Artículos de revista (Inst. Salud Tropical)
Permanent URI for this collectionhttps://hdl.handle.net/10171/52056
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- Highlighting the interplay of microRNAs from Leishmania parasites and infected-host cells(Cambridge University Press, 2021) Carrera-Silva, E.A. (Eugenio Antonio); Ali-Hassanzadeh, M. (Mohammad); Ghani, E. (Esmaeel); Karimazar, M. (Mohammadreza); Mansouri, R. (Reza); Barazesh, A. (Afshin); Nguewa, P.A. (Paul Alain); Rashidi, S. (Sajad)Leishmania parasites, the causative agents of leishmaniasis, are protozoan parasites with the ability to modify the signalling pathway and cell responses of their infected host cells. These parasite strategies alter the host cell environment and conditions favouring their replication, survival and pathogenesis. Since microRNAs (miRNAs) are able to post-transcriptionally regulate gene expression processes, these biomolecules can exert critical roles in controlling Leishmania-host cell interplay. Therefore, the identification of relevant miRNAs differentially expressed in Leishmania parasites as well as in infected cells, which affect the host fitness, could be critical to understand the infection biology, pathogenicity and immune response against these parasites. Accordingly, the current review aims to address the differentially expressed miRNAs in both, the parasite and infected host cells and how these biomolecules change cell signalling and host immune responses during infection. A deep understanding of these processes could provide novel guidelines and therapeutic strategies for managing and treating leishmaniasis.
- Comparison of antibacterial activity and cytotoxicity of silver nanoparticles and silver-loaded montmorillonite and saponite(Elsevier, 2023) Gil-Korilis, A. (Adrián); Gamazo, C. (Carlos); Cojocaru, M. (Mihail); Andrade, N.J. (Natália J.); Berzosa-Suñer, M. (Melibea); Ciuffi, K.J. (Katia J.)Although silver nanoparticles are known for their antibacterial activity, little research has been carried out on what synthesis method provides the most effective particles. In this study, silver nanoparticles were synthesised via chemical reduction by using silver nitrate as the silver precursor, ascorbic acid as the reducing agent and sodium citrate as the stabilising agent. The solutions were adjusted to several pH values employing sodium hydroxide, citric acid or nitric acid. Dynamic light scattering and absorption spectra in the ultraviolet/visible region characterisation revealed that employing nitric acid to adjust the pH produced more varied and larger silver particle sizes. Then, silver nanoparticles were supported on montmorillonite and saponite through wet impregnation or ion exchange methods. Scanning electron microscopy, energy-dispersive X-ray spectroscopy and transmission electron microscopy characterisation confirmed that silver nanoparticles were successfully loaded onto the clay minerals. Next, the antibacterial activity of the samples was evaluated against Escherichia coli and Staphylococcus aureus by determining their minimum inhibitory concentrations and minimum bactericidal concentrations. The free silver nanoparticles did not show any antibacterial activity at 125 mg/L. In contrast, the silver-loaded samples obtained by wet impregnation and with a higher silver content displayed the strongest antibacterial effect. Finally, the cytotoxicity of the samples was determined in GM07492-A cell line by using an XTT colorimetric assay. The calculated IC50 values revealed that the supported silver nanoparticles were barely toxic. Thus, the silver-loaded clay minerals obtained here are promising antibacterial materials with a high-grade safety profile.
