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Dive into the research topics where Yurena Navarro is active.

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Featured researches published by Yurena Navarro.


The Journal of Infectious Diseases | 2014

Whole Genome Sequencing Analysis of Intrapatient Microevolution in Mycobacterium tuberculosis: Potential Impact on the Inference of Tuberculosis Transmission

Laura Pérez-Lago; Iñaki Comas; Yurena Navarro; Fernando González-Candelas; Marta Herranz; Emilio Bouza; Darío García-de-Viedma

BACKGROUND It has been accepted that the infection by Mycobacterium tuberculosis (M. tuberculosis) can be more heterogeneous than considered. The emergence of clonal variants caused by microevolution events leading to population heterogeneity is a phenomenon largely unexplored. Until now, we could only superficially analyze this phenomenon by standard fingerprinting (RFLP and VNTR). METHODS In this study we applied whole genome sequencing for a more in-depth analysis of the scale of microevolution both at the intrapatient and interpatient scenarios. RESULTS We found that the amount of variation accumulated within a patient can be as high as that observed between patients along a chain of transmission. Intrapatient diversity was found both at the extrapulmonary and respiratory sites, meaning that this variability can be transmitted and impact on the inference of transmission events. One of the events studied allowed us to track for a single strain the complete process of (i) interpatient microevolution, (ii) intrapatient respiratory variation, and (iii) isolation of different variants at different infected sites of this patient. CONCLUSIONS Our study adds new data to the understanding of variability in M. tuberculosis in a wide clinical scenario and alerts about the difficulties of establishing thresholds to differentiate relatedness in M. tuberculosis with epidemiological purposes.


Journal of Clinical Microbiology | 2011

Systematic Survey of Clonal Complexity in Tuberculosis at a Populational Level and Detailed Characterization of the Isolates Involved

Yurena Navarro; Marta Herranz; Laura Pérez-Lago; Miguel Martínez Lirola; María Jesús Ruiz-Serrano; Emilio Bouza; Darío García de Viedma

ABSTRACT Clonally complex infections by Mycobacterium tuberculosis are progressively more accepted. Studies of their dimension in epidemiological scenarios where the infective pressure is not high are scarce. Our study systematically searched for clonally complex infections (mixed infections by more than one strain and simultaneous presence of clonal variants) by applying mycobacterial interspersed repetitive-unit (MIRU)–variable-number tandem-repeat (VNTR) analysis to M. tuberculosis isolates from two population-based samples of respiratory (703 cases) and respiratory-extrapulmonary (R+E) tuberculosis (TB) cases (71 cases) in a context of moderate TB incidence. Clonally complex infections were found in 11 (1.6%) of the respiratory TB cases and in 10 (14.1%) of those with R+E TB. Among the 21 cases with clonally complex TB, 9 were infected by 2 independent strains and the remaining 12 showed the simultaneous presence of 2 to 3 clonal variants. For the 10 R+E TB cases with clonally complex infections, compartmentalization (different compositions of strains/clonal variants in independent infected sites) was found in 9 of them. All the strains/clonal variants were also genotyped by IS6110-based restriction fragment length polymorphism analysis, which split two MIRU-defined clonal variants, although in general, it showed a lower discriminatory power to identify the clonal heterogeneity revealed by MIRU-VNTR analysis. The comparative analysis of IS6110 insertion sites between coinfecting clonal variants showed differences in the genes coding for a cutinase, a PPE family protein, and two conserved hypothetical proteins. Diagnostic delay, existence of previous TB, risk for overexposure, and clustered/orphan status of the involved strains were analyzed to propose possible explanations for the cases with clonally complex infections. Our study characterizes in detail all the clonally complex infections by M. tuberculosis found in a systematic survey and contributes to the characterization that these phenomena can be found to an extent higher than expected, even in an unselected population-based sample lacking high infective pressure.


Research in Veterinary Science | 2014

Current knowledge and pending challenges in zoonosis caused by Mycobacterium bovis: a review.

Laura Pérez-Lago; Yurena Navarro; Darío García-de-Viedma

Mycobacterium bovis is both the causative agent of bovine tuberculosis (TB) and a zoonotic pathogen. In humans, considerably fewer cases of TB are caused by M. bovis than M. tuberculosis; nevertheless, diagnostic limitations mean that currently available data on prevalence grossly underestimate the true dimension of the problem. The routes of transmission from animals to humans are well known and include direct exposure to infected animals or consumption of contaminated animal products. Application of fingerprinting tools facilitates analysis of the molecular epidemiology of M. bovis in animal-to-human and human-to-human transmission. Apart from cattle and M. bovis, other animal species and members within the M. tuberculosis complex can contribute to the zoonosis. Improvements in diagnostic techniques, application of more advanced discriminatory genotyping tools, and collaboration between veterinary and human health care researchers are key to our understanding of this zoonosis.


