Biology subjects

Rasid, O.

Publications and source records attributed to Rasid, O..

5 recordsLinked to original sources

bioRxiv2024

Spatial mapping of dextran sodium sulphate-induced intestinal inflammation and its systemic effects

Inflammatory bowel disease (IBD) is a multifactorial disease and patients frequently experience extraintestinal manifestations affecting multiple sites. Causes of systemic inflammation remain poorly understood but molecules originating from the intestine likely play a role, with microbial and host small molecules polarizing host immune cells towards a pro- or anti-inflammatory phenotype. Using the dextran sodium sulphate (DSS) mouse model, which mimics the disrupted barrier function, microbial dysbiosis and immune cell dysregulation of IBD, we investigated metabolomic and phenotypic changes at intestinal and systemic sites. Using spatial biology approaches we mapped distribution and relative abundance of molecules and cell types across a range of tissues revealing significant changes in DSS-treated mice. Molecules identified as contributing to the statistical separation of treated from control mice were spatially localized within organs to determine their effects on cellular phenotypes through imaging mass cytometry. This spatial approach identified both intestinal and systemic molecular drivers of inflammation, including several not previously implicated in inflammation linked to IBD or the systemic effects of intestinal inflammation. Metabolic and inflammatory pathway interplay underpins systemic disease and determining drivers at the molecular level may aid the development of new targeted therapies.

molecular biology↗

bioRxiv2023

Streptococcus pneumoniae drives specific and lasting Natural Killer cell memory

NK cells are important mediators of innate immunity and play an essential role for host protection against infection, although their responses to bacteria are poorly understood. Recently NK cells were shown to display memory properties, as characterized by an epigenetic signature leading to a stronger secondary response. Although NK cell memory could be a promising mechanism to fight against infection, it has not been described upon bacterial infection. Here, we reveal that NK cells develop specific and long-term memory following sub-lethal infection with the extracellular pathogen Streptococcus pneumoniae. Memory NK cells display intrinsic sensing and response to bacteria in vitro, in a manner that is enhanced post-bacterial infection. In addition, their transfer into naive mice confer protection from lethal infection for at least 12 weeks. Interestingly, NK cells display enhanced cytotoxic molecule production upon secondary stimulation and their protective role is dependent on Perforin and independent of IFN{gamma}. Thus, our study identifies a new role for NK cells during bacterial infection, opening the possibility to harness innate immune memory for therapeutic purposes.

microbiology↗

bioRxiv2020

Streptococcus pneumoniae infection promotes histone H3 dephosphorylation by modulating host PP1 phosphatase

Pathogenic bacteria can alter host gene expression through post-translational modifications of histones. We show for the first time that a natural colonizer, Streptococcus pneumoniae, also induces specific histone modifications, including robust dephosphorylation of histone H3 on serine 10, during infection of respiratory epithelial cells. Two bacterial factors are important for the induction of this modification: the bacterial toxin PLY, a pore-forming toxin, and the pyruvate oxidase SpxB, an enzyme responsible for H2O2 production. The combined effects of PLY and H2O2 lead to host signaling which culminates in H3S10 dephosphorylation, mediated by the host cell phosphatase PP1. Strikingly, S. pneumoniae infection induces dephosphorylation and associated activation of PP1 catalytic activity. Colonization of cells, which lacked active PP1, resulted in the impairment of intracellular S. pneumoniae survival. Interestingly, PP1 activation mediating H3S10 dephosphorylation is not restricted to S. pneumoniae and appears to be a general epigenomic mechanism favoring intracellular survival.

microbiology↗

bioRxiv2019

Pneumococcal carriage requires KDM6B, a histone demethylase, for its unique inflammatory signature

Streptococcus pneumoniae is a natural colonizer of the human upper respiratory tract and an opportunistic pathogen. After colonization, bacteria either remain in the human upper respiratory tract, or may progress to cause pneumococcal disease. Although epithelial cells are among the first to encounter pneumococci, the cellular processes and contribution of epithelial cells to the host response are poorly understood. Here, we show a S. pneumoniae serotype 6B ST90 strain, which does not cause disease in a murine infection model, induces a unique NF-{kappa}B signature response distinct from an invasive disease causing isolate of serotype 4 (TIGR4). This signature is characterized by activation of p65 (RelA) and requires a histone demethylase, KDM6B. At the molecular level, we show that interaction of the 6B strain with epithelial cells leads to chromatin remodeling within the IL-11 promoter in a KDM6B dependent manner, where KDM6B specifically demethylates histone H3 lysine 27 di-methyl. Chromatin remodeling of the IL-11 locus facilitates p65 access to three NF-{kappa}B sites, which are otherwise inaccessible when stimulated by IL-1{beta} or TIGR4. Finally, we demonstrate through chemical inhibition of KDM6B, with GSK-J4 inhibitor, and through exogenous addition of IL-11 that the host responses to 6B ST90 and TIGR4 strains can be interchanged both in vitro and in a murine model of infection in vivo. Our studies hereby reveal how a chromatin modifier governs cellular responses during infection.

microbiology↗

bioRxiv2018

NK cells acquire epigenetic memory of LPS-induced systemic inflammation

Natural killer cells are unique mediators of innate immunity, and as such, an attractive target for immunotherapy. Following viral infection, NK cells display immune memory properties, defined by heightened responses to re-stimulation, an expansion of specific NK cell sup-populations and a protective role against re-infection. However, similar memory to bacterial infection or systemic inflammation, and the molecular mechanisms behind NK cell memory remain elusive. Here we show that following LPS-induced endotoxemia in mice, NK cells acquire cell-intrinsic memory properties as displayed by an amplified production of IFN{gamma} upon secondary stimulation. NK cell memory is acquired even under the post-endotoxemic suppressive environment and is detectable for at least 9 weeks. Furthermore, we define an epigenetic mechanism essential for NK cell memory, where an H3K4me1-marked latent enhancer is uncovered at the ifng locus. Chemical inhibition of histone methyltransferase activity erased the enhancer and prevented NK cells from acquiring memory. Thus, NK cells develop memory to LPS during endotoxemia, in a histone methylation-dependent manner, which ensures a heightened response to secondary stimulation and confers protection against bacterial infection.

immunology↗