deletions without antibiotic-resistance markers in the genes phoP, coding for a transcription factor key for the regulation of M. tuberculosis virulence, and fadD26, essential for the synthesis of the complex lipids phthiocerol dimycocerosates (DIM), one of the major mycobacterial virulence factors. The resultant strain MTBVAC exhibits safety and biodistribution profiles similar to BCG and confers superior protection in preclinical studies. These features have enabled MTBVAC to be the first live attenuated M. tuberculosis vaccine to enter clinical evaluation.
Microbes and Infection | 2009
Julián Pardo; Juan Ignacio Aguiló; Alberto Anel; Praxedis Martin; Lars Joeckel; Christoph Borner; Reiner Wallich; Arno Müllbacher; Christopher J. Froelich; Markus M. Simon
The granule exocytosis pathway of cytotoxic lymphocytes (Tc and NK cells) is critical for control of tumor development and viral infections. Granule-associated perforin and granzymes are key components in Tc cell-mediated function(s). On the basis of studies that showed granzymes A, B, C, K and M, to induce apoptosis in vitro, all granzymes were thought to also induce cell death in vivo. This review summarizes our present understanding of the biological processes elicited by purified granzyme A and granzyme as well as the processes induced by the more physiologically relevant cytotoxic cells secreting these proteases. The combined evidence supports the concept that the granule secretion pathway is not mono-specific but rather poly-functional including induction of pro-inflammatory cytokines, besides their widely appreciated apoptotic properties.
Cellular Microbiology | 2013
Juan Ignacio Aguiló; Henar Alonso; Santiago Uranga; Dessislava Marinova; Ainhoa Arbués; A. de Martino; Alberto Anel; Marta Monzón; Juan José Badiola; Julián Pardo; Roland Brosch; Carlos Martín
Apoptosis modulation is a procedure amply utilized by intracellular pathogens to favour the outcome of the infection. Nevertheless, the role of apoptosis during infection with Mycobacterium tuberculosis, the causative agent of human tuberculosis, is subject of an intense debate and still remains unclear. In this work, we describe that apoptosis induction in host cells is clearly restricted to virulent M. tuberculosis strains, and is associated with the capacity of the mycobacteria to secrete the 6 kDa early secreted antigenic target ESAT‐6 bothunder in vitro and in vivo conditions. Remarkably, only apoptosis‐inducing strains are able to propagate infection into new cells, suggesting that apoptosis is used by M. tuberculosis as a colonization mechanism. Finally, we demonstrate that in vitro modulation of apoptosis affects mycobacterial cell‐to‐cell spread capacity, establishing an unambiguous relationship between apoptosis and propagation of M. tuberculosis. Our data further indicate that BCG and MTBVAC vaccines are inefficient in inducing apoptosis and colonizing new cells, correlating with the strong attenuation profile of these strains previously observed in vitro and in vivo.
European Journal of Immunology | 2012
Jonathan K. Nambiar; Rachel Pinto; Juan Ignacio Aguiló; Kiyoshi Takatsu; Carlos Martín; Warwick J. Britton; James A. Triccas
Definition of protective immunity induced by effective vaccines is important for the design of new pathogen control strategies. Inactivation of the PhoP response‐regulator in Mycobacterium tuberculosis results in a highly attenuated strain that demonstrates impressive protective efficacy in pre‐clinical models of tuberculosis. In this report we demonstrate that the protection afforded by the M. tuberculosis phoP mutant strain is associated with the long‐term maintenance of CD4+ T‐cell memory. Immunization of mice with SO2 resulted in enhanced expansion of M. tuberculosis‐specific CD4+ T cells compared with vaccination with the BCG vaccine, with an increased frequency of these cells persisting at extended time‐points after vaccination. Strikingly, vaccination with SO2 resulted in sustained generation of CD4+ T cells displaying a central memory phenotype, a property not shared by BCG. Further, SO2 vaccination markedly improved the generation of polyfunctional cytokine‐secreting CD4+ T cells compared with BCG vaccination. The improved generation of functionally competent memory T cells by SO2 correlated with augmented recall responses in SO2‐vaccinated animals after challenge with virulent M. tuberculosis. This study defines a mechanism for the protective effect of the SO2 vaccine and suggests that deletion of defined virulence networks may provide vaccine strains with potent immuno‐stimulatory properties.