- Development and evaluation of the Galleria mellonella (greater wax moth) infection model to study Brucella host-pathogen interaction(2023) Loperena-Barber, M. (Maite); Salvador-Bescós, M. (Miriam); Moriyon, I. (Ignacio); Zuñiga-Ripa, A. (Amaia); Aragón-Aranda, B. (Beatriz); Elizalde-Bielsa, A. (Aitor); Conde-Alvarez, R. (Raquel)Brucellosis is a zoonotic disease caused by Gram-negative bacteria of the genus Brucella. These pathogens cause long-lasting infections, a process in which Brucella modifications in the lipopolysaccharide (LPS) and envelope lipids reduce pathogen-associated molecular pattern (PAMP) recognition, thus hampering innate immunity activation. In vivo models are essential to investigate bacterial virulence, mice being the most used model. However, ethical and practical considerations impede their use in high-throughput screening studies. Although lacking the complexity of the mammalian immune system, insects share key-aspects of innate immunity with mammals, and Galleria mellonella has been used increasingly as a model. G. mellonella larvae have been shown useful in virulence analyses, including Gram-negative pathogens like Klebsiella pneumoniae and Legionella pneumophila. To assess its potential to study Brucella virulence, we first evaluated larva survival upon infection with representative Brucella species (i.e.B. abortus 2308W, B. microti CCM4915 and B. suis biovar 2) and mutants in the VirB type-IV secretion system (T4SS) or in the LPS-O-polysaccharide (O-PS). As compared to K.pneumoniae, the Brucella spp. tested induced a delayed and less severe mortality profile consistent with an escape of innate immunity detection. Brucella replication within larvae was affected by the lack of O-PS, which is reminiscent of their attenuation in natural hosts. On the contrary, replication was not affected by T4SS dysfunction and the mutant induced only slightly less mortality (not statistically significant) than its parental strain. We also evaluated G. mellonella to efficiently recognise Brucella and their LPS by quantification of the pro-phenoloxidase system and melanisation activation, using Pseudomonas LPS as a positive control. Among the brucellae, only B. microti LPS triggered an early-melanisation response consistent with the slightly increased endotoxicity of this species in mice. Therefore, G. mellonella represents a tool to screen for potential Brucella factors modulating innate immunity, but its usefulness to investigate other mechanisms relevant in Brucella intracellular life is limited.
- Repurposing the antibacterial agents peptide 19-4LF and peptide 19-2.5 for treatment of cutaneous leishmaniasis(2022) Peña-Guerrero, J. (José); Brandenburg, K. (Klaus); Larrea, E. (Esther); Abdel-Sater, F. (Fadi); Espuelas, S. (Socorro); Martinez-de-Tejada, G. (Guillermo); El-Dirany, R. (Rima); Moreno-Amatria, E. (Esther); Fernández-Rubio, C. (Celia); Nguewa, P.A. (Paul Alain)The lack of safe and cost-effective treatments against leishmaniasis highlights the urgent need to develop improved leishmanicidal agents. Antimicrobial peptides (AMPs) are an emerging category of therapeutics exerting a wide range of biological activities such as anti-bacterial, anti-fungal, anti-parasitic and anti-tumoral. In the present study, the approach of repurposing AMPs as antileishmanial drugs was applied. The leishmanicidal activity of two synthetic anti-lipopolysaccharide peptides (SALPs), so-called 19-2.5 and 19-4LF was characterized in Leishmania major. In vitro, both peptides were highly active against intracellular Leishmania major in mouse macrophages without exerting toxicity in host cells. Then, q-PCR-based gene profiling, revealed that this activity was related to the downregulation of several genes involved in drug resistance (yip1), virulence (gp63) and parasite proliferation (Cyclin 1 and Cyclin 6). Importantly, the treatment of BALB/c mice with any of the two AMPs caused a significant reduction in L. major infective burden. This effect was associated with an increase in Th1 cytokine levels (IL-12p35, TNF-¿, and iNOS) in the skin lesion and spleen of the L. major infected mice while the Th2-associated genes were downregulated (IL-4 and IL-6). Lastly, we investigated the effect of both peptides in the gene expression profile of the P2X7 purinergic receptor, which has been reported as a therapeutic target in several diseases. The results showed ...
