Biology subjects

Feldmann, J.

Publications and source records attributed to Feldmann, J..

9 recordsLinked to original sources

bioRxiv2020

Local adaptation in populations of Mycobacterium tuberculosis endemic to the Indian Ocean Rim

Lineage 1 (L1) and 3 (L3) are two lineages of the Mycobacterium tuberculosis complex (MTBC), causing tuberculosis (TB) in humans. L1 and L3 are endemic to the Rim of the Indian Ocean, the region that accounts for most of the worlds new TB cases. Despite their relevance for this region, L1 and L3 remain understudied. Here we analyzed 2,938 L1 and 2,030 L3 whole genome sequences originating from 69 countries. We show that South Asia played a central role in the dispersion of these two lineages to neighboring regions. Moreover, we found that L1 exhibits signatures of local adaptation at the esxH locus, a gene coding for a secreted effector that targets the human endosomal sorting complex, and is included in several vaccine candidates. Our study highlights the importance of genetic diversity in the MTBC, and sheds new light on two of the most important MTBC lineages affecting humans.

genomics↗

bioRxiv2020

Bio-Inspired Molecular Bridging in a Hybrid Perovskite Leads to Enhanced Stability and Tunable Properties

Hybrid organic-inorganic halide perovskites demonstrate high potential in several applications such as solar cells, field-effect transistors, light-emitting diodes and more. However, the main drawback which limits their use in such applications is their low stability in humid conditions. In this paper we implement one of Natures strategies found in bio-crystals in order to improve the stability of the hybrid perovskite methylammonium lead bromide (MAPbBr3) in water, as well as to tune its structure, optical and thermal properties. This was achieved, for the first time, by the incorporation of amino acids into the lattice of MAPbBr3. The amino acid lysine, which possesses two NH3+ groups, is incorporated into the hybrid unit cell, by substituting two methylammonium ions and serves as a "molecular bridge". This incorporation induces a decrease in the lattice parameter of the host, accompanied with an increase in the band gap and noticeable changes in its morphology. Furthermore, we observed an increase in thermal expansion coefficient and a shift of the phase transformation temperature of the hybrid crystal. The level of amino acid incorporation depends on the conditions of crystallization, which also influence the extent of MAPbBr3 band gap changes. Notably, lysine incorporation strongly increases the perovskite stability in water. This study demonstrates the unique and promising approach to tune the properties and stability of hybrid perovskites via this novel bio-inspired route.

bioengineering↗

bioRxiv2020

Network analysis identifies regulators of lineage-specific phenotypes in Mycobacterium tuberculosis

The Mycobacterium tuberculosis (Mtb) complex includes ten phylogenetically distinct human-adapted lineages with varying geographical distributions and pathogenicity. Lineage 1 (L1) is associated with low virulence, while Lineage 2 (L2) is linked to hyper-virulence, increased transmission, and drug resistance. We performed multi-layer comparative analyses integrating whole-genome sequencing with quantitative transcriptomic and proteomic profiling of a panel of L1 and L2 clinical strains, each grown under two in vitro conditions. Our data revealed variable correlations between transcript and protein levels across strains and gene categories, indicating lineage-specific post-translational regulation. Transcriptional and translational differences scaled with phylogenetic distance, with one in three SNPs on average leading to gene expression changes. A newly developed genome-scale transcriptional regulatory model identified master transcription factors--closely linked to the sigma factor network--whose targets were differentially expressed between L1 and L2. Notably, DosR proteins showed higher basal levels and a stronger nitric oxide (NO) response in L2. Time-course validation using an Rv1985c induction and wild-type H37Rv under hypoxia and reaeration confirmed the role of Rv1985c in the differentially expressed genes between L1 and L2. These findings suggest that limited genetic variation can translate into significant phenotypic differences via differential regulation of key transcriptional networks. HighlightsO_LIProteomic and transcriptomic characterization of fully sequenced diverse L1 and L2 clinical strains of Mtb. C_LIO_LIPost translational control mechanisms for regulatory and virulence genes are mitigated in Mtb L2. C_LIO_LIA genome-scale transcriptional framework identifies DosR, Rv1985c, Lsr2 and Rv0691c as master transcription factors responsible for differential target gene expression in L2 compared to L1 strains. C_LIO_LIL1 and L2 DosR proteins respond differently to nitric oxide stress, thus determining a relevant phenotype. C_LIO_LITime-course phenotypic and transcriptomic data under hypoxia and reaeration validate Rv1985c as a key transcription factor differentiating L2 and L1 strains. C_LI

systems biology↗

bioRxiv2019

The Evolution of Fluoroquinolone-Resistance in Mycobacterium tuberculosis is Modulated by the Genetic Background