Tuberculosis | 2011
Henar Alonso; Juan Ignacio Aguiló; Sofía Samper; Jose A. Caminero; María Isolina Campos-Herrero; Brigitte Gicquel; Roland Brosch; Carlos Martín; Isabel Otal
The capacity of infection and the ability of Mycobacterium tuberculosis strains belonging to the Beijing family to spread rapidly probably result from genetic advantages and unidentified mechanisms of virulence not yet thoroughly investigated. Among the mechanisms proposed to be responsible for the varying virulence phenotypes of M. tuberculosis strains we find IS6110 insertions, genetic reorganizations and deletions, which have strong influences on fitness. Beijing family is one of the lineages with the highest number of copies of IS6110. By studying genetic markers characteristic for this lineage, here we have characterized the clinical isolate M. tuberculosis GC1237 strain responsible for important epidemic outbreaks in the Gran Canary Island. We have identified and analyzed each point of insertion of IS6110 using a bacterial artificial chromosome (BAC) library of this strain, in addition to the use of other approximations. Nineteen copies of IS6110 have been localized in GC1237 genome of which, four copies of IS6110 can act as a promoter and we have focused in the characterization of one copy located 31 bp upstream of the essential gene Rv2179c and compared to the reference strain H37Rv.
Journal of Immunology | 2010
Seyma Charni; Geoffroy de Bettignies; Moeez G. Rathore; Juan Ignacio Aguiló; Peter J. van den Elsen; Delphine Haouzi; Robert A. Hipskind; José Antonio Enríquez; Margarita Sanchez-Beato; Julián Pardo; Alberto Anel; Martin Villalba
Most cancer cells use anaerobic-like glycolysis to generate energy instead of oxidative phosphorylation. They also avoid recognition by CTLs, which occurs primarily through decreasing the level of MHC class I (MHC-I) at the cell surface. We find that the two phenomena are linked; culture conditions that force respiration in leukemia cells upregulate MHC-I transcription and protein levels at the cell surface, whereas these decrease in cells forced to perform fermentation as well as in leukemia cells lacking a functional mitochondrial respiratory chain. Forced respiration leads to increased expression of the MAPK ERK5, which activates MHC-I gene promoters, and ERK5 accumulation in mitochondria. Respiration-induced MHC-I upregulation is reversed upon short hairpin RNA-mediated ERK5 downregulation and by inactive mutants of ERK5. Moreover, short hairpin RNA for ERK5 leukemia cells do not tolerate forced respiration. Thus, the expression of ERK5 and MHC-I is linked to cell metabolism and notably diminished by the metabolic adaptations found in tumor cells.
Journal of Immunology | 2009
Juan Ignacio Aguiló; Johan Garaude; Julián Pardo; Martin Villalba; Alberto Anel
Protein kinase C-θ (PKCθ) was initially isolated as an important PKC isoform expressed in T cells, although its expression is not restricted to these cells. Despite the central function of PKCθ in several immune responses, its role in the antitumor response against MHC class I (MHC-I)-negative cells has not been investigated. This is an important issue because most tumor cells growing in vivo down-regulate MHC-I expression to escape the CTL-mediated response. In the present work, we show that in vivo development of a MHC-I-deficient tumor (RMA-S) is much favored in PKCθ−/− mice compared with wild-type mice. This is associated with a reduced recruitment of NK cells to the site of tumor development and a reduced activation status of recruited NK cells. This correlates with a reduced ex vivo and in vivo cytotoxic potential of NK cells isolated from PKCθ−/− mice treated with polyinosinic:polycytidylic acid. Consistently, polinosinic:cytidilic acid treatment induces PKCθ expression and activation of its enzymatic activity in NK cells in an indirect manner. These observations underline the relevance of PKCθ as a key molecule in NK cell-mediated antitumor immune surveillance.