- Mining the proteome of Toxoplasma parasites seeking vaccine and diagnostic candidates(2022) Sánchez-Montejo, J. (Javier); Ali-Hassanzadeh, M. (Mohammad); Bahreini, M.S. (Mohammad Saleh); Karimazar, M. (Mohammadreza); Mansouri, R. (Reza); Manzano-Román, R. (Raúl); Savardashtaki, A. (Amir); Nguewa, P.A. (Paul Alain); Rashidi, S. (Sajad)Simple Summary The One Health concept to toxoplasmosis highlights that the health of humans is closely related to the health of animals and our common environment. Toxoplasmosis outcomes might be severe and fatal in patients with immunodeficiency, diabetes, and pregnant women and infants. Consequently, the development of effective vaccine and diagnostic strategies is urgent for the elimination of this disease. Proteomics analysis has allowed the identification of key proteins that can be utilized in the development of novel disease diagnostics and vaccines. This work presents relevant proteins found in the proteome of the life cycle-specific stages of Toxoplasma parasites. In fact, it brings together the main functionality key proteins from Toxoplasma parasites coming from proteomic approaches that are most likely to be useful in improving the disease management, and critically proposes innovative directions to finally develop promising vaccines and diagnostics tools. Toxoplasma gondii is a pathogenic protozoan parasite that infects the nucleated cells of warm-blooded hosts leading to an infectious zoonotic disease known as toxoplasmosis. The infection outcomes might be severe and fatal in patients with immunodeficiency, diabetes, and pregnant women and infants. The One Health approach to toxoplasmosis highlights that the health of humans is closely related to the health of animals and our common environment. The presence of drug resistance and side effects, the further improvement of sensitivity and specificity of serodiagnostic tools and the potentiality of vaccine candidates to induce the host immune response are considered as justifiable reasons for the identification of novel targets for the better management of toxoplasmosis. Thus, the identification of new critical proteins in the proteome of Toxoplasma parasites can also be helpful in designing and test more effective drugs, vaccines, and diagnostic tools. Accordingly, in this study we present important proteins found in the proteome of the life cycle-specific stages of Toxoplasma parasites that are potential diagnostic or vaccine candidates. The current study might help to understand the complexity of these parasites and provide a possible source of strategies and biomolecules that can be further evaluated in the pathobiology of Toxoplasma parasites and for diagnostics and vaccine trials against this disease.
- Leishmaniasis en Navarra (1976-2018): actualización(Gobierno de Navarra, 2022) Burguete-Mikeo, A. (Aroia); Nguewa, P.A. (Paul Alain)La leishmaniasis es endémica en países de la cuenca mediterránea. En el presente estudio se revisa la información disponible sobre la leishmaniasis en Navarra y en regiones limítrofes en el periodo 1976-2018, y se aporta una visión general de la situación de esta enfermedad a nivel nacional, desde el vector hasta el hombre. La tasa de incidencia de leishmaniasis disminuyó en Aragón entre 2008 y 2018 respecto a la década anterior, mientras que en Navarra y La Rioja casi se duplicaron los casos por 100.000 habitantes; el País Vasco también presentó un aumento en la incidencia. El incremento de casos a nivel nacional ha sido significativo desde 2015, en parte debido a la inclusión de la leishmaniasis como enfermedad de declaración obligatoria. Si bien su incidencia en humanos no parece preocupante, la leishmaniasis es hoy una realidad en España, por lo que es necesario vigilar globalmente su evolución.
- 2-Hydroxylation of acinetobacter baumannii lipid a contributes to virulence(American Society for Microbiology, 2019) Kidd, T.J. (Timothy J.); Bengoechea, J.A. (José A.); Bartholomew, T.L. (Toby L.); Sá-Pessoa, J. (Joana); RaquelAcinetobacter baumannii causes a wide range of nosocomial infections. This pathogen is considered a threat to human health due to the increasingly frequent isolation of multidrug-resistant strains. There is a major gap in knowledge on the infection biology of A. baumannii, and only a few virulence factors have been characterized, including lipopolysaccharide. The lipid A expressed by A. baumannii is hepta-acylated and contains 2-hydroxylaurate. The late acyltransferases controlling the acylation of lipid A have been already characterized. Here, we report the characterization of A. baumannii LpxO, which encodes the enzyme responsible for the 2-hydroxylation of lipid A. By genetic methods and mass spectrometry, we demonstrate that LpxO catalyzes the 2-hydroxylation of the laurate transferred by A. baumannii LpxL. LpxO-dependent lipid A 2-hydroxylation protects A. baumannii from polymyxin B, colistin, and human -defensin 3. LpxO contributes to the survival of A. baumannii in human whole blood and is required for pathogen survival in the waxmoth Galleria mellonella. LpxO also protects Acinetobacter from G. mellonella antimicrobial peptides and limits their expression. Further demonstrating the importance of LpxO-dependent modification in immune evasion, 2-hydroxylation of lipid A limits the activation of the mitogen-activated protein kinase Jun N-terminal protein kinase to attenuate inflammatory responses. In addition, LpxO-controlled lipid A modification mediates the production of the anti-inflammatory cytokine interleukin-10 (IL-10) via the activation of the transcriptional factor CREB. IL-10 in turn limits the production of inflammatory cytokines following A. baumannii infection. Altogether, our studies suggest that LpxO is a candidate for the development of anti-A. baumannii drugs.
