Biology subjects

Henriques-Normark, B.

Publications and source records attributed to Henriques-Normark, B..

6 recordsLinked to original sources

bioRxiv2026

Klebsiella pneumoniae T6SS exacerbates gut inflammation promoting tumorigenesis.

Dysbiosis and bacterial pathobionts contribute to inflammation in IBD and CRC, yet the molecular drivers of this process remain unclear. We identify the Klebsiella pneumoniae type VI secretion system (T6SS) as a key promoter of intestinal inflammation and tumor progression. Metagenomic analyses revealed enrichment of T6SS encoding genes in the gut microbiota of IBD patients during inflammatory flares. In zebrafish and mouse models, K. pneumoniae T6SS activity exacerbated inflammation and promoted colorectal tumor growth. Mechanistically, T6SS firing enhanced the secretion of LPS via outer membrane vesicles (OMVs), driving NF-{kappa}B activation and interferon signalling in host cells. In vivo, T6SS-dependent inflammation was associated with the expansion of regulatory T-cell subsets and an immunosuppressive tumor microenvironment. These findings redefine the T6SS as a microbial determinant of host inflammation and cancer progression, highlighting T6SS inhibition as a potential therapeutic approach for IBD and CRC. HighlightsO_LIT6SS-encoding Enterobacteria are enriched in the gut microbiota of IBD patients C_LIO_LIKlebsiella pneumoniae T6SS exacerbates colitis in mice C_LIO_LIT6SS activity enhances outer membrane vesicle secretion and LPS release C_LIO_LIT6SS promotes colorectal tumorigenesis and immune dysregulation C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/715367v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1c99341org.highwire.dtl.DTLVardef@e2d0eborg.highwire.dtl.DTLVardef@1021387org.highwire.dtl.DTLVardef@1502c97_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Crystallographic and NMR studies of Streptococcus pneumonia LCP protein PsrSp indicate the importance of dynamics in four long loops for ligand specificity

The crystal structure of the extracellular region of the second pneumococcal LCP, a polyisoprenyl-teichoic acid-peptidoglycan teichoic acid transferase PsrSp, was determined and refined to 2.15[A] resolution. Despite the low sequence homology with other LCP proteins, the PsrSp maintains the fold of the LCP domain and the positions of the 15 residues suggested to participate in the transferase function are conserved. The empty tunnel found in the PsrSp between the central {beta}-sheet and three -helices is wide enough to accommodate polyisoprenyl-teichoic acid. Comparison of the crystallographic temperature factors of LCP from distinct bacteria demonstrated that the four long loops located close to the teichoic acid and peptidoglycan binding sites have different relative mobility. To compare the dynamics of the PsrSp in crystalline state and in solution, NMR spectra were recorded, and 88% of the residues were assigned in the 1H-15N TROSY HSQC spectra. Comparison of the secondary structure of the crystal structure of PsrSp with NMR data demonstrated a perfect concordance between the results using these two methods. Moreover, the relative mobility of the essential loops estimated from the crystallographic B-factor is in good agreement with order parameter S2, predicted from chemical shift. We hypothesize that the dynamics of these loops are important for the substrate promiscuity of LCP proteins.

microbiology↗

bioRxiv2020

Neuronal death in pneumococcal meningitis is triggered by pneumolysin and pilus-1 interactions with β-actin

Neuronal damage is a major consequence of bacterial meningitis, but little is known about mechanisms that lead to neuronal death. Streptococcus pneumoniae (pneumococcus) is a leading cause of bacterial meningitis and many survivors develop neurological sequelae after the acute infection has resolved, possibly due to neuronal damage. Here, we studied mechanisms for pneumococcal interactions with neurons. Using human primary neurons and co-immunoprecipitation assays, we showed that pneumococci interact with the cytoskeleton protein {beta}-actin through the pilus-1 adhesin RrgA and the cytotoxin pneumolysin (Ply), thereby promoting adhesion and uptake into neurons and neuronal death. Using our bacteremia-derived meningitis mouse model, we observed that RrgA- and Ply-expressing pneumococci co-localize with neuronal {beta}-actin. We found that pneumococcal-infected neurons show increased intracellular Ca2+ levels depending on RrgA and mainly Ply which likely cause actin cytoskeleton disassembly leading to neuronal damage. Finally, neuronal death caused by pneumococcal infection could be inhibited using antibody against {beta}-actin.

