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Geographic divergence of methicillin-resistant Staphylococcus aureus ST5-SCCmecI in the aftermath of a major earthquake and tsunami: impact of a plasmid harboring heavy metal resistance genes
(American Society for Microbiology, 2025-04-09)
Jose R. W. Martínez
;
Manuel Alcalde-Rico
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Estefanía Jara-Videla
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Jinnethe Reyes
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Lina P. Carvajal
(MRSA) is a major public health menace. The global spread of MRSA is characterized by successive waves of epidemic clones dominating specific geographical regions. The acquisition of genes encoding resistance to heavy metals (HMRGs) is thought to be a key feature in the geographic divergence of MRSA. However, the cause-effect relationship between the presence of HMRGs and the divergence of MRSA clones remains to be clarified. In this study, we assessed the role that HMRGs may have played in the evolutionary divergence of the MRSA ST5-SCC <jats:italic>mec</jats:italic> I lineage in Latin America. We conducted a genomic characterization of 113 MRSA clinical isolates from six Latin American healthcare centers, including 53 isolates collected from two cities in Chile (Santiago and Concepción). We found a plasmid (pSCL4752) harboring arsenic, cadmium, and mercury resistance genes in 65% ( <jats:italic>n</jats:italic> = 71) of the ST5-SCC <jats:italic>mec</jats:italic> I isolates. We also observed a geographic divergence associated with the presence of pSCL4752 in Chilean isolates, with a higher frequency in isolates from Concepción (88%) compared to Santiago (29%). Interestingly, a molecular clock analysis revealed that this divergence occurred in the aftermath of an 8.8 Mw earthquake and tsunami that struck the Concepción area in 2010. Moreover, our results demonstrate that the carriage of pSCL4752 can be beneficial or detrimental for ST5-SCC <jats:italic>mec</jats:italic> I isolates, depending on the environmental availability of these heavy metals. Our results suggest that the divergence of the ST5-SCC <jats:italic>mec</jats:italic> I MRSA lineage in Latin America could have been fostered by environmental disasters and influenced by the presence/absence of HMRGs harbored in a plasmid. </jats:p> <jats:sec> <jats:title>IMPORTANCE</jats:title> <jats:p> Methicillin-resistant <jats:italic>Staphylococcus aureus</jats:italic> (MRSA) is a major cause of life-threatening infections worldwide and a growing public health concern. The rise of antibiotic-resistant bacteria, such as MRSA, is often linked to genetic adaptations that enhance their survival. Our research sheds light on how environmental changes, such as those triggered by a natural disaster, can influence the evolution and geographic spread of a highly resistant MRSA lineage in Latin America. We identified a plasmid carrying genes for resistance to arsenic, cadmium, and mercury, which was associated with the geographic divergence of the ST5-SCC <jats:italic>mec</jats:italic> I MRSA lineage, with striking differences in its prevalence between regions affected by a major earthquake and tsunami. By linking environmental events to pathogen evolution, our study highlights the role of ecological pressures in the spread of MRSA. These findings emphasize the need to integrate environmental monitoring into public health strategies to better understand the global challenge of antimicrobial resistance.
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Resilience of mobility network to dynamic population response across COVID-19 interventions: Evidences from Chile
(Public Library of Science (PLoS), 2025-02-20)
Pasquale Casaburi
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Lorenzo Dall’Amico
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Nicolò Gozzi
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Kyriaki Kalimeri
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Anna Sapienza
The COVID-19 pandemic highlighted the importance of non-traditional data sources, such as mobile phone data, to inform effective public health interventions and monitor adherence to such measures. Previous studies showed how socioeconomic characteristics shaped population response during restrictions and how repeated interventions eroded adherence over time. Less is known about how different population strata changed their response to repeated interventions and how this impacted the resulting mobility network. We study population response during the first and second infection waves of the COVID-19 pandemic in Chile and Spain. Via spatial lag and regression models, we investigate the adherence to mobility interventions at the municipality level in Chile, highlighting the significant role of wealth, labor structure, COVID-19 incidence, and network metrics characterizing business-as-usual municipality connectivity in shaping mobility changes during the two waves. We assess network structural similarities in the two periods by defining mobility hotspots and traveling probabilities in the two countries. As a proof of concept, we simulate and compare outcomes of an epidemic diffusion occurring in the two waves. While differences exist between factors associated with mobility reduction across waves in Chile, underscoring the dynamic nature of population response, our analysis reveals the resilience of the mobility network across the two waves. We test the robustness of our findings recovering similar results for Spain. Finally, epidemic modeling suggests that historical mobility data from past waves can be leveraged to inform future disease spatial invasion models in repeated interventions. This study highlights the value of historical mobile phone data for building pandemic preparedness and lessens the need for real-time data streams for risk assessment and outbreak response. Our work provides valuable insights into the complex interplay of factors driving mobility across repeated interventions, aiding in developing targeted mitigation strategies.
