Biology subjects

Lenzi, L.

Publications and source records attributed to Lenzi, L..

6 recordsLinked to original sources

bioRxiv2025

Cytokines of the Interleukin-1 superfamily and Interleukin-6 are associated with neuroinflammation and brain injury in Herpes Simplex Virus Encephalitis

Herpes simplex virus (HSV) is the leading cause of encephalitis, with high rates of morbidity and mortality. Dysregulated immune responses have been associated with poor outcomes in small series, driving interest in immunotherapies. However, the key mediators of neuropathology, their cellular sources, and responsiveness to corticosteroid treatment remain unknown. We present findings from an RCT of dexamethasone in 55 adults with HSV encephalitis, alongside a representative murine model. Clinical severity and adverse outcomes were associated with neuroglial injury biomarkers (GFAP, tau, UCH-L1), increased cerebral oedema on MRI, and higher IL-1RA, IL-18, and IL-6. These mediators were more abundant in matched CSF than serum, and were not reduced by dexamethasone. In the model, neurons, astrocytes and microglia robustly expressed IL-1 and IL-6, supporting their CNS origin. These findings identify IL-1 and IL-6 signalling as key drivers of immunopathology in HSV encephalitis and potential therapeutic targets to mitigate neuroinflammation and improve outcomes. FundingNational Institute for Health and Care Research (grant number 12/205/28).

neuroscience↗

bioRxiv2023

The interfascicular matrix of energy storing tendons houses heterogenous cell populations disproportionately affected by ageing

Energy storing tendons such as the human Achilles and equine superficial digital flexor tendon (SDFT) are prone to injury, with incidence increasing with ageing. The interfascicular matrix (IFM), which binds tendon fascicles, plays a key role in energy storing tendon mechanics, and ageing alterations to the IFM negatively impact tendon function. While the mechanical role of the IFM in tendon function is well-established, the biological role of IFM-resident cell populations remains to be elucidated. Therefore, the aim of this study was to identify IFM-resident cell populations and establish how these populations are affected by ageing. Cells from young and old SDFTs were subjected to single cell RNA-sequencing, and immunolabelling for markers of each resulting population used to localise cell clusters. Eleven cell clusters were identified, including tenocytes, endothelial cells, mural cells and immune cells. One tenocyte cluster localised to the fascicular matrix, whereas nine clusters localised to the IFM. Interfascicular tenocytes and mural cells were preferentially affected by ageing, with differential expression of genes related to senescence, dysregulated proteostasis and inflammation. This is the first study to uncover the importance of the IFM niche for a diverse range of cell populations, and to identify age-related alterations specific to IFM-localised cells.

cell biology↗

bioRxiv2022

Esr1+ hypothalamic-habenula neurons shape aversive states.

Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) drive aversive responses. We used Patch-seq guided multimodal classification to define the structural and functional heterogeneity of the LHA-LHb pathway. Our classification identified six glutamatergic neuron types with unique electrophysiological properties, molecular profiles, and projection patterns. We found that genetically-defined LHA-LHb neurons signal distinct aspects of emotional or naturalistic behaviors: Esr1+ LHA-LHb neurons induce aversion, whereas Npy+ LHA-LHb neurons control rearing behavior. Repeated optogenetic drive of Esr1+ LHA-LHb neurons induces a behaviorally persistent aversive state, and large-scale recordings showed a region-specific neural representation of the aversive state in the prelimbic region of the prefrontal cortex. We further found that exposure to unpredictable mild shocks induced a sex-specific sensitivity to develop a stress state in female mice, which was associated with a specific shift in the intrinsic properties of bursting-type Esr1+ LHA-LHb neurons. In summary, we describe the diversity of LHA-LHb neuron types, and provide evidence for the role of Esr1+ neurons in aversion and sexually dimorphic stress sensitivity.