microbiology↗

bioRxiv2019

Fighting the spread of antibiotic resistance with bacterial competence inhibitors

Streptococcus pneumoniae is a commensal of the human nasopharynx, but it can also cause severe life-threatening antibiotic-resistant infections. Antibiotic consumption drives the spread of resistance by inducing S. pneumoniae competence leading to the uptake of exogenous DNA and horizontal gene transfer (HGT). We have identified potent inhibitors of competence, collectively called COM-blockers. We show that COM-blockers inhibit HGT by perturbing the proton motive force, thereby disrupting the export of the peptide that regulates competence. COM-blockers do not affect growth or compromise antibiotic activity at their active concentrations, and we did not observe any resistance development against them. Used as adjuvants of antibiotics, COM-blockers provide a strategy to reduce the spread of virulence factors and antibiotic resistance in human pathogens.\n\nOne Sentence SummaryAntibiotic adjuvants block competence

microbiology↗

bioRxiv2018

Comparative genomic analysis of the emerging pathogen Streptococcus pseudopneumoniae: novel insights into virulence determinants and identification of a novel species-specific molecular marker

Streptococcus pseudopneumoniae is a close relative of the major human pathogen S. pneumoniae. While initially considered as a commensal species, it has been increasingly associated with lower-respiratory tract infections and high prevalence of antimicrobial resistance (AMR). S. pseudopneumoniae is difficult to identify using traditional typing methods due to similarities with S. pneumoniae and other members of the mitis group (SMG). Using phylogenetic and comparative genomic analyses of SMG genomes, we identified a new molecular marker specific for S. pseudopneumoniae and absent from any other bacterial genome sequenced to date. We found that a large number of known virulence and colonization genes are present in the core S. pseudopneumoniae genome and we reveal the impressive number of known and new surface-exposed proteins encoded by this species. Phylogenetic analyses of S. pseudopneumoniae show that specific clades are associated with allelic variants of core proteins. Resistance to tetracycline and macrolides, the two most common resistances, were encoded by Tn916-like integrating conjugative elements and Mega-2. Overall, we found a tight association of genotypic determinants of AMR as well as phenotypic AMR with a specific lineage of S. pseudopneumoniae. Taken together, our results sheds light on the distribution in S. pseudopneumoniae of genes known to be important during invasive disease and colonization and provide insight into features that could contribute to virulence, colonization and adaptation.\n\nImportanceS. pseudopneumoniae is an overlooked pathogen emerging as the causative agent of lower-respiratory tract infections and associated with chronic obstructive pulmonary disease (COPD) and exacerbation of COPD. However, much remains unknown on its clinical importance and epidemiology, mainly due to the lack of specific means to distinguish it from S. pneumoniae. Here, we provide a new molecular marker entirely specific for S. pseudopneumoniae. Furthermore, our research provides a deep analysis of the presence of virulence and colonization genes, as well as AMR determinants in this species. Our results provide crucial information and pave the way for further studies aiming at understanding the pathogenesis and epidemiology of S. pseudopneumoniae.

microbiology↗

bioRxiv2017

Detection Of Human Disease Conditions By Single-Cell Morpho-Rheological Phenotyping Of Whole Blood

Blood is arguably the most important bodily fluid and its analysis provides crucial health status information. A first routine measure to narrow down diagnosis in clinical practice is the differential blood count, determining the frequency of all major blood cells. What is lacking to advance initial blood diagnostics is an unbiased and quick functional assessment of blood that can narrow down the diagnosis and generate specific hypotheses. To address this need, we introduce the continuous, cell-by-cell morpho-rheological (MORE) analysis of whole blood, without labeling, enrichment or separation, at rates of 1,000 cells/sec. In a drop of blood we can identify all major blood cells and characterize their pathological changes in several disease conditions in vitro and in patient samples. This approach takes previous results of mechanical studies on specifically isolated blood cells to the level of application directly in whole blood and adds a functional dimension to conventional blood analysis.

biophysics↗