Etthel Windels

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Windels

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Etthel

ORCID

0000-0003-2106-6765

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Publications 1 - 8 of 8

Onset of infectiousness explains differences in transmissibility across Mycobacterium tuberculosis lineages
Windels, Etthel; Valenzuela Agüí, Cecilia; De Jong, Bouke C.; et al. (2025)
Epidemics
Mycobacterium tuberculosis complex (MTBC) lineages show substantial variability in virulence, but the epidemiological consequences of this variability have not been studied in detail. Here, we aimed for a lineage-specific epidemiological characterization by applying phylodynamic models to genomic data from different countries, representing the most abundant MTBC lineages. Our results suggest that all lineages are associated with similar durations and levels of infectiousness, resulting in similar reproductive numbers. However, L1 and L6 are associated with a delayed onset of infectiousness, leading to longer periods between subsequent transmission events. Together, our findings highlight the role of MTBC genetic diversity in tuberculosis disease progression and transmission.
Enrichment of Persister Cells Through Β-Lactam-Induced Filamentation and Size Separation
Windels, Etthel; Van den Bergh, Bram; Michiels, Jan (2021)
Methods in Molecular Biology ~ Bacterial Persistence
Analyzing persisters at the single-cell level is crucial to properly define their phenotypic traits. However, single-cell analyses are challenging due to the rare and temporary nature of persister cells, thus requiring their rapid and efficient enrichment in a culture. Existing methods to isolate persisters from a bacterial population show important shortcomings, including contamination with susceptible cells and/or cell debris, which complicate subsequent microscopic analyses. We here describe a protocol to enrich persisters in a culture using β-lactam-induced filamentation followed by size separation. This protocol minimizes the amount of cell debris in the final sample, facilitating single-cell studies of persister cells.
The relative transmission fitness of multidrug-resistant Mycobacterium tuberculosis in a drug resistance hotspot
Loiseau, Chloé; Windels, Etthel; Gygli, Sebastian M.; et al. (2023)
Nature Communications
Multidrug-resistant tuberculosis (MDR-TB) is among the most frequent causes of death due to antimicrobial resistance. Although only 3% of global TB cases are MDR, geographical hotspots with up to 40% of MDR-TB have been observed in countries of the former Soviet Union. While the quality of TB control and patient-related factors are known contributors to such hotspots, the role of the pathogen remains unclear. Here we show that in the country of Georgia, a known hotspot of MDR-TB, MDR Mycobacterium tuberculosis strains of lineage 4 (L4) transmit less than their drug-susceptible counterparts, whereas most MDR strains of L2 suffer no such defect. Our findings further indicate that the high transmission fitness of these L2 strains results from epistatic interactions between the rifampicin resistance-conferring mutation RpoB S450L, compensatory mutations in the RNA polymerase, and other pre-existing genetic features of L2/Beijing clones that circulate in Georgia. We conclude that the transmission fitness of MDR M. tuberculosis strains is heterogeneous, but can be as high as drug-susceptible forms, and that such highly drug-resistant and transmissible strains contribute to the emergence and maintenance of hotspots of MDR-TB. As these strains successfully overcome the metabolic burden of drug resistance, and given the ongoing rollout of new treatment regimens against MDR-TB, proper surveillance should be implemented to prevent these strains from acquiring resistance to the additional drugs.
Antibiotic dose and nutrient availability differentially drive the evolution of antibiotic resistance and persistence
Windels, Etthel; Cool, Lloyd; Persey, Eline; et al. (2024)
The ISME Journal
Effective treatment of bacterial infections proves increasingly challenging due to the emergence of bacterial variants that endure antibiotic exposure. Antibiotic resistance and persistence have been identified as two major bacterial survival mechanisms, and several studies have shown a rapid and strong selection of resistance or persistence mutants under repeated drug treatment. Yet, little is known about the impact of the environmental conditions on resistance and persistence evolution and the potential interplay between both phenotypes. Based on the distinct growth and survival characteristics of resistance and persistence mutants, we hypothesized that the antibiotic dose and availability of nutrients during treatment might play a key role in the evolutionary adaptation to antibiotic stress. To test this hypothesis, we combined high-throughput experimental evolution with a mathematical model of bacterial evolution under intermittent antibiotic exposure. We show that high nutrient levels during antibiotic treatment promote selection of high-level resistance, but that resistance mainly emerges independently of persistence when the antibiotic concentration is sufficiently low. At higher doses, resistance evolution is facilitated by the preceding or concurrent selection of persistence mutants, which ensures survival of populations in harsh conditions. Collectively, our experimental data and mathematical model elucidate the evolutionary routes toward increased bacterial survival under different antibiotic treatment schedules, which is key to designing effective antibiotic therapies.
HIV co-infection is associated with reduced Mycobacterium tuberculosis transmissibility in sub-Saharan Africa
Windels, Etthel; Wampande, Eddie M.; Joloba, Moses L.; et al. (2024)
PLoS Pathogens