- The novel serine/threonine protein kinase LmjF.22.0810 from leishmania major may be involved in the resistance to drugs such as paromomycin(MDPI AG, 2019) Algarabel, M. (Miriam); Peña-Guerrero, J. (José); Vacas, A. (Andrés); Larrea, E. (Esther); García-Sosa, A.T. (Alfonso T.); Fernández-Rubio, C. (Celia); Nguewa, P.A. (Paul Alain); Formiga, F.R. (Fabio R.)The identification and clarification of the mechanisms of action of drugs used against leishmaniasis may improve their administration regimens and prevent the development of resistant strains. Herein, for the first time, we describe the structure of the putatively essential Ser/Thr kinase LmjF.22.0810 from Leishmania major. Molecular dynamics simulations were performed to assess the stability of the kinase model. The analysis of its sequence and structure revealed two druggable sites on the protein. Furthermore, in silico docking of small molecules showed that aminoglycosides preferentially bind to the phosphorylation site of the protein. Given that transgenic LmjF.22.0810-overexpressing parasites displayed less sensitivity to aminoglycosides such as paromomycin, our predicted models support the idea that the mechanism of drug resistance observed in those transgenic parasites is the tight binding of such compounds to LmjF.22.0810 associated with its overexpression. These results may be helpful to understand the complex machinery of drug response in Leishmania.
- Discovery and validation of Lmj_04_BRCT domain, a novel therapeutic target: identification of candidate drugs for leishmaniasis(2021) Peña-Guerrero, J. (José); Burguete-Mikeo, A. (Aroia); García-Sosa, A.T. (Alfonso T.); El-Dirany, R. (Rima); Fernández-Rubio, C. (Celia); Nguewa, P.A. (Paul Alain)Since many of the currently available antileishmanial treatments exhibit toxicity, low effectiveness, and resistance, search and validation of new therapeutic targets allowing the development of innovative drugs have become a worldwide priority. This work presents a structure-based drug discovery strategy to validate the Lmj_04_BRCT domain as a novel therapeutic target in Leishmania spp. The structure of this domain was explored using homology modeling, virtual screening, and molecular dynamics studies. Candidate compounds were validated in vitro using promastigotes of Leishmania major, L. amazonensis, and L. infantum, as well as primary mouse macrophages infected with L. major. The novel inhibitor CPE2 emerged as the most active of a group of compounds against Leishmania, being able to significantly reduce the viability of promastigotes. CPE2 was also active against the intracellular forms of the parasites and significantly reduced parasite burden in murine macrophages without exhibiting toxicity in host cells. Furthermore, L. major promastigotes treated with CPE2 showed significant lower expression levels of several genes (alpha-tubulin, Cyclin CYCA, and Yip1) related to proliferation and treatment resistance. Our in silico and in vitro studies suggest that the Lmj_04_BRCT domain and its here disclosed inhibitors are new potential therapeutic options against leishmaniasis.
- Corrigendum: genetic and phenotypic characterization of the etiological agent of canine orchiepididymitis smooth brucella sp. BCCN84.3(Frontiers Media SA, 2019) Suárez-Esquivel, M. (Marcela); Cloeckaert, A. (Axel); Chacon-Diaz, C. (Carlos); Moriyon, I. (Ignacio); Gonnet, M. (Mathieu); Víquez-Ruiz, E. (Eunice); Campos, E. (Elena); Zygmunt, M. (Michel); Thomson, N.R. (Nicholas R.); Aragón-Aranda, B. (Beatriz); Muñoz, P. (Pilar); Blasco, J.M. (J. M.); Baker, K.S. (Kate S.); Moreno, E. (Edgardo); Ruíz-Villalobos, N. (Nazareth); Guzman-Verri, C. (Caterina); RaquelIn the original article, there was an error. In the Funding statement is written that MZ was granted with a fellowship from SEP, Universidad de Costa Rica. The correct Initials are MS-E.