Journal of Clinical Microbiology | 2013

Splitting of a Prevalent Mycobacterium bovis Spoligotype by Variable Number Tandem Repeat Typing Reveals High Heterogeneity in an Evolving Clonal Group

Sabrina Rodriguez-Campos; Yurena Navarro; Beatriz Romero; Lucía de Juan; Javier Bezos; Ana Mateos; Noel H. Smith; Glyn Hewinson; Lucas Domínguez; Darío García-de-Viedma; Alicia Aranaz

ABSTRACT Mycobacterium bovis populations in countries with persistent bovine tuberculosis usually show a prevalent spoligotype with a wide geographical distribution. This study applied mycobacterial interspersed repetitive-unit–variable-number tandem-repeat (MIRU-VNTR) typing to a random panel of 115 M. bovis isolates that are representative of the most frequent spoligotype in the Iberian Peninsula, SB0121. VNTR typing targeted nine loci: ETR-A (alias VNTR2165), ETR-B (VNTR2461), ETR-D (MIRU4, VNTR580), ETR-E (MIRU31, VNTR3192), MIRU26 (VNTR2996), QUB11a (VNTR2163a), QUB11b (VNTR2163b), QUB26 (VNTR4052), and QUB3232 (VNTR3232). We found a high degree of diversity among the studied isolates (discriminatory index [D] = 0.9856), which were split into 65 different MIRU-VNTR types. An alternative short-format MIRU-VNTR typing targeting only the four loci with the highest variability values was found to offer an equivalent discriminatory index. Minimum spanning trees using the MIRU-VNTR data showed the hypothetical evolution of an apparent clonal group. MIRU-VNTR analysis was also applied to the isolates of 176 animals from 15 farms infected by M. bovis SB0121; in 10 farms, the analysis revealed the coexistence of two to five different MIRU types differing in one to six loci, which highlights the frequency of undetected heterogeneity.


International Journal of Medical Microbiology | 2013

Differences in gene expression between clonal variants of Mycobacterium tuberculosis emerging as a result of microevolution

Laura Pérez-Lago; Yurena Navarro; Marta Herranz; Emilio Bouza; Darío García-de-Viedma

Clonal variants of Mycobacterium tuberculosis can emerge as a result of microevolution in a single host or after sequential infection of different hosts. The significance of subtle genotypic variations is still unknown. In three of the four loci analyzed from clonal variants differing in only one MIRU-VNTR locus, we found that the expression of the adjacent genes was modulated differently. These data highlight the potential advantages that acquisition of subtle variability may have in M. tuberculosis.


Clinical Microbiology and Infection | 2011

A novel method for the rapid and prospective identification of Beijing Mycobacterium tuberculosis strains by high-resolution melting analysis

M. Alonso; Yurena Navarro; F. Barletta; M. Martínez Lirola; E. Gotuzzo; Emilio Bouza; D. García de Viedma

Genotypic analysis of Mycobacterium tuberculosis (MTB) has enabled the definition of several lineages. The Beijing family, which is considered highly virulent and transmissible, has been associated with resistance in certain settings and involved in severe outbreaks, making it one of the most closely-monitored lineages. Therefore, rapid prospective identification of Beijing MTB strains could be relevant. In the present study, we evaluate a real-time PCR followed by high-resolution melting (HRM) based on the identification of a single nucleotide polymorphism (SNP) in the Rv2629 gene which defines Beijing lineage (A191C for Beijing genotype and A191A for non-Beijing genotype). This combined methodology efficiently differentiated Beijing and non-Beijing strains in 100% of the isolates from a collection of reference strains without requiring specific DNA probes. Additionally, HRM was able to assign a Beijing/non-Beijing genotype in 90.9% of the respiratory specimens assayed. Its applicability was tested on a Peruvian sample of circulating MTB strains, in which it identified 10.7% as belonging to the Beijing genotype; this proportion reached 20% in the North Lima area. HRM analysis of the A191C SNP is a rapid, reliable, and sensitive method for the efficient prospective survey of high-risk Beijing MTB strains, even in developing settings where MTB culture is often not available.


