Biology subjects

Herrmann, J.-L.

Publications and source records attributed to Herrmann, J.-L..

7 recordsLinked to original sources

bioRxiv2024

Curcumin-mediated NRF2 induction limits inflammatory damage in preclinical models of cystic fibrosis

Overactive inflammation is directly correlated with airway damage and early death in individuals with cystic fibrosis (CF), a genetic disorder caused by mutation in the CFTR gene. Reducing the impact of inflammatory damage is therefore a major concern in CF. Several studies indicate that a decrease in the nuclear factor erythroid 2-related factor-2 (NRF2) signaling in people with CF may hamper their ability to alleviate oxidative stress and inflammation, although the role of NRF2 in CF inflammatory damage has not been determined. Therefore, we examined whether the phytochemical curcumin, an activator of NRF2, might provide a beneficial effect in the context of CF. Herein, combining Cftr-depleted zebrafish larvae as innovative biomedical model with CF patient-derived airway organoids (AOs), we sought to understand how NRF2 dysfunction leads to abnormal inflammatory status and impaired tissue remodeling, and determine the effects of curcumin in reducing inflammation and tissue damage in CF. We demonstrate that NFR2 is instrumental in efficiently regulating inflammatory and repair processes in vivo, thereby preventing acute neutrophilic inflammation and tissue damage. Importantly, curcumin treatment restores NRF2 activity in both CF zebrafish and AOs. Curcumin reduces neutrophilic inflammation in CF context, by rebalancing the production of epithelial ROS and pro-inflammatory cytokines. Furthermore, curcumin alleviates CF-associated tissue remodeling and allows tissue repair to occur. Our findings demonstrate that curcumin reduces inflammatory damage by restoring normal NRF2 activity, since disruption of Nrf2 pathway abrogated the effect of treatment in CF zebrafish. This work highlights the protective role of NRF2 in limiting inflammation and injury, and show that therapeutic strategies to normalize NRF2 activity using curcumin might simultaneously reduce inflammation and enhance tissue repair, and thus prevent infectious and inflammatory lung damage in CF.

immunology↗

bioRxiv2023

Lsr2, a pleiotropic regulator at the core of the infectious strategy of Mycobacterium abscessus

Mycobacterium abscessus is a non-tuberculous mycobacterium, causing lung infections in cystic fibrosis patients. During pulmonary infection, M. abscessus switches from smooth (Mabs-S) to rough (Mabs-R) morphotypes, the latter being hyper-virulent. Previously, we isolated the lsr2 gene as differentially expressed during S-to-R transition. lsr2 encodes a pleiotropic transcription factor that falls under the superfamily of nucleoid-associated proteins (NAPs). Here, we used two functional genomics methods, RNA-seq and ChIP-seq, to elucidate the molecular role of Lsr2 in the pathobiology of M. abscessus. Transcriptomic analysis shows that Lsr2 differentially regulates gene expression across both morphotypes, most of which are involved in several key cellular processes of M. abscessus, including host adaptation and antibiotic resistance. These results were confirmed through RT-qPCR, as well as by minimum inhibitory concentration (MIC) tests and infection tests on macrophages in the presence of antibiotics. ChIP-seq analysis revealed that Lsr2 extensively binds the M. abscessus genome at AT-rich sequences and appears to form long domains that participate in the repression of its target genes. Unexpectedly, the genomic distribution of Lsr2 revealed no distinctions between Mabs-S and Mabs-R, implying more intricate mechanisms at play for achieving target selectivity. IMPORTANCELsr2 is a crucial transcription factor and chromosome organizer involved in intracellular growth and virulence in the smooth and rough morphotypes of Mycobacterium abscessus (Mabs). Using RNA-seq and ChIP-seq, we investigated the molecular role of Lsr2 in gene expression regulation along with its distribution on Mabs genome. Our study demonstrates the pleiotropic regulatory role of Lsr2, regulating the expression of many genes coordinating essential cellular and molecular processes in both morphotypes. In addition, we have elucidated the role of Lsr2 in antibiotic resistance both in vitro and in vivo, where lsr2 mutant strains display heightened sensitivity to antibiotics. Through ChIP-seq, we reported the widespread distribution of Lsr2 on Mabs genome, revealing a direct repressive effect due to its extensive binding on promoters or coding sequences of its targets. This study unveils the significant regulatory role of Lsr2, intricately intertwined with its function in shaping the organization of the Mabs genome.

