Biology subjects

van Soolingen, D.

Publications and source records attributed to van Soolingen, D..

8 recordsLinked to original sources

bioRxiv2025

Verification of emerging genomic mutations in Mycobacterium tuberculosis allows transmission chains to be distinguished in an epidemiological typing cluster extending over thirty years.

Whole genome sequencing (WGS) is able to identify epidemiological links between Mycobacterium tuberculosis isolates. Recent clustering can be ruled out using a pre-defined single nucleotide polymorphism (SNP) threshold. If WGS clusters grow significantly over time limited genetic variability hampers epidemiological investigations. Newly emerging (informative) SNPs in isolates of an extended cluster growing for more than 30 years to >150 cases in the Netherlands were analysed. WGS data was analyzed from 61 sequencing files from 54 patients. Genomic positions that varied within the cluster isolates were carefully screened for minority populations in other isolates from the cluster. A transmission scheme was generated on the basis of WGS data alone then compared to the epidemiological information available. Fifty-two informative SNPs were identified, eight of which were also detected as mixed variants. One emerging SNP in dnaA (1199G>A R400H) has been observed in other transmitted strains and may be under selection. There was high concordance between the transmission chains suggested on basis of the newly emerging SNPs and scenarios identified using classical epidemiological cluster investigations. Analysis of filtered SNPs accumulating in the genome of M. tuberculosis in large clusters contains information on transmission dynamics and can be used to support epidemiological investigations.

microbiology↗

bioRxiv2024

Understanding the epidemiology and pathogenesis of Mycobacterium tuberculosis with non-redundant pangenome and population genetics

Tuberculosis is a major public health threat demanding more than one million lives every year. Many challenges exist to defeat this deadly infectious disease which address the importance of a thorough understanding of the biology of the causative agent Mycobacterium tuberculosis (MTB). We generated a non-redundant pangenome of 420 epidemic MTB strains from China. We estimate that MTB strains have a pangenome of 4,278 genes encoding 4,183 proteins, of which 3,438 of which are core genes. However, due to 99,694 interruptions in 2,447 coding genes, only 1,651 may be translated in all samples, which dramatically reduces the number of active core genes. Of these interruptions, 67,315 (67.52%) could be classified by various genetic variations detected by currently available tools, and more than half of them are due to structure variations, mostly small indels. We further describe differential evolutionary patterns of genes under the influences of selective pressure, population structure and background selection. While selective pressure is ubiquitous among these coding genes, evolutionary adaptations primarily occur in 1,313 genes. Genes located in the cell wall and membrane region are under the strongest selective pressure, while biological processes including regulation of transcription, translation and regulation of growth are under strongest background selection in MTB. The metabolism of fatty acids may be an outstanding example of evolutionary adaption for MTB under current selective pressure. This study provides a comprehensive view on the genetic diversity and evolution patterns of coding genes in MTB which may deepen our understanding of its epidemiology and pathogenicity.

microbiology↗

bioRxiv2024

Phylogenomic and genomic analysis reveals unique and shared genetic signatures of Mycobacterium kansasii complex species

Species belonging to the Mycobacterium kansasii complex (MKC) are frequently isolated from humans and the environment and can cause serious diseases. The most common MKC infections are caused by the species M. kansasii (stricto sensu), leading to tuberculosis-like disease. However, a broad spectrum of virulence, antimicrobial resistance and pathogenicity of these non-tuberculous mycobacteria (NTM) are observed across the MKC. Many genomic aspects of the MKC that relate to these broad phenotypes are not well elucidated. Here, we performed genomic analyses from a collection of 665 MKC strains, isolated from environmental, animal and human sources. We inferred the MKC pangenome, mobilome, resistome, virulome and defense systems and show that the MKC species harbors unique and shared genomic signatures. High frequency of presence of prophages and different types of defense systems was observed. We found that the M. kansasii species splits into four lineages, of which three are lowly represented and mainly in Brazil, while one lineage is dominant and globally spread. Moreover, we show that four sub-lineages of this most distributed M. kansasii lineage emerged during the 20th century. Further analysis of the M. kansasii genomes revealed almost 300 regions of difference contributing to genomic diversity, as well as fixed mutations that may explain the M. kansasiis increased virulence and drug resistance. RepositoriesBioProject PRJNA1048499. Impact statementMycobacterium kansasii complex (MKC) is a group of closely related non-tuberculous mycobacteria species, recognized as a significant source of human infection. Species belonging to the MKC may present a broad spectrum of virulence, antimicrobial resistance and pathogenicity and there is a lack of knowledge about their genomic content related to these broad phenotypes. We have provided whole genomic sequencing DNA for 342 MKC isolates and, together with public data, investigated the MKC pangenome, mobilome, resistome, virulome and defense systems and show unique and shared genetic signatures within MKC species. Furthermore, with phylogenomic and bayesian population analysis, we inferred the distribution and emergence of the Mycobacterium kansasii species lineages and sub-lineages. This study has considerably expanded the MKC available data, by providing genomic sequences of isolates from countries and global regions with unknown or poorly MKC data until now. Data summaryNGS data generated in the study are available in the NCBI Sequence Read Archive (SRA) repository under the accession number PRJNA1048499 and the accession numbers for all data sets used are provided in Supplementary Table 1.

