Biology subjects

Svensson, M.

Publications and source records attributed to Svensson, M..

7 recordsLinked to original sources

bioRxiv2025

Neutrophil-neuronal crosstalk drives arthritis-induced pain

Pain in rheumatoid arthritis (RA) often persists despite effective control of inflammation, suggesting distinct mechanisms driving nociception. In both patients and animal models, pain severity does not strongly correlate with the degree of inflammation1,2. Sensory neurons, with cell bodies located in the dorsal root ganglia (DRG), innervate peripheral tissues, including joints, and transmit pain signals to the central nervous system. Crosstalk between sensory neurons and immune cells occurs at all of these sites. While sensory neurons can be directly activated by immune mediators, it remains unclear whether pain-like behaviour in antibody-induced arthritis models arises independently of immune cell activity, or which immune cell populations and mediators are required to activate pronociceptive mechanisms. Through temporal profiling of the CAIA joint-DRG transcriptomic axis, we identified SEMA4D and OSM signalling as candidate molecular mediators of neutrophil-neuron communication and neuronal sprouting. The joint-DRG atlas also revealed persistent changes in the fibroblast-immune cellular composition of the joint, along with molecular changes in DRG neurons. We showed that mechanical and cold hypersensitivity, as well as sprouting of CGRP+ nociceptive fibers in synovial tissue of mice with collagen antibody-induced arthritis (CAIA), require neutrophils but not macrophages. Analysis of publicly available datasets showed that neutrophils from the synovium of RA patients express high levels of SEMA4D and OSM, and corresponding expression of their receptors, PLEXINB1 and OSMR, in human DRG neurons, underscoring the translational relevance of this axis. Both murine and human-derived DRG neurons sprout in response to OSM. Our findings demonstrate that neutrophils produce molecules that act as cues for nociceptor sensitization and structural remodelling. Targeting these molecules could improve the efficacy of RA treatments by reducing pain while simultaneously preventing disease progression.

immunology↗

bioRxiv2025

mRNA-LNP vaccines against Hepatitis B virus induce protective immune responses in preventive and chronic mouse challenge models

Over 300 million people worldwide suffer from chronic hepatitis B virus infections that can cause serious liver damage and hepatocellular carcinoma. Ineffective innate and adaptive immune responses characterize these chronic infections, making the development of a therapeutic vaccine an urgent medical need. While current vaccines can prevent HBV infections, they are ineffective in treating chronic disease. This study investigated lipid nanoparticle (LNP)-formulated nucleoside-modified mRNA vaccines encoding Hepatitis B surface antigen (HBsAg) for prophylactic and therapeutic applications. We found that HBsAg mRNA-LNP vaccines induced robust humoral and cellular immune responses, outperforming the protein-based vaccine approved for human use. The incorporation of an MHC class I signal peptide further enhanced Th1-biased responses preventing HBV infections in a mouse model. Importantly, mRNA-LNP vaccination led to seroconversion, HBsAg clearance, and strong T cell responses in a chronically infected mouse model. These findings highlight the potential of mRNA-LNP as an alternative and effective vaccine modality for HBV prophylaxis and therapeutic use in treating chronic infections.

immunology↗

bioRxiv2024

Structural basis for collagen recognition by the Streptococcus pyogenes M3 protein and its involvement in biofilm

The M protein is an essential virulence factor of Streptococcus pyogenes, or group A streptococcus (GAS), one of the most common and dangerous human pathogens. Molecular and functional characterization of M protein variants and their interactions with host components is crucial for understanding streptococcal pathogenesis and vaccine development. The M3 protein is produced by the prevalent emm3 GAS serotype, which is frequently associated with severe invasive diseases. Here we characterize the interaction of M3 with human collagens through detailed structural and biochemical binding analysis. High-resolution structures of the N-terminal M3 domain in the free state as well as bound to a collagen peptide derived from the Collagen Ligands Collection reveal a novel T-shaped protein fold that presents binding sites complementing the characteristic topology of collagen triple helices. The structure of the M3/collagen peptide complex explains how emm3 GAS and related streptococci, such as the emerging human pathogen Streptococcus dysgalactiae subsp. equisimilis, can target collagens to enable colonization of various tissues. In line with this, we demonstrate that the M3/collagen interaction promotes enhanced biofilm formation of emm3 GAS in an emm type specific manner, which can be inhibited with the recombinant M3 N-terminal domain fragment. Further, emm3 GAS are shown to colocalize with collagen in tissue biopsies from patients with necrotizing soft tissue infections, where GAS biofilms are common. This observation is reproduced in infected organotypic skin models. Together, these data provide detailed molecular insights into an important streptococcal virulence mechanism with implications for the understanding of invasive infections, strategies for treating biofilm and M-protein based vaccine design.

microbiology↗

bioRxiv2024

Comparison of whole-genome assemblies of European river lamprey (Lampetra fluviatilis) and brook lamprey (Lampetra planeri)