Journal of Clinical Microbiology | 2011

Evaluation of the Inaccurate Assignment of Mixed Infections by Mycobacterium tuberculosis as Exogenous Reinfection and Analysis of the Potential Role of Bacterial Factors in Reinfection

Ana Isabel Martín; Marta Herranz; Yurena Navarro; Sandra Lasarte; María Jesús Ruiz Serrano; Emilio Bouza; Darío García de Viedma

ABSTRACT Molecular analysis of recurrent tuberculosis has revealed that a second episode may be caused by a strain of Mycobacterium tuberculosis other than that involved in the first infection, thus indicating that exogenous reinfection plays a role in recurrence. We focused on two aspects of reinfection that have received little attention. First, we evaluated whether a lack of methodological refinement could lead to inaccurate assignment of mixed infections as exogenous reinfection, in which a differential selection of each of the coinfecting strains occurred over time. We used the mycobacterial interspersed repetitive-unit–variable-number tandem-repeat (MIRU-VNTR) method to genotype 122 isolates from 40 patients with recurrent tuberculosis. We identified 11/40 (27.5%) cases with genotypic differences between the isolates involved in the sequential episodes. Major genotypic differences were found in 8/11 cases, suggesting exogenous reinfection; in the remaining 3 cases, subtle genotypic differences were observed, probably indicating microevolution from a parental strain. In all cases, only a single strain was detected for the isolate(s) from each episode, thus ruling out the possibility that reinfection could correspond to undetected mixed infection. Second, we analyzed the infectivity of a selection of 12 strains from six cases with genotypically different strains between episodes. No main differences were observed in an ex vivo model of infection between the strains involved in the first episodes and those involved in the recurrent episodes. In our setting, our results suggest the following: (i) the possibility of misassignment of mixed infection as exogenous reinfection is improbable, and (ii) bacterial infectivity does not seem to play a role in exogenous reinfection.


Emerging Infectious Diseases | 2015

Co-infection with Drug-Susceptible and Reactivated Latent Multidrug-Resistant Mycobacterium tuberculosis.

Laura Pérez-Lago; Miguel Martínez Lirola; Yurena Navarro; Marta Herranz; María Jesús Ruiz-Serrano; Emilio Bouza; Darío García-de-Viedma

To the Editor: Genotyping of Mycobacterium tuberculosis (MTB) has identified mixed infections involving >1 MTB strain (1–4), which are clinically relevant when different susceptibility patterns are involved (4–7). We describe a tuberculosis (TB) case-patient with mixed infection in an area of moderate incidence. In a low-resistance setting (monoresistance 4.6%; multiresistance 1.7%), 1 of the strains was drug susceptible and the other was multidrug-resistant (MDR). Molecular fingerprinting and epidemiologic research revealed that the infection corresponded to a recent infection by a susceptible strain and reactivation of an MDR TB strain. The patient was an HIV-negative woman, 47 years of age, who had immigrated to Spain from Romania and had been living in Almeria for >3 years. TB was diagnosed in May 2014; she had experienced symptoms for 2 months. Her diagnosis was confirmed 3 years after being studied in Almeria as a close contact of her husband, also from Romania, who had tested positive for MDR TB (resistant to rifampin and isoniazid). When she was observed in the contact trace, she tested positive for purified protein derivative, had been vaccinated against the M. bovis bacillus Calmette-Guerin strain, and had no radiologic findings or clinical symptoms. Based on the susceptibility profile of her husband, prophylaxis was not prescribed. Her husband adhered to anti-TB treatment for 20 months; all microbiological control test results had been negative since 2 months after starting therapy. Because her infection was thought to originate from previous contact with an MDR TB case-patient, we assessed her sputum samples for resistance using GenoType-MTBDR-plus (Hain-Lifescience, Nehren, Rhineland-Paltinate, Germany). The test showed hybridization with the same mutant probes (rpoB-MUT3; katG-MUT1) as those of her husband, the assumed index MDR TB case-patient (Figurepanel A). The pattern was indeterminate because the hybridization for the mutant probes was faint, and intense hybridization was observed for all the wt probes (Figure panel A). Results suggested the simultaneous presence of an MDR strain and a susceptible strain in a respiratory specimen. The presence of the MDR TB strain was confirmed by the phenotypic antibiogram in a BBL MGIT mycobacteria growth indicator tube (Becton Dickinson, Franklin Lakes, NJ, USA) after the isolate had been cultured. GeneXpert (Cepheid, Sunnyvale, CA, USA) was used to analyze 2 respiratory specimens. Results indicated susceptibility to rifampin, revealing the limitations of this test: the use of probes targeting the wt sequences failed to detect resistant strains that coexist with a susceptible strain (7). Figure Identification of co-infection with drug-susceptible and reactivated latent multidrug-resistant Mycobacterium tuberculosis (MDR TB). A) Genotype of multidrug-resistant tuberculosis (MDR TB) and results for the MDR TB index patient and for 2 respiratory ... To ascertain the likelihood of 2 co-infecting strains, we analyzed the specimen and the cultured isolate by mycobacterial interspersed repetitive unit–variable number tandem repeat (MIRU-VNTR), which is highly sensitive for detecting complex infections (8,9). Double alleles were found at 12 loci (Figure, panel B), confirming co-infection. Peaks in the electropherograms suggested that 1 of the 2 strains was under-represented and its proportion was lower in the cultured isolates (Figure, panel C), indicating that culturing diminished its representation of the minority strain. This finding was consistent with the inability of the GenoType test to detect the MDR strain when applied to the cultured isolate (Figure, panel A). We also detected lower fitness for the MDR strain compared to the susceptible strain (p<0.01) (Technical Appendix Table). Proportions of the resistant and susceptible strains were determined by plating on Middlebrook 7H11 +/− isoniazid (0.4 μL/mL) and counting single colonies. Because 2% of the colonies were of the resistant strain, we separated the strains and concluded: 1) the strain cultured in the presence of an antimicrobial drug coincided in the population exclusively with the MDR strain from the husband (as shown by MIRU-VNTR); and 2) the co-infecting MDR strain was a minority strain that was under-represented in the cultured isolate. To analyze the origin of the susceptible strain, we investigated its MIRU-VNTR type in the population-based molecular epidemiology survey (10) and found another 4 cases (from 2008, 2011 [2 cases], and 2014). Three case-patients had emigrated from Romania, and all 5 case-patients lived in the same area of Almeria. These data indicated that the susceptible strain was circulating in the geographic/epidemiological context of the current case-patient before and when she tested positive for that strain; therefore, she likely acquired the susceptible strain through recent transmission. The presence of susceptible and resistant strains in a patient should be considered even in moderate incidence settings and where resistance rates are not high. Underdetection of these cases could lead to misinterpretation when MDR became apparent after treatment of susceptible strains. Diagnostic laboratories could easily screen for mixed infections by applying MIRU-VNTR. However, only by integrating clonal analysis, refined molecular typing, and epidemiologic data from universal genotyping programs can we clarify the reasons underlying complex MTB infections. For this case-patient, a recent infection with a susceptible strain coincided with or could have triggered reactivation of a latent infection involving an MDR strain acquired through close contact years previously. We emphasize the alteration of the true clonal complexity of an infection induced by culturing specimens and that some commercial tests do not identify complex MTB infections. These findings are particularly relevant when the infection involves resistant strains such as those found in this case-patient. Technical Appendix: In vitro fitness of the multidrug-resistant and susceptible Mycobacterium tuberculosis strains involved in the mixed infection. Click here to view.(106K, pdf)