Fluoroquinolones (FQ) form the backbone in experimental treatment regimens against drug-susceptible tuberculosis. However, little is known on whether the genetic variation present in natural populations of Mycobacterium tuberculosis (Mtb) affects the evolution of FQ-resistance (FQ-R). To investigate this question, we used a set of Mtb strains that included nine genetically distinct drug-susceptible clinical isolates, and measured their frequency of resistance to the FQ ofloxacin (OFX) in vitro. We found that the Mtb genetic background led to differences in the frequency of OFX-resistance (OFX-R) that spanned two orders of magnitude and substantially modulated the observed mutational profiles for OFX-R. Further in vitro assays showed that the genetic background also influenced the minimum inhibitory concentration and the fitness effect conferred by a given OFX-R mutation. To test the clinical relevance of our in vitro work, we surveyed the mutational profile for FQ-R in publicly available genomic sequences from clinical Mtb isolates, and found substantial Mtb lineage-dependent variability. Comparison of the clinical and the in vitro mutational profiles for FQ-R showed that 45% and 19% of the variability in the clinical frequency of FQ-R gyrA mutations in Lineage 2 and Lineage 4 strains, respectively, can be attributed to how Mtb evolves FQ-R in vitro. As the Mtb genetic background strongly influenced the evolution of FQ-R in vitro, we conclude that the genetic background of Mtb also impacts the evolution of FQ-R in the clinic.\n\nSignificanceNewer generations of fluoroquinolones form the backbone in many experimental treatment regimens against M. tuberculosis (Mtb). While the genetic variation in natural populations of Mtb can influence resistance evolution to multiple different antibiotics, it is unclear whether it modulates fluoroquinolone-resistance evolution as well. Using a combination of in vitro assays coupled with genomic analysis of clinical isolates, we provide the first evidence illustrating the Mtb genetic backgrounds substantial role in fluoroquinolone-resistance evolution, and highlight the importance of bacterial genetics when studying the prevalence of fluoroquinolone-resistance in Mtb. Our work may provide insights into how to maximize the timespan in which fluoroquinolones remain effective in clinical settings, whether as part of current standardized regimens, or in new regimens against Mtb.

microbiology↗

bioRxiv2019

Model-based integration of genomics and metabolomics reveals SNP functionality in Mycobacterium tuberculosis

Human tuberculosis is caused by members of the Mycobacterium tuberculosis complex (MTBC) and presents variable disease outcomes. The variation has primarily been attributed to host and environmental factors, but recent evidence indicates an additional role of genetic diversity among MTBC clinical strains. Here, we used metabolomics to unravel the potential role of genetic variations in conferring strain-specific adaptive capacity and vulnerability. To systematically identify functionality of single nucleotide polymorphisms (SNPs), we developed a constraint-based approach that integrates metabolomic and genomic data. Model-based predictions were systematically tested against independent metabolome data; they correctly classified SNP effects in pyruvate kinase and suggested a genetic basis for strain-specific sensitivity to the antibiotic para-aminosalicylic acid. Our method is broadly applicable to mutations in enzyme-encoding genes across microbial life, opening new possibilities for identifying strain-specific metabolic vulnerabilities that could lead to more selective treatment strategies.

systems biology↗

bioRxiv2018

Resource misallocation as a mediator of fitness costs in antibiotic resistance.

Antimicrobial resistance poses a threat to global health and the economy. It is widely accepted that, in the absence of antibiotics, drug resistance mutations carry a fitness cost. In the case of rifampicin resistance in fast-growing bacteria, this cost stems from a reduced transcription rate of the RNA polymerase resulting in slower ribosome biosynthesis. However, this relationship does not apply in the slow-growing Mycobacterium tuberculosis, where the true mechanism of fitness cost of rifampicin resistance as well as the impact of compensatory evolution remain unknown. Here we show, using global transcriptomic and proteomic profiling of selected M. tuberculosis mutants and clinical strains, that the fitness cost of rifampicin resistance in M. tuberculosis is the result of the physiological burden caused by aberrant gene expression. We further show that the perceived burden can be increased, effectively suppressing the emergence of drug resistance.