evolutionary biology↗

bioRxiv2023

The appearance of sugI mixed loci in three individuals during treatment for MDR-TB, supports the involvement of sugI in Mycobacterium tuberculosis d-cycloserine resistance in vivo.

To study the adaptation of multi-drug resistant Mycobacterium tuberculosis (MDR-TB) during treatment patients diagnosed with MDR-TB were recruited into an observational study. Clinical data and M. tuberculosis DNA at diagnosis and between seven days and two months of MDR-TB treatment were collected. The drugs prescribed were recorded. Interpretable WGS data from 118 isolates from 54 participants was obtained (11 in Belarus and 43 in Moldova) and screened for the presence of unfixed single nucleotide polymorphisms (mixed SNPs / loci). This study was performed shortly after the publication of the 2019 WHO consolidated guidelines on drug-resistant tuberculosis treatment. Existing drug supplies and procurement in one country after the switch to the all oral MDR-TB regimen in addition to patient factors, influenced the selection of and exposure to drugs. Confidently mixed SNPs were identified in samples from multiple participants in only five genes (gyrA, pncA, Rv1129c, Rv1148c, and sugI). All other genes with confidently mixed SNPs were identified in isolates from only a single individual. A significant proportion of the participants (52 of 54 participants) received d-cycloserine as part of their initial treatment, most participants who initially received d-cycloserine did not receive bedaquiline in their initial regimen (all at one site). Three different mixed SNPs were identified in sugI gene from a follow up isolate from three participants (P7A, P7T, and Q6stop). Mutations in sugI have previously been reported in spontaneous in vitro d-cycloserine resistant mutants. Alterations in the sugI gene may indicate a sub optimal d-cycloserine containing regimen and potentially be of clinical significance with respect to adaptation to d-cycloserine. Monitoring the accumulation of low frequency escape mutants may help identify regimens insufficiently powerful to block the accumulation of antimicrobial resistance mutants and identify drug(s) at risk of resistance selection.

microbiology↗

bioRxiv2019

Genetic profiling of Mycobacterium tuberculosis \"modern\" Beijing strains from Southwest Colombia

Beijing strains of Mycobacterium tuberculosis (lineage2) have been associated with drug-resistance and transmission of tuberculosis worldwide. Most of the Beijing strains identified in the Colombian pacific coast exhibited a multidrug resistant (MDR) phenotype, in contrast with the phenotype observed in Beijing isolates from other South-American countries. We wanted to evaluate the clonality and genetic background of the Beijing strains isolated in Colombia that belong mostly to the spoligo-international type (SIT) 190. Out of 37 Beijing stains characterized in an 8-years period, we identified five Beijing clones; 36 that belong to the SIT190 type and only one to SIT1. Two loci in VNTR typing: MIRU 39 and QUB11b exhibited the highest level of variation among these strains. Out of the 37 Beijing strains, only one was drug susceptible, 28 represented MDR-TB, four extensively drug resistant TB (XDR-TB) and four pre-XDR-TB. The mutations rpoB S531L and katG S315T1 were the most common among the MDR strains as reported elsewhere. Whole genome sequencing analysis allowed us to classify them as modern lineage Beijing strains, sharing up to 76 out of the 275 SNPs described in Beijing strains, as identified worldwide by Schurch et al; including 54 non-synonymous SNPs and 23 silent mutations. We were also able to confirm the presence of 8 specific SNPs that were so far only found in the Beijing strains from Colombia. The presence of modern Beijing strains, most of them representing MDR-TB, suggests a different origin of this M. tuberculosis lineage compared to other Beijing strains found in neighboring countries, such as Peru. The specific 8-SNP signature confirmed the identity of these Colombian Beijing MDR strains. This work may serve as a genetic baseline to study the evolution and spread of M. tuberculosis Beijing strains in Colombia, which play an important role in the control of MDR-TB.

