Person: Echeverz SarasĂșa, Maite
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Echeverz SarasĂșa
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Maite
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Ciencias de la Salud
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0000-0002-4153-4549
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Publication Open Access Coordinated cyclic-di-GMP repression of salmonella motility through YcgR and cellulose(American Society for Microbiology, 2013) Zorraquino Salvo, Violeta; GarcĂa MartĂnez, Begoña; Latasa Osta, Cristina; Echeverz SarasĂșa, Maite; Toledo Arana, Alejandro; Valle Turrillas, Jaione; Lasa Uzcudun, Ăñigo; Solano Goñi, Cristina; IdAB. Instituto de AgrobiotecnologĂa / Agrobioteknologiako Institutua; Gobierno de Navarra / Nafarroako Gobernua: 1312/2010Cyclic di-GMP (c-di-GMP) is a secondary messenger that controls a variety of cellular processes, including the switch between a biofilm and a planktonic bacterial lifestyle. This nucleotide binds to cellular effectors in order to exert its regulatory functions. In Salmonella, two proteins, BcsA and YcgR, both of them containing a c-di-GMP binding PilZ domain, are the only known c-di-GMP receptors. BcsA, upon c-di-GMP binding, synthesizes cellulose, the main exopolysaccharide of the biofilm matrix. YcgR is dedicated to c-di-GMP-dependent inhibition of motility through its interaction with flagellar motor proteins. However, previous evidences indicate that in the absence of YcgR, there is still an additional element that mediates motility impairment under high c-di-GMP levels. Here we have uncovered that cellulose per se is the factor that further promotes inhibition of bacterial motility once high c-di-GMP contents drive the activation of a sessile lifestyle. Inactivation of different genes of the bcsABZC operon, mutation of the conserved residues in the RxxxR motif of the BcsA PilZ domain, or degradation of the cellulose produced by BcsA rescued the motility defect of ÎycgR strains in which high c-di-GMP levels were reached through the overexpression of diguanylate cyclases. High c-di-GMP levels provoked cellulose accumulation around cells that impeded flagellar rotation, probably by means of steric hindrance, without affecting flagellum gene expression, exportation, or assembly. Our results highlight the relevance of cellulose in Salmonella lifestyle switching as an architectural element that is both essential for biofilm development and required, in collaboration with YcgR, for complete motility inhibition.Publication Open Access A DIVA vaccine strain lacking RpoS and the secondary messenger c-di-GMP for protection against salmonellosis in pigs(BioMed Central, 2020) Gil Puig, Carmen; Latasa Osta, Cristina; GarcĂa Ona, Enrique; LĂĄzaro, Isidro; Labairu, Javier; Echeverz SarasĂșa, Maite; Burgui Erice, Saioa; GarcĂa MartĂnez, Begoña; Lasa Uzcudun, Ăñigo; Solano Goñi, Cristina; Ciencias de la Salud; Osasun Zientziak; Universidad PĂșblica de Navarra / Nafarroako Unibertsitate Publikoa; Gobierno de Navarra / Nafarroako Gobernua, IIM 13329.RI1Salmonellosis is the second most common food-borne zoonosis in the European Union, with pigs being a major reservoir of this pathogen. Salmonella control in pig production requires multiple measures amongst which vaccination may be used to reduce subclinical carriage and shedding of prevalent serovars, such as Salmonella enterica serovar Typhimurium. Live attenuated vaccine strains offer advantages in terms of enhancing cell mediated immunity and allowing inoculation by the oral route. However, main failures of these vaccines are the limited cross-protection achieved against heterologous serovars and interference with serological monitoring for infection. We have recently shown that an attenuated S. Enteritidis strain (ÎXIII) is protective against S. Typhimurium in a murine infection model. ÎXIII strain harbours 13 chromosomal deletions that make it unable to produce the sigma factor RpoS and synthesize cyclic-di-GMP (c-di-GMP). In this study, our objectives were to test the protective effects of ÎXIII strain in swine and to investigate if the use of ÎXIII permits the discrimination of vaccinated from infected pigs. Results show that oral vaccination of pre-weaned piglets with ÎXIII cross-protected against a challenge with S. Typhimurium by reducing faecal shedding and ileocaecal lymph nodes colonization, both at the time of weaning and slaughter. Vaccinated pigs showed neither faecal shedding nor tissue persistence of the vaccine strain at weaning, ensuring the absence of ÎXIII strain by the time of slaughter. Moreover, lack of the SEN4316 protein in ÎXIII strain allowed the development of a serological test that enabled the differentiation of infected from vaccinated animals (DIVA).Publication Open Access Experimental polymorphism survey in intergenic regions of the icaADBCR locus in Staphylococcus aureus isolates from periprosthetic joint infections(MDPI, 2022) Morales Laverde, Liliana Andrea; Echeverz SarasĂșa, Maite; Trobos, Margarita; Solano Goñi, Cristina; Lasa Uzcudun, Ăñigo; Ciencias de la Salud; Osasun ZientziakStaphylococcus aureus is a leading cause of prosthetic joint infections (PJI) characterized by bacterial biofilm formation and recalcitrance to immune-mediated clearance and antibiotics. The molecular events behind PJI infection are yet to be unraveled. In this sense, identification of polymorphisms in bacterial genomes may help to establish associations between sequence variants and the ability of S. aureus to cause PJI. Here, we report an experimental nucleotide-level survey specifically aimed at the intergenic regions (IGRs) of the icaADBCR locus, which is responsible for the synthesis of the biofilm exopolysaccharide PIA/PNAG, in a collection of strains sampled from PJI and wounds. IGRs of the icaADBCR locus were highly conserved and no PJI-specific SNPs were found. Moreover, polymorphisms in these IGRs did not significantly affect transcription of the icaADBC operon under in vitro laboratory conditions. In contrast, an SNP within the icaR coding region, resulting in a V176E change in the transcriptional repressor IcaR, led to a significant increase in icaADBC operon transcription and PIA/PNAG production and a reduction in S. aureus virulence in a Galleria mellonella infection model. In conclusion, SNPs in icaADBCR IGRs of S. aureus isolates from PJI are not associated with icaADBC expression, PIA/PNAG production and adaptation to PJI.Publication Open Access Salmonella biofilm development depends on the phosphorylation status of RcsB(American Society for Microbiology, 2012) Latasa Osta, Cristina; GarcĂa MartĂnez, Begoña; Echeverz SarasĂșa, Maite; Toledo Arana, Alejandro; Valle Turrillas, Jaione; Campoy SĂĄnchez, Susana; GarcĂa del Portillo, Francisco; Solano Goñi, Cristina; Lasa Uzcudun, Ăñigo; IdAB. Instituto de AgrobiotecnologĂa / Agrobioteknologiako Institutua; Gobierno de Navarra / Nafarroako Gobernua: IIM13329.RI1The Rcs phosphorelay pathway is a complex signaling pathway involved in the regulation of many cell surface structures in enteric bacteria. In response to environmental stimuli, the sensor histidine kinase (RcsC) autophosphorylates and then transfers the phosphate through intermediary steps to the response regulator (RcsB), which, once phosphorylated, regulates gene expression. Here, we show that Salmonella biofilm development depends on the phosphorylation status of RcsB. Thus, unphosphorylated RcsB, hitherto assumed to be inactive, is essential to activate the expression of the biofilm matrix compounds. The prevention of RcsB phosphorylation either by the disruption of the phosphorelay at the RcsC or RcsD level or by the production of a nonphosphorylatable RcsB allele induces biofilm development. On the contrary, the phosphorylation of RcsB by the constitutive activation of the Rcs pathway inhibits biofilm development, an effect that can be counteracted by the introduction of a nonphosphorylatable RcsB allele. The inhibition of biofilm