genomics↗

bioRxiv2021

Roscovitine exacerbates Mycobacterium abscessus infection by reducing NADPH oxidase-dependent neutrophil trafficking

Persistent neutrophilic inflammation associated with chronic pulmonary infection causes progressive lung injury and eventually death in individuals with cystic fibrosis (CF), a genetic disease caused by bi-allelic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We therefore examined whether Roscovitine, a cyclin-dependent kinase inhibitor that (in other conditions) reduces inflammation while promoting host defence, might provide a beneficial effect in the context of CF. Herein, using CFTR-depleted zebrafish larvae as an innovative vertebrate model of CF immuno-pathophysiology, combined with murine and human approaches, we sought to determine the effects of Roscovitine on innate immune responses to tissue injury and pathogens in CF condition. We show that Roscovitine exerts anti-inflammatory and pro-resolution effects in neutrophilic inflammation induced by infection or tail amputation in zebrafish. Roscovitine reduces overactive epithelial ROS-mediated neutrophil trafficking, by reducing DUOX2/NADPH-oxidase activity, and accelerates inflammation resolution by inducing neutrophil apoptosis and reverse migration. Importantly, while Roscovitine efficiently enhances intracellular bacterial killing of Mycobacterium abscessus in human CF macrophages ex vivo, we found that treatment with Roscovitine results in worse infection in mouse and zebrafish models. By interfering with DUOX2/NADPH oxidase-dependent ROS production, Roscovitine reduces the number of neutrophils at infection sites, and consequently compromises granuloma formation and maintenance, favouring extracellular multiplication of M. abscessus and more severe infection. Our findings bring important new understanding of the immune-targeted action of Roscovitine and have significant therapeutic implications for safety targeting inflammation in CF.

microbiology↗

bioRxiv2021

Cutibacterium acnes clonal complexes display various growth rates in blood culture bottles used for diagnosing orthopedic device related infections

Blood-culture bottles (BCBs) are widely used to improve the diagnosis of orthopedic device-related infections. Data is scarce on the growth of Cutibacterium acnes and its genotypes in BCBs under real-life clinical conditions. We studied 39 cases of revision arthroplasty for which at least one intraoperative sample yielded a pure C. acnes culture from anaerobic BCBs (BD Bactec Lytic/10 Anaerobic/F [Lytic Ana]) and/or solid media. Genotyping of C. acnes isolates from the 39 cases allowed: i) the identification of 49 non-redundant isolates belonging to four clonal complexes (CCs): CC18, CC28, CC36, and CC53 and ii) the determination of infectant and contaminant strains. Under real-life clinical conditions, Lytic Ana alone was more often positive for contaminants than infectant strains (18/36 [50%] versus 2/13 [15.4%]; p = 0.047). The time to detection (TTD) values in Lytic Ana were shorter for CC53 than other CCs (mean [SD] TTD: 77 [15] versus 165 [71] hours; p = 0.02). CC53 was confirmed to grow faster than other CCs by studying an enlarged panel of 70 genotyped C. acnes strains inoculated in vitro into Lytic Ana vials (mean [SD] TTD: 73 [13] versus 122 [50] hours; p < 0.001). The use of Lytic Ana BCBs in orthopedics increases the recovery rate of C. acnes but leads to the isolation of proportionally more contaminants than true infectant strains. TTD values are much shorter for CC53 strains, irrespective of their being infectant or contaminant. TTD does not solely reflect the bacterial load of samples but also clonal complex-related traits.

microbiology↗

bioRxiv2019

Mycobacterium abscessus virulence traits unraveled by transcriptomic profiling in amoeba and macrophages

Free-living amoebae might represent an evolutionary niche. In order to get more insights into the potential amoebal training ground for Mycobacterium abscessus, we characterized its full transcriptome in amoeba (Ac) and macrophages (M{varphi}), as well as the Mycobacterium chelonae intra-Ac transcriptome for comparison. Up-regulated genes in Ac allowed M. abscessus to resist environmental stress and induce defense mechanisms, as well as showing switch from carbohydrate carbon sources to fatty acid metabolism. Eleven genes implicated in the adaptation to intracellular stress, were mutated, with all but one confirmed to be involved in M. abscessus intra-M{varphi} survival. Cloning two of these genes in M. chelonae increased its intra-M{varphi} survival. One mutant was particularly attenuated in M{varphi} that corresponded to the deletion of an Eis N-acetyl transferase protein (MAB_4532c). Taken together, M. abscessus transcriptomes revealed the intracellular lifestyle of the mycobacteria, with Ac largely contributing to the enhancement of M. abscessus intra-M{varphi} survival.