microbiology↗

bioRxiv2019

A model of tuberculosis clustering in low incidence countries reveals more on-going transmission in the United Kingdom than the Netherlands between 2010 and 2015.

Tuberculosis (TB) is a major public health threat, including in low TB incidence countries, through a combination of imported infection and onward transmission. Using data from the Enhanced Tuberculosis Surveillance system in the United Kingdom (UK) and the Netherlands (NL) Tuberculosis Register, we developed a mathematical model of TB importation and transmission in low-incidence settings. We apply this method to compare the effective reproduction number for TB, the contribution of importation and the role of superspreaders in the UK and the NL. We estimate that on average, between 2010 and 2015, a TB case generated 0{middle dot}41(0{middle dot}30,0{middle dot}60) secondary cases in the UK, and 0{middle dot}24(0{middle dot}14,0{middle dot}48) secondary cases in the NL. A majority of cases did not generate any secondary cases. Recent transmission accounted for 26% (21%,36%) of UK cases and 19%(11%,31%) of NL cases. We predict that reducing UK transmission rates to those observed in NL would result in 538(266,818) fewer cases annually in the UK. This methodology reveals common transmission mechanisms across two low-incidence countries and can be applied to other settings. Control policies aimed at limiting spread have a role to play in eliminating TB in low incidence countries.

epidemiology↗

bioRxiv2018

Genome wide association with quantitative resistance phenotypes in Mycobacterium tuberculosis reveals novel resistance genes and regulatory regions

Drug resistance is threatening attempts at tuberculosis epidemic control. Molecular diagnostics for drug resistance that rely on the detection of resistance-related mutations could expedite patient care and accelerate progress in TB eradication. We performed minimum inhibitory concentration testing for 12 anti-TB drugs together with Illumina whole genome sequencing on 1452 clinical Mycobacterium tuberculosis (MTB) isolates. We then used a linear mixed model to evaluate genome wide associations between mutations in MTB genes or noncoding regions and drug resistance, followed by validation of our findings in an independent dataset of 792 patient isolates. Novel associations at 13 genomic loci were confirmed in the validation set, with 2 involving noncoding regions. We found promoter mutations to have smaller average effects on resistance levels than gene body mutations in genes where both can contribute to resistance. Enabled by a quantitative measure of resistance, we estimated the heritability of the resistance phenotype to 11 anti-TB drugs and identify a lower than expected contribution from known resistance genes. We also report the proportion of variation in resistance levels explained by the novel loci identified here. This study highlights the complexity of the genomic mechanisms associated with the MTB resistance phenotype, including the relatively large number of potentially causative or compensatory loci, and emphasizes the contribution of the noncoding portion of the genome.

evolutionary biology↗

bioRxiv2017

A novel multi SNP based method for identifying subspecies and associated lineages and sub-lineages of the Mycobacterium tuberculosis complex by whole genome sequencing

The clinical phenotype of zoonotic tuberculosis, its contribution to the global burden of disease and prevalence are poorly understood and probably underestimated. This is partly because currently available laboratory and in silico tools have not been calibrated to accurately identify all subspecies of the Mycobacterium tuberculosis complex (Mtbc). We here present the first such tool, SNPs to Identify TB ( SNP-IT). Applying SNP-IT to a collection of clinical genomes from a UK reference laboratory, we demonstrate an unexpectedly high number of M. orygis isolates. These are seen at a similar rate to M. bovis which attracts much health protection resource and yet M. orygis cases have not been previously described in the UK. From an international perspective it is possible that M. orygis is an underestimated zoonosis. As whole genome sequencing is increasingly integrated into the clinical setting, accurate subspecies identification with SNP-IT will allow the clinical phenotype, host range and transmission mechanisms of subspecies of the Mtbc to be studied in greater detail.

microbiology↗