microbiology↗

bioRxiv2018

Insights into the genetic diversity of Mycobacterium tuberculosis in Tanzania

BackgroundHuman tuberculosis (TB) is caused by seven phylogenetic lineages of the Mycobacterium tuberculosis complex (MTBC), Lineage 1-7. Recent advances in rapid genotyping of MTBC based on single nucleotide polymorphisms (SNP), allow for rapid and phylogenetically robust strain classification, paving the way for defining genotype-phenotype relationships in clinical settings. Such studies have revealed that, in addition to host and environmental factors, different strains of the MTBC influence the outcome of TB infection and disease. In Tanzania, such molecular epidemiological studies of TB however are scarce in spite of a high TB burden.\n\nMethods and FindingsHere we used a SNP-typing method to genotype a nationwide collection of 2,039 MTBC clinical isolates obtained from new and retreatment TB cases diagnosed in 2012 and 2013. Four lineages, namely Lineage 1-4 were identified. The distribution and frequency of these lineages varied across the regions but overall, Lineage 4 was the most frequent (n=866, 42.5%), followed by Lineage 3 (n=681, 33.4%) and 1 (n=336, 16.5%), with Lineage 2 being the least frequent (n=92, 4.5%). A total of 64 (3.1%) isolates could not be assigned to any lineage. We found Lineage 2 to be associated with female sex (adjusted odds ratio [aOR] 2.25; 95% confidence interval [95% CI] 1.38 - 3.70, p<0.001) and retreatment (aOR 1.78; 95% CI 1.00 - 3.02, p=0.040). We found no associations between MTBC lineage and patient age or HIV status. Our sublineage typing based on spacer oligotyping revealed the presence of mainly EAI, CAS and LAM families. Finally, we detected low levels of multidrug resistant isolates among a subset of retreatment cases\n\nConclusionsThis study provides novel insights into the influence of pathogen-related factors on the TB epidemic in Tanzania.

epidemiology↗

bioRxiv2018

Multiple Introductions of the Mycobacterium tuberculosis Lineage 2 Beijing into Africa over centuries

The Lineage 2-Beijing (L2-Beijing) sub-lineage of Mycobacterium tuberculosis has received much attention due to its high virulence, fast disease progression, and association with antibiotic resistance. Despite several reports of the recent emergence of L2-Beijing in Africa, no study has investigated the evolutionary history of this sub-lineage on the continent. In this study, we used whole genome sequences of 817 L2 clinical strains from 14 geographical regions globally distributed to investigate the origins and onward spread of this lineage in Africa. Our results reveal multiple introductions of L2-Beijing into Africa linked to independent bacterial populations from East-and Southeast Asia. Bayesian analyses further indicate that these introductions occurred during the past 300 years, with most of these events pre-dating the antibiotic era. Hence, the success of L2-Beijing in Africa is most likely due to its hypervirulence and high transmissibility rather than drug resistance.

evolutionary biology↗

bioRxiv2018

Reference Set of Mycobacterium tuberculosis Clinical Strains: A tool for research and product development

The Mycobacterium tuberculosis complex (MTBC) causes tuberculosis (TB) in humans and various other mammals. The human-adapted members of the MTBC comprise seven phylogenetic lineages that differ in their geographical distribution. There is growing evidence that this phylogenetic diversity modulates the outcome of TB infection and disease. For decades, TB research and development has focused on the two canonical MTBC reference strains H37Rv and Erdman, both of which belong to Lineage 4. Relying on only a few laboratory-adapted strains can be misleading as study results might not be directly transferrable to clinical settings where patients are infected with a diverse array of strains, including drug-resistant variants. Here, we argue for the need to expand TB research and development by incorporating the phylogenetic diversity of the MTBC. To facilitate such work, we have assembled a group of 20 genetically well-characterized clinical strains representing the seven known human-adapted MTBC lineages. With the \"MTBC clinical strains reference set\" we aim to provide a standardized resource for the TB community. We hope it will enable more direct comparisons between studies that explore the physiology of MTBC beyond the lab strains used thus far. We anticipate that detailed phenotypic analyses of this reference strain set will increase our understanding of TB biology and assist in the development of new control tools that are universally effective.

microbiology↗