development by phosphorylated RcsB is due to the repression of CsgD expression, through a mechanism dependent on the accumulation of the small noncoding RNA RprA. Our results indicate that unphosphorylated RcsB plays an active role for integrating environmental signals and, more broadly, that RcsB phosphorylation acts as a key switch between planktonic and sessile life-styles in Salmonella enterica serovar Typhimurium.Publication Open Access Evaluation of a Salmonella strain lacking the secondary messenger c-di-GMP and RpoS as a live oral vaccine(Public Library of Science, 2016) Latasa Osta, Cristina; Echeverz SarasĂșa, Maite; GarcĂa Ona, Enrique; Burgui Erice, Saioa; Casares, Noelia; HervĂĄs Stubbs, Sandra; Lasarte, Juan JosĂ©; Lasa Uzcudun, Ăñigo; Solano Goñi, Cristina; GarcĂa MartĂnez, Begoña; Gil Puig, Carmen; IdAB. Instituto de AgrobiotecnologĂa / Agrobioteknologiako Institutua; Gobierno de Navarra / Nafarroako Gobernua: IIM 13329.RI1Salmonellosis is one of the most important bacterial zoonotic diseases transmitted through the consumption of contaminated food, with chicken and pig related products being key reservoirs of infection. Although numerous studies on animal vaccination have been performed in order to reduce Salmonella prevalence, there is still a need for an ideal vaccine. Here, with the aim of constructing a novel live attenuated Salmonella vaccine candidate, we firstly analyzed the impact of the absence of cyclic-di-GMP (c-di-GMP) in Salmonella virulence. Cdi-GMP is an intracellular second messenger that controls a wide range of bacterial processes, including biofilm formation and synthesis of virulence factors, and also modulates the host innate immune response. Our results showed that a Salmonella multiple mutant in the twelve genes encoding diguanylate cyclase proteins that, as a consequence, cannot synthesize c-di-GMP, presents a moderate attenuation in a systemic murine infection model. An additional mutation of the rpoS gene resulted in a synergic attenuating effect that led to a highly attenuated strain, referred to as ÎXIII, immunogenic enough to protect mice against a lethal oral challenge of a S. Typhimurium virulent strain. ÎXIII immunogenicity relied on activation of both antibody and cell mediated immune responses characterized by the production of opsonizing antibodies and the induction of significant levels of IFN-Îł, TNF- α, IL-2, IL-17 and IL-10. ÎXIII was unable to form a biofilm and did not survive under desiccation conditions, indicating that it could be easily eliminated from the environment. Moreover, ÎXIII shows DIVA features that allow differentiation of infected and vaccinated animals. Altogether, these results show ÎXIII as a safe and effective live DIVA vaccinePublication Open Access Role of sodium salicylate in Staphylococcus aureus quorum sensing, virulence, biofilm formation and antimicrobial susceptibility(Frontiers Media, 2022) Turner, Adam Benedict; Gerner, Erik; Firdaus, Rininta; Echeverz SarasĂșa, Maite; WerthĂ©n, MarĂa; Thomsen, Peter; Almqvist, SofĂa; Trobos, Margarita; Ciencias de la Salud; Osasun ZientziakThe widespread threat of antibiotic resistance requires new treatment options. Disrupting bacterial communication, quorum sensing (QS), has the potential to reduce pathogenesis by decreasing bacterial virulence. The aim of this study was to investigate the influence of sodium salicylate (NaSa) on Staphylococcus aureus QS, virulence production and biofilm formation. In S. aureus ATCC 25923 (agr III), with or without serum, NaSa (10 mM) downregulated the agr QS system and decreased the secretion levels of alpha-hemolysin, staphopain A and delta-hemolysin. Inhibition of agr expression caused a downregulation of delta-hemolysin, decreasing biofilm dispersal and increasing biofilm formation on polystyrene and titanium under static conditions. In contrast, NaSa did not increase biofilm biomass under flow but caused one log10 reduction in biofilm viability on polystyrene pegs, resulting in biofilms being twice as