Persons living with HIV are known to be at increased risk of developing tuberculosis (TB) disease upon infection with Mycobacterium tuberculosis (Mtb). However, it has remained unclear how HIV co-infection affects subsequent Mtb transmission from these patients. Here, we customized a Bayesian phylodynamic framework to estimate the effects of HIV co-infection on the Mtb transmission dynamics from sequence data. We applied our model to four Mtb genomic datasets collected in sub-Saharan African countries with a generalized HIV epidemic. Our results confirm that HIV co-infection is a strong risk factor for developing active TB. Additionally, we demonstrate that HIV co-infection is associated with a reduced effective reproductive number for TB. Stratifying the population by CD4+ T-cell count yielded similar results, suggesting that, in this context, CD4+ T-cell count is not a better predictor of Mtb transmissibility than HIV infection status alone. Together, our genome-based analyses complement observational household contact studies, and more firmly establish the negative association between HIV co-infection and Mtb transmissibility.
Back-to-Africa introductions of Mycobacterium tuberculosis as the main cause of tuberculosis in Dar es Salaam, Tanzania
Zwyer, Michaela; Rutaihwa, Liliana K.; Windels, Etthel; et al. (2023)
PLoS Pathogens
In settings with high tuberculosis (TB) endemicity, distinct genotypes of the Mycobacterium tuberculosis complex (MTBC) often differ in prevalence. However, the factors leading to these differences remain poorly understood. Here we studied the MTBC population in Dar es Salaam, Tanzania over a six-year period, using 1,082 unique patient-derived MTBC whole-genome sequences (WGS) and associated clinical data. We show that the TB epidemic in Dar es Salaam is dominated by multiple MTBC genotypes introduced to Tanzania from different parts of the world during the last 300 years. The most common MTBC genotypes deriving from these introductions exhibited differences in transmission rates and in the duration of the infectious period, but little differences in overall fitness, as measured by the effective reproductive number. Moreover, measures of disease severity and bacterial load indicated no differences in virulence between these genotypes during active TB. Instead, the combination of an early introduction and a high transmission rate accounted for the high prevalence of L3.1.1, the most dominant MTBC genotype in this setting. Yet, a longer co-existence with the host population did not always result in a higher transmission rate, suggesting that distinct life-history traits have evolved in the different MTBC genotypes. Taken together, our results point to bacterial factors as important determinants of the TB epidemic in Dar es Salaam.
Population Bottlenecks Strongly Affect the Evolutionary Dynamics of Antibiotic Persistence
Windels, Etthel; Fox, Richard; Yerramsetty, Krishna; et al. (2021)
Molecular Biology and Evolution
Bacterial persistence is a potential cause of antibiotic therapy failure. Antibiotic-tolerant persisters originate from phenotypic differentiation within a susceptible population, occurring with a frequency that can be altered by mutations. Recent studies have proven that persistence is a highly evolvable trait and, consequently, an important evolutionary strategy of bacterial populations to adapt to high-dose antibiotic therapy. Yet, the factors that govern the evolutionary dynamics of persistence are currently poorly understood. Theoretical studies predict far-reaching effects of bottlenecking on the evolutionary adaption of bacterial populations, but these effects have never been investigated in the context of persistence. Bottlenecking events are frequently encountered by infecting pathogens during host-to-host transmission and antibiotic treatment. In this study, we used a combination of experimental evolution and barcoded knockout libraries to examine how population bottlenecking affects the evolutionary dynamics of persistence. In accordance with existing hypotheses, small bottlenecks were found to restrict the adaptive potential of populations and result in more heterogeneous evolutionary outcomes. Evolutionary trajectories followed in small-bottlenecking regimes additionally suggest that the fitness landscape associated with persistence has a rugged topography, with distinct trajectories toward increased persistence that are accessible to evolving populations. Furthermore, sequencing data of evolved populations and knockout libraries after selection reveal various genes that are potentially involved in persistence, including previously known as well as novel targets. Together, our results do not only provide experimental evidence for evolutionary theories, but also contribute to a better understanding of the environmental and genetic factors that guide bacterial adaptation to antibiotic treatment.
Ecology, global diversity and evolutionary mechanisms in the Mycobacterium tuberculosis complex
Goig, Galo A.; Windels, Etthel; Loiseau, Chloé; et al. (2025)
Nature Reviews Microbiology
With the COVID-19 pandemic receding, tuberculosis (TB) is again the number one cause of human death to a single infectious agent. TB is caused by bacteria that belong to the Mycobacterium tuberculosis complex (MTBC). Recent advances in genome sequencing have provided new insights into the ecology and evolution of the MTBC. This includes the discovery of new phylogenetic lineages within the MTBC, a deeper understanding of the host tropism among the various animal-adapted lineages, enhanced knowledge on the evolutionary dynamics of antimicrobial resistance and transmission, as well as a better grasp of the within-host MTBC diversity. Moreover, advances in long-read sequencing are increasingly highlighting the relevance of structural genomic variation in the MTBC. These findings not only shed new light on the biology and epidemiology of TB, but also give rise to new questions and research avenues. The purpose of this Review is to summarize these new insights and discuss their implications for global TB control.

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