microbiology↗

bioRxiv2018

Close proximity interactions support transmission of ESBL-K. pneumoniae but not ESBL-E. coli in healthcare settings

Antibiotic-resistance of hospital-acquired infections is a major public health issue. The worldwide emergence and diffusion of extended-spectrum {beta}-lactamase (ESBL)-producing Enterobacteriaceae, including Escherichia coli (ESBL-EC) and Klebsiella pneumoniae (ESBL-KP), is of particular concern. Preventing their nosocomial spread requires understanding their transmission. Using Close Proximity Interactions (CPIs), measured by wearable sensors, and weekly ESBL-EC- and ESBL-KP-carriage data, we traced their possible transmission paths among 329 patients in a 200-bed long-term care facility over 4 months. Based on phenotypically defined resistance profiles to 12 antibiotics, new bacterial acquisitions were tracked. Extending a previously proposed statistical method, the CPI networks ability to support observed incident colonization episodes of ESBL-EC and ESBL-KP was tested. Finally, mathematical modeling based on our findings assessed the effect of several infection-control measures. A potential infector was identified in the CPI network for 80% (16/20) of ESBL-KP acquisition episodes. The lengths of CPI paths between ESBL-KP incident cases and their potential infectors were shorter than predicted by chance (P = 0.02), indicating that CPI-network relationships were consistent with dissemination. Potential ESBL-EC infectors were identified for 54% (19/35) of the acquisitions, with longer-than-expected lengths of CPI paths. These contrasting results yielded differing impacts of infection control scenarios, with contact reduction interventions proving less effective for ESBL-EC than for ESBL-KP. These results highlight the widely variable transmission patterns among ESBL-producing Enterobacteriaceae species CPI networks supported ESBL-KP, but not ESBL-EC spread. These outcomes could help design more specific surveillance and control strategies to prevent in-hospital Enterobacteriaceae dissemination.\n\nAuthor summaryTracing extended-spectrum {beta}-lactamase (ESBL) dissemination in hospitals is an important step in the fight against the spread of multi-drug resistant bacteria. Indeed, understanding ESBL spreading dynamics will help identify efficient control interventions. In the i-Bird study, patients and hospital staff from a French long-term care facility in France carried a wearable sensor to capture their interactions at less than 1.5 meters, every 30 seconds over a 4-month period. Every week, patients were also swabbed to detect carriage of ESBL-producing Enterobacteriaceae. Based on the analysis of these longitudinal data, this study shows that ESBL-producing Klebsiella pneumoniae (ESBL-KP) mostly spreads during close-proximity interactions between individuals, while this is not the case for ESBL-producing Escherichia coli (ESBL-EC), suggesting that ESBL-KP but not ESBL-EC may be controlled by contact reduction interventions.

epidemiology↗

bioRxiv2017

Predicting susceptibility to tuberculosis based on gene expression profiling in dendritic cells

Tuberculosis (TB) is a deadly infectious disease, which kills millions of people every year. The causative pathogen, Mycobac-terium tuberculosis (MTB), is estimated to have infected up to a third of the worlds population; however, only approximately 10% of infected healthy individuals progress to active TB. Despite evidence for heritability, it is not currently possible to predict who may develop TB. To explore approaches to classify susceptibility to TB, we infected with MTB dendritic cells (DCs) from putatively resistant individuals diagnosed with latent TB, and from susceptible individuals that had recovered from active TB. We measured gene expression levels in infected and non-infected cells and found hundreds of differentially expressed genes between susceptible and resistant individuals in the non-infected cells. We further found that genetic polymorphisms nearby the differentially expressed genes between susceptible and resistant individuals are more likely to be associated with TB susceptibility in published GWAS data. Lastly, we trained a classifier based on the gene expression levels in the non-infected cells, and demonstrated decent performance on our data and an independent data set. Overall, our promising results from this small study suggest that training a classifier on a larger cohort may enable us to accurately predict TB susceptibility.

genomics↗