susceptible to rifampicin. A concentrationdependent effect of NaSa was further observed, where high concentrations (10 mM) decreased agr expression, while low concentrations (â€0.1 mM) increased agr expression. In S. aureus 8325-4 (agr I), a high concentration of NaSa (10 mM) decreased hla expression, and a low concentration of NaSa (â€1 mM) increased rnaIII and hla expression. The activity of NaSa on biofilm formation was dependent on agr type and material surface. Eight clinical strains isolated from prosthetic joint infection (PJI) or wound infection belonging to each of the four agr types were evaluated. The four PJI S. aureus strains did not change their biofilm phenotype with NaSa on the clinically relevant titanium surface. Half of the wound strains (agr III and IV) did not change the biofilm phenotype in the 3D collagen wound model. In addition, compared to the control, ATCC 25923 biofilms formed with 10 mM NaSa in the collagen model were more susceptible to silver. It is concluded that NaSa can inhibit QS in S. aureus, decreasing the levels of toxin production with certain modulation of biofilm formation. The effect on biofilm formation was dependent on the strain and material surface. It is suggested that the observed NaSa inhibition of bacterial communication is a potential alternative or adjuvant to traditional antibiotics.Publication Open Access Lack of the PGA exopolysaccharide in Salmonella as an adaptive trait for survival in the host(Public Library of Science, 2017) Echeverz SarasĂșa, Maite; GarcĂa MartĂnez, Begoña; Sabalza BaztĂĄn, Amaia; Valle Turrillas, Jaione; GabaldĂłn Estevan, Juan Antonio; Solano Goñi, Cristina; Lasa Uzcudun, Ăñigo; IdAB. Instituto de AgrobiotecnologĂa / Agrobioteknologiako InstitutuaMany bacteria build biofilm matrices using a conserved exopolysaccharide named PGA or PNAG (poly-ÎČ-1,6-N-acetyl-D-glucosamine). Interestingly, while E. coli and other members of the family Enterobacteriaceae encode the pgaABCD operon responsible for PGA synthesis, Salmonella lacks it. The evolutionary force driving this difference remains to be determined. Here, we report that Salmonella lost the pgaABCD operon after the divergence of Salmonella and Citrobacter clades, and previous to the diversification of the currently sequenced Salmonella strains. Reconstitution of the PGA machinery endows Salmonella with the capacity to produce PGA in a cyclic dimeric GMP (c-di-GMP) dependent manner. Outside the host, the PGA polysaccharide does not seem to provide any significant benefit to Salmonella: resistance against chlorine treatment, ultraviolet light irradiation, heavy metal stress and phage infection remained the same as in a strain producing cellulose, the main biofilm exopolysaccharide naturally produced by Salmonella. In contrast, PGA production proved to be deleterious to Salmonella survival inside the host, since it increased susceptibility to bile salts and oxidative stress, and hindered the capacity of S. Enteritidis to survive inside macrophages and to colonize extraintestinal organs, including the gallbladder. Altogether, our observations indicate that PGA is an antivirulence factor whose loss may have been a necessary event during Salmonella speciation to permit survival inside the host.Publication Open Access Biofilm dispersion and quorum sensing(Elsevier, 2014) Solano Goñi, Cristina; Echeverz SarasĂșa, Maite; Lasa Uzcudun, Ăñigo; IdAB. Instituto de AgrobiotecnologĂa / Agrobioteknologiako Institutua; Gobierno de Navarra / Nafarroako Gobernua: IIM13329.RI1Biofilm development and quorum sensing are closely interconnected processes. Biofilm formation is a cooperative group behaviour that involves bacterial populations living embedded in a self produced extracellular matrix. Quorum sensing (QS) is a cell-cell communication mechanism that synchronizes gene expression in response to population cell density. Intuitively, it would appear that QS might coordinate the switch to a biofilm lifestyle when the population density reaches a threshold