2
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Discovery of novel genetic syndromes in Latin America: Opportunities and challenges
(2024)
Víctor Faundes
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REPETTO LISBOA, MARIA GABRIELA
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Leonardo E. Valdivia
Scopus© Citations 2 1
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New insights on the molecular mechanisms of collateral sprouting after peripheral nerve injury
(2021)
FelipeA Court
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DOMINIQUE LEMAITRE MUJICA
10Scopus© Citations 12
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Validation of an NGS Panel Designed for Detection of Actionable Mutations in Tumors Common in Latin America
(2021)
Mauricio Salvo
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Evelin González-Feliú
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Jessica Toro
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Iván Gallegos
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Ignacio Maureira
<jats:p>Next-generation sequencing (NGS) is progressively being used in clinical practice. However, several barriers preclude using this technology for precision oncology in most Latin American countries. To overcome some of these barriers, we have designed a 25-gene panel that contains predictive biomarkers for most current and near-future available therapies in Chile and Latin America. Library preparation was optimized to account for low DNA integrity observed in formalin-fixed paraffin-embedded tissue. The workflow includes an automated bioinformatic pipeline that accounts for the underrepresentation of Latin Americans in genome databases. The panel detected small insertions, deletions, and single nucleotide variants down to allelic frequencies of 0.05 with high sensitivity, specificity, and reproducibility. The workflow was validated in 272 clinical samples from several solid tumor types, including gallbladder (GBC). More than 50 biomarkers were detected in these samples, mainly in BRCA1/2, KRAS, and PIK3CA genes. In GBC, biomarkers for PARP, EGFR, PIK3CA, mTOR, and Hedgehog signaling inhibitors were found. Thus, this small NGS panel is an accurate and sensitive method that may constitute a more cost-efficient alternative to multiple non-NGS assays and costly, large NGS panels. This kind of streamlined assay with automated bioinformatics analysis may facilitate the implementation of precision medicine in Latin America.</jats:p>
2Scopus© Citations 13
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Mutation in a SARS-CoV-2 Haplotype from Sub-Antarctic Chile Reveals New Insights into the Spike’s Dynamics
(2021)
Jorge González-Puelma
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Jacqueline Aldridge
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Marco Montes de Oca
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Mónica Pinto
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Roberto Uribe-Paredes
<jats:p>The emergence of SARS-CoV-2 variants, as observed with the D614G spike protein mutant and, more recently, with B.1.1.7 (501Y.V1), B.1.351 (501Y.V2) and B.1.1.28.1 (P.1) lineages, represent a continuous threat and might lead to strains of higher infectivity and/or virulence. We report on the occurrence of a SARS-CoV-2 haplotype with nine mutations including D614G/T307I double-mutation of the spike. This variant expanded and completely replaced previous lineages within a short period in the subantarctic Magallanes Region, southern Chile. The rapid lineage shift was accompanied by a significant increase of cases, resulting in one of the highest incidence rates worldwide. Comparative coarse-grained molecular dynamic simulations indicated that T307I and D614G belong to a previously unrecognized dynamic domain, interfering with the mobility of the receptor binding domain of the spike. The T307I mutation showed a synergistic effect with the D614G. Continuous surveillance of new mutations and molecular analyses of such variations are important tools to understand the molecular mechanisms defining infectivity and virulence of current and future SARS-CoV-2 strains.</jats:p>
1Scopus© Citations 9
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Delineation of functionally essential protein regions for 242 neurodevelopmental genes
(2022)
Sumaiya Iqbal
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Tobias Brünger
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PEREZ PALMA, EDUARDO ESTEBAN
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Marie Macnee
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Andreas Brunklaus
<jats:title>Abstract</jats:title> <jats:p>Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are ‘variants of uncertain significance’. To safely enrol patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can ‘tolerate’ missense variants and which ones are ‘essential’ and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the 3D structure context of proteins can also provide insights into the molecular mechanisms of disease variants.</jats:p> <jats:p>We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14 377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including &gt;360 000 NDD patients and population controls, we found that missense variants at Essential3D sites are 8-fold enriched in patients.</jats:p> <jats:p>In summary, we developed a comprehensive protein structure set for 242 NDDs and identified 14 377 Essential3D sites in these. All data are available at https://es-ndd.broadinstitute.org for interactive visual inspection to enhance variant interpretation and development of mechanistic hypotheses for 242 NDDs genes. The provided resources will enhance clinical variant interpretation and in silico drug target development for NDD-associated genes and encoded proteins.</jats:p>
1Scopus© Citations 6 1