International Journal of Medical Microbiology | 2013

Unmasking subtle differences in the infectivity of microevolved Mycobacterium tuberculosis variants coinfecting the same patient.

Yurena Navarro; Laura Pérez-Lago; Fernanda Sislema; Marta Herranz; Lucía de Juan; Emilio Bouza; Darío García-de-Viedma

Clonal variants of Mycobacterium tuberculosis can emerge as a result of microevolution phenomena. The functional significance of these subtle genetic rearrangements is normally disregarded. We show that clonal variants from two patients had different infective behaviours in some in vitro cellular infection models but not in others. Microevolution may have a subtle impact on infectivity, but specific experimental conditions are needed to unmask it.


Journal of Clinical Microbiology | 2015

Persistent Infection by a Mycobacterium tuberculosis Strain That Was Theorized To Have Advantageous Properties, as It Was Responsible for a Massive Outbreak

Laura Pérez-Lago; Yurena Navarro; Pedro Montilla; Iñaki Comas; Marta Herranz; Carlos Rodríguez-Gallego; María Jesús Ruiz Serrano; Emilio Bouza; Darío García de Viedma

ABSTRACT The strains involved in tuberculosis outbreaks are considered highly virulent and transmissible. We analyzed the case of a patient in Madrid, Spain, who was persistently infected over an 8-year period by the same Beijing Mycobacterium tuberculosis strain. The strain was responsible for a severe outbreak on Gran Canaria Island. The case provides us with a unique opportunity to challenge our assumptions about M. tuberculosis Beijing strains. No clinical/radiological findings consistent with a virulent strain were documented, and the in vitro growth rate of the strain in macrophages was only moderate. No secondary cases stemming from this prolonged active case were detected in the host population. The strain did not acquire resistance mutations, despite constant treatment interruptions, and it remained extremely stable, as demonstrated by the lack of single-nucleotide-polymorphism (SNP)-based differences between the sequential isolates. Our data suggest that the general assumption about M. tuberculosis Beijing strains having advantageous properties (in terms of virulence, transmissibility, and the tendency to acquire mutations and resistance) is not always accurate.

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Emilio Bouza

Complutense University of Madrid

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Beatriz Romero

Complutense University of Madrid

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Lucas Domínguez

Spanish National Research Council

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Lucía de Juan

Complutense University of Madrid

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Iñaki Comas

Spanish National Research Council

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