We present haplotype-resolved whole-genome assemblies from one individual European river lamprey (Lampetra fluviatilis) and one individual brook lamprey (Lampetra planeri), usually regarded as sister species. The genome assembly of L. fluviatilis consists of pseudo-haplotype one, spanning 1073 Mb and pseudo-haplotype two, spanning 963 Mb. Likewise for the L. planeri specimen, the genome assembly spans 1049 Mb and 960 Mb for pseudo-haplotypes one and two, respectively. Both the L. fluviatilis pseudo-haplotypes have been scaffolded into 82 pseudo-chromosomes, with the same number for the L. planeri pseudo-haplotypes. All four pseudo-haplotype assemblies were annotated, identifying 21,479 and 16,973 genes in pseudo-haplotypes one and two for L. fluviatilis, and 24,961 and 21,668 genes in pseudo-haplotypes one and two for L. planeri. A comparison of the genomes of L. fluviatilis and L. planeri, alongside a separate chromosome level assembly of L. fluviatilis from the UK, indicates that they form a species complex, potentially representing distinct ecotypes. This is further supported by phylogenetic analyses of the three reference Lampetra genomes in addition to sea lamprey (Petromyzon marinus).

genomics↗

bioRxiv2024

ATF4 orchestrates IL-1α-induced senescence in adult neural stem cells

Adult neural stem cells (NSC) are a potential source for the regeneration of damaged tissue during neuropathological conditions, but much remains unexplored. In an attempt to study the influence of neuroinflammation on NSCs, we generated a transgenic reporter rat strain that expresses the Discosoma sp. red (DsRed) fluorophore in NSCs and subjected it to traumatic brain injury (TBI). Transcriptomic analysis of NSCs isolated from TBI revealed an enrichment of stress response genes that pertained to endoplasmic reticulum (ER) stress and integrated stress response (ISR). Downstream analysis on NSC cultures pinpointed IL-1 as a trigger of ISR in these cells. At concentration levels similar to the ones measured post-TBI in rats, IL-1 induced the translation of activating transcription factor 4 (ATF4), an ISR master regulator. Further, ATF4 was necessary for the IL-1 -dependent induction of a senescent profile in NSCs, which included a metabolic shift towards glycolysis, induction of senescence-associated secretory phenotype, SASP, and cell cycle arrest. In summary, the ISR/ATF4 pathway seems to play a major role in NSC function during neuroinflammation and provides a therapeutic tool for protecting the NSC pool during these conditions.

neuroscience↗

bioRxiv2023

Alpha-toxin elicited CX3CL1-release via ADAM10 in Staphylococcus aureus pneumoniaimpairs bactericidal function of human monocytes

Staphylococcus aureus is an important human pathogen causing severe invasive infections. Pathogenesis is attributed to a wide array of virulence factors, including several potent exotoxins such as the pore-forming alpha-toxin. In this study, we found that patients with S. aureus respiratory tract infections had elevated CX3CL1 levels in airway fluid and plasma. Using humanized organotypic lung models, we observed that stimulation of lung epithelium with alpha-toxin induce an intensified CX3CL1 expression apically in the epithelium as well as the release of CX3CL1. Blocking alpha-toxin or ADAM10 activity in organotypic lung using an alpha-toxin-blocking antibody or a specific ADAM-10 inhibitor confirmed their role in modulating CX3CL1 cleavage and release. Analyses of CD14+ human monocytes in combination with a CX3CR1 inhibitor revealed that alpha-toxin-mediated CX3CL1 release induce CX3CL1-dependent chemotaxis. In line with these data, lung tissue from patients with S. aureus respiratory tract infection showed elevated CX3CL1 and CD14 staining as compared to tissue from patients with non-infectious lung diseases. Functional studies of monocytes showed that CX3CL1 released by lung models resulted in upregulated CD83 and downregulated CD86, as well as impaired killing of phagocytosed S. aureus. Furthermore, stimulation of monocytes with soluble CX3CL1 hampered their reactive-oxygen and nitric-oxide production. Taken together, our data show that S. aureus triggers the release of lung epithelial CX3CL1; a process found to be dependent on the alpha-toxins effect on ADAM10 mediating cytotoxicity and resulting in impaired monocyte phagocytic killing. Hence, we identify an immunomodulatory effect of alpha-toxin involving the CX3CL1-ADAM10 axis extending beyond the cytolysis function.

microbiology↗

bioRxiv2023

Bamboozle: A bioinformatic tool for identification and quantification of intraspecific barcodes

Evolutionary changes in populations of microbes, such as microalgae, cannot be traced using conventional metabarcoding loci as they lack intraspecific resolution. Consequently, selection and competition processes amongst strains of the same species cannot be resolved without elaborate isolation, culturing, and genotyping efforts. Bamboozle, a new bioinformatic tool introduced here, scans a species entire genome and identifies allele-rich barcodes that enable direct identification of different strains from a common population, and a single DNA sample, using amplicon sequencing. We demonstrate its usefulness by identifying hypervariable barcoding loci (<500 bp) from genomic data in two microalgal species, the diploid diatom Skeletonema marinoi, and the haploid chlorophyte Chlamydomonas reinhardtii. Across the genomes, only 26 loci capable of resolving all available strains genotypes were identified, all of which are within protein-coding genes of variable metabolic function. Single nucleotide polymorphisms (SNPs) provided the most reliable genetic markers, and amongst 55 strains of S. marinoi, three 500 bp loci contained, on average, 46 SNPs, 103 unique alleles, and displayed 100% heterozygosity. The prevalence of heterozygosity was identified as a novel opportunity to improve strain quantification and detect false positive artefacts during denoising of amplicon sequences. Finally, we illustrate how metabarcoding of a single genetic locus can be used to track strain abundances of 58 strains of S. marinoi in an artificial selection experiment. As future genomics datasets become available and DNA sequencing technologies develop, Bamboozle has flexible user settings enabling optimal barcodes to be designed for other species and applications.

evolutionary biology↗