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Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes
(2022)
Tobias Brünger
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PEREZ PALMA, EDUARDO ESTEBAN
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Ludovica Montanucci
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Michael Nothnagel
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Rikke S Møller
<jats:title>Abstract</jats:title> <jats:p>Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. As a consequence, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion-channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated.</jats:p> <jats:p>We sought to systematically identify biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion-channel families. We collected and curated 3049 pathogenic variants from hundreds of neurodevelopmental and other disorders and 12 546 population variants for 30 ion channel or channel subunits for which a high-quality protein structure was available. Using a wide range of bioinformatics approaches, we computed 163 structural features and tested them for pathogenic variant enrichment. We developed a novel 3D spatial distance scoring approach that enables comparisons of pathogenic and population variant distribution across protein structures.</jats:p> <jats:p>We discovered and independently replicated that several pore residue properties and proximity to the pore axis were most significantly enriched for pathogenic variants compared to population variants. Using our 3D scoring approach, we showed that the strongest pathogenic variant enrichment was observed for pore-lining residues and alpha-helix residues within 5Å distance from the pore axis centre and not involved in gating. Within the subset of residues located at the pore, the hydrophobicity of the pore was the feature most strongly associated with variant pathogenicity. We also found an association between the identified properties and both clinical phenotypes and functional in vitro assays for voltage-gated sodium channels (SCN1A, SCN2A, SCN8A) and N-methyl-D-aspartate receptor (GRIN1, GRIN2A, GRIN2B) encoding genes. In an independent expert-curated dataset of 1422 neurodevelopmental disorder pathogenic patient variants and 679 electrophysiological experiments, we show that pore axis distance is associated with seizure age of onset and cognitive performance as well as differential gain versus loss-of-channel function.</jats:p> <jats:p>In summary, we identified biological properties associated with ion-channel malfunction and show that these are correlated with in vitro functional readouts and clinical phenotypes in patients with neurodevelopmental disorders. Our results suggest that clinical decision support algorithms that predict variant pathogenicity and function are feasible in the future.</jats:p>
1Scopus© Citations 13 6
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Immune-related IncRNA LINC00944 responds to variations in ADAR1 levels and it is associated with breast cancer prognosis
(2021)
Pamela R. de Santiago
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Alejandro Blanco
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Fernanda Morales
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Katherine Marcelain
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Olivier Harismendy
2Scopus© Citations 38
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Contemporary Clinical and Molecular Epidemiology of Vancomycin-Resistant Enterococcal Bacteremia: A Prospective Multicenter Cohort Study (VENOUS I)
(2021)
German A Contreras
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MUNITA SEPULVEDA, JOSE MANUEL
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Shelby Simar
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Courtney Luterbach
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An Q Dinh
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Vancomycin-resistant enterococci (VRE) are major therapeutic challenges. Prospective contemporary data characterizing the clinical and molecular epidemiology of VRE bloodstream infections (BSIs) are lacking.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>The Vancomycin-Resistant Enterococcal BSI Outcomes Study (VENOUS I) is a prospective observational cohort of adult patients with enterococcal BSI in 11 US hospitals. We included patients with Enterococcus faecalis or Enterococcus faecium BSI with ≥1 follow-up blood culture(s) within 7 days and availability of isolate(s) for further characterization. The primary study outcome was in-hospital mortality. Secondary outcomes were mortality at days 4, 7, 10, 12, and 15 after index blood culture. A desirability of outcome ranking was constructed to assess the association of vancomycin resistance with outcomes. All index isolates were subjected to whole genome sequencing.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Forty-two of 232 (18%) patients died in hospital and 39 (17%) exhibited microbiological failure (lack of clearance in the first 4 days). Neutropenia (hazard ratio [HR], 3.13), microbiological failure (HR, 2.4), VRE BSI (HR, 2.13), use of urinary catheter (HR, 1.85), and Pitt BSI score ≥2 (HR, 1.83) were significant predictors of in-hospital mortality. Microbiological failure was the strongest predictor of in-hospital mortality in patients with E faecium bacteremia (HR, 5.03). The impact of vancomycin resistance on mortality in our cohort changed throughout the course of hospitalization. Enterococcus faecalis sequence type 6 was a predominant multidrug-resistant lineage, whereas a heterogeneous genomic population of E faecium was identified.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Failure of early eradication of VRE from the bloodstream is a major factor associated with poor outcomes.</jats:p> </jats:sec>
5Scopus© Citations 42

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