level. However, compelling evidence obtained in different bacterial species coincides in that activation of QS occurs in the formed biofilm and activates the maturation and disassembly of the biofilm in a coordinate manner. The aim of this review is to illustrate, using four bacterial pathogens as examples, the emergent concept that QS activates the biofilm dispersion process.Publication Open Access Insights into c-di-GMP signaling and the PGA exopolysaccharide biological functions using Salmonella as a model organism(2017) Echeverz SarasĂșa, Maite; Lasa Uzcudun, Ăñigo; Solano Goñi, Cristina; ProducciĂłn Agraria; Nekazaritza EkoizpenaSalmonella es un patĂłgeno alimentario de gran relevancia clĂnica capaz de adherirse a superficies y formar comunidades bacterianas embebidas en una matriz que ellas mismas producen denominadas biofilms. Esta matriz confiere a las bacterias protecciĂłn frente a agentes externos, aumentando su tolerancia frente a condiciones ambientales adversas, agentes antimicrobianos o el sistema inmune del hospedador. Existe una vĂa de señalizaciĂłn, mediada por el dinucleĂłtido cĂclico, c-di- GMP, que controla en muchas especies bacterianas la sĂntesis de diversos componentes de la matriz del biofilm, de manera que concentraciones elevadas de este nucleĂłtido activan la producciĂłn de la matriz y por lo tanto del biofilm. La formaciĂłn de biofilms en explotaciones agropecuarias y lugares donde se procesan alimentos es una fuente potencial de contaminaciĂłn y de transmisiĂłn de este patĂłgeno. Diversas medidas de higiene y seguimiento han sido implementadas por las autoridades para el control de esta bacteria; sin embargo alrededor de 93 millones de personas en todo el mundo sufren salmonelosis cada año. Por ello, la bĂșsqueda de medidas alternativas de control, basadas en la vacunaciĂłn animal, asĂ como el estudio de los mecanismos de patogenicidad y formaciĂłn de biofilm de Salmonella han sido el objeto de este trabajo.Publication Open Access Functional analysis of intergenic regulatory regions of genes encoding surface adhesins in Staphylococcus aureus isolates from periprosthetic joint infections(Elsevier, 2022) Morales Laverde, Liliana Andrea; Trobos, Margarita; Echeverz SarasĂșa, Maite; Solano Goñi, Cristina; Lasa Uzcudun, Ăñigo; Ciencias de la Salud; Osasun ZientziakStaphylococcus aureus is a leading cause of prosthetic joint infections (PJI). Surface adhesins play an important role in the primary attachment to plasma proteins that coat the surface of prosthetic devices after implantation. Previous efforts to identify a genetic component of the bacterium that confers an enhanced capacity to cause PJI have focused on gene content, kmers, or single-nucleotide polymorphisms (SNPs) in coding sequences. Here, using a collection of S. aureus strains isolated from PJI and wounds, we investigated whether genetic variations in the regulatory region of genes encoding surface adhesins lead to differences in their expression levels and modulate the capacity of S. aureus to colonize implanted prosthetic devices. The data revealed that S. aureus isolates from the same clonal complex (CC) contain a specific pattern of SNPs in the regulatory region of genes encoding surface adhesins. As a consequence, each clonal lineage shows a specific profile of surface proteins expression. Co-infection experiments with representative isolates of the most prevalent CCs demonstrated that some lineages have a higher capacity to colonize implanted catheters in a murine infection model, which correlated with a greater ability to form a biofilm on coated surfaces with plasma proteins. Together, results indicate that differences in the expression level of surface adhesins may modulate the propensity of S. aureus strains to cause PJI. Given the high conservation of surface proteins among staphylococci, our work lays the framework for investigating how diversification at intergenic regulatory regions affects the capacity of S. aureus to colonize the surface of medical implants.