PLOS ONE | 2012
Adriana Aporta; Ainhoa Arbués; Juan Ignacio Aguiló; Marta Monzón; Juan José Badiola; Alba de Martino; Nadia L. Ferrer; Dessislava Marinova; Alberto Anel; Carlos Martín; Julián Pardo
It has been proposed that Mycobacterium tuberculosis virulent strains inhibit apoptosis and trigger cell death by necrosis of host macrophages to evade innate immunity, while non-virulent strains induce typical apoptosis activating a protective host response. As part of the characterization of a novel tuberculosis vaccine candidate, the M. tuberculosis phoP mutant SO2, we sought to evaluate its potential to induce host cell death. The parental M. tuberculosis MT103 strain and the current vaccine against tuberculosis Bacillus Calmette-Guérin (BCG) were used as comparators in mouse models in vitro and in vivo. Our data reveal that attenuated SO2 was unable to induce apoptotic events neither in mouse macrophages in vitro nor during lung infection in vivo. In contrast, virulent MT103 triggers typical apoptotic events with phosphatidylserine exposure, caspase-3 activation and nuclear condensation and fragmentation. BCG strain behaved like SO2 and did not induce apoptosis. A clonogenic survival assay confirmed that viability of BCG- or SO2-infected macrophages was unaffected. Our results discard apoptosis as the protective mechanism induced by SO2 vaccine and provide evidence for positive correlation between classical apoptosis induction and virulent strains, suggesting apoptosis as a possible virulence determinant during M. tuberculosis infection.
Journal of Immunology | 2009
Seyma Charni; Juan Ignacio Aguiló; Johan Garaude; Geoffroy de Bettignies; Chantal Jacquet; Robert A. Hipskind; Dinah S. Singer; Alberto Anel; Martin Villalba
Tumor cell-based vaccines are currently used in clinical trails, but they are in general poorly immunogenic because they are composed of cell extracts or apoptotic cells. Live tumor cells should be much better Ags provided that they are properly processed by the host immune system. We show herein that stable expression of a small hairpin RNA for ERK5 (shERK5) decreases ERK5 levels in human and mouse leukemic cells and leads to their elimination by NK cells in vivo. The shERK5 cells show down-regulation of MHC class I expression at the plasma membrane. Accordingly, ectopic activation of the ERK5 pathway induces MHC class I gene expression. Coinjection of shERK5-expressing cells into the peritoneum diminishes survival of engrafted wild-type tumor cells. Moreover, s.c. injection of shERK5-expressing cells strongly diminishes tumor development by wild-type cells. Our results show that shERK5 expression in leukemia cells effectively attenuates their tumor activity and allows their use as a tumor cell-based vaccine.
Molecular Immunology | 2008
Johan Garaude; Sandra Kaminski; Seyma Charni; Juan Ignacio Aguiló; Chantal Jacquet; Marc Plays; Javier Hernandez; Fernando Rodriguez; Robert A. Hipskind; Alberto Anel; Martin Villalba
The cancer immunosurveillance hypothesis has found strong experimental support in recent years. It is believed that cytotoxic lymphocytes are important effectors in this process. PKCtheta plays an essential role in proliferation, activation and survival of these cells, but also proliferation and survival of leukemic T cells. In light of this, we tested the role of PKCtheta in T cell leukemia progression by inducing this disease in wild-type (wt) and PKCtheta-deficient mice with moloney-murine leukemia virus (M-MuLV). Leukemic PKCtheta(-/-) and wild-type (wt) mice showed the same profile of leukemic cell types, similar spleen and thymus sizes and comparable hematocrits. In contrast, disease incidence was higher and disease onset more rapid in PKCtheta(-/-) mice. Transfer of leukemic T cells from wt donors into PKCtheta-deficient and wt recipients induced leukemia in 100% and 40% of the mice, respectively. Interestingly, leukemic cells from PKCtheta(-/-) donors induced the disease in only 50% of the PKCtheta-deficient and 10% of the wt recipients. Intravenous injection of low numbers of EL4 cells induced tumors earlier in PKCtheta(-/-) mice. Taken together, our results show that PKCtheta is essential for the immune response to leukemia in mice and raise questions about the chronic treatment of humans with PKCtheta inhibitors.