neuroscience↗

bioRxiv2019

Transient CRISPR immunity leads to coexistence with phages

Phages play a major role in shaping the composition, evolution and function of bacterial communities. While bacteria and phages coexist in many natural environments, their coexistence is often short-lived in the lab due to the evolution of phage resistance. However, fitness costs associated with resistance and mutational loss of resistance alleles may limit the durability of acquired resistances, potentially allowing phages to re-invade the population. Here, we explore this idea in the context of bacteria that evolve CRISPR-based immunity against their phages. Consistent with previous studies, we found that the bacterium Pseudomonas aeruginosa PA14 evolved high levels of CRISPR-based immunity and low levels of surface-based resistance following infection with phage DMS3vir, which led to rapid phage extinction. However, when these pre-immunized bacterial populations were subsequently challenged with the same phage, they failed to clear the infection and instead stably coexisted with the phage. Analysis of bacterial genotypes and phenotypes over time explained why CRISPR-Cas immunity provides only a transient advantage: in the absence of phage (i.e. following the initial phage extinction) formerly CRISPR-immune bacteria regain sensitivity due to evolutionary loss of spacers, whereas in the presence of phage (i.e. upon reinfection) selection favours surface-based resistance over CRISPR immunity. The latter results from an infection-induced fitness cost of CRISPR-immunity that is due to phage gene expression prior to target DNA cleavage by the immune system. Together, these results show that CRISPR-Cas immune systems provide only a transient benefit to bacteria upon phage infection and help to explain why bacteria and phages can coexist in natural environments even when bacteria carry CRISPR-Cas adaptive immune systems that allow for rapid acquisition of immunity against phages.

microbiology↗

bioRxiv2018

Application of long read sequencing to determine expressed antigen diversity in Trypanosoma brucei infections

AO_SCPLOWBSTRACTC_SCPLOWAntigenic variation is employed by many pathogens to evade the host immune response, and Trypanosoma brucei has evolved a complex system to achieve this phenotype, involving sequential use of variant surface glycoprotein (VSG) genes encoded from a large repertoire of [~]2,000 alleles. T. brucei express multiple, sometimes closely related, VSGs in a population at any one time, and the ability to resolve and analyse this diversity has been limited. We applied long read sequencing (PacBio) to VSG amplicons generated from blood extracted from batches of mice sacrificed at time points (days 3, 6, 10 and 12) post-infection with T. brucei TREU927. The data showed that long read sequencing is reliable for resolving allelic differences between VSGs, and demonstrated that there is significant expressed diversity (449 VSGs detected across 20 mice) and across the timeframe of study there was a clear semi-reproducible pattern of expressed diversity (median of 27 VSGs per sample at day 3 post infection (p.i.), 82 VSGs at day 6 p.i., 187 VSGs at day 10 p.i. and 132 VSGs by day 12 p.i.). There was also consistent detection of one VSG dominating expression across replicates at days 3 and 6, and emergence of a second dominant VSG across replicates by day 12. The innovative application of ecological diversity analysis to VSG reads enabled characterisation of hierarchical VSG expression in the dataset, and resulted in a novel method for analysing such patterns of variation. Additionally, the long read approach allowed detection of mosaic VSG expression from very few reads - this was observed as early as day 3, the earliest that such events have been detected. Therefore, our results indicate that long read analysis is a reliable tool for resolving diverse allele expression profiles, and provides novel insights into the complexity and nature of VSG expression in trypanosomes, revealing significantly higher diversity than previously shown and identifying mosaic gene formation unprecedentedly early during the infection process.

genomics↗

bioRxiv2017

Comparison Of The Human Gastric Microbiota In Hypochlorhydric States Arising As A Result Of Helicobacter pylori-Induced Atrophic Gastritis, Autoimmune Atrophic Gastritis And Proton Pump Inhibitor Use

ObjectiveSeveral conditions associated with reduced gastric acid secretion confer an altered risk of developing a gastric malignancy. Helicobacter pylori-induced atrophic gastritis predisposes to gastric adenocarcinoma, autoimmune atrophic gastritis is a precursor of type I gastric neuroendocrine tumours, whereas proton pump inhibitor (PPI) use does not affect stomach cancer risk. We hypothesised that each of these conditions was associated with specific alterations in the gastric microbiota and that this influenced subsequent tumour risk.\n\nDesign95 patients (in groups representing normal stomach, PPI treated, H. pylori gastritis, H. pylori-induced atrophic gastritis and autoimmune atrophic gastritis) were selected from a cohort of 1400. RNA extracted from gastric corpus biopsies was analysed using 16S rRNA sequencing (MiSeq).\n\nResultsSamples from normal stomachs and patients treated with PPIs demonstrated similarly high microbial diversity. Patients with autoimmune atrophic gastritis also exhibited relatively high microbial diversity, but with samples dominated by Streptococcus. H. pylori colonisation was associated with decreased microbial diversity and reduced complexity of co-occurrence networks. H. pylori-induced atrophic gastritis resulted in lower bacterial abundances and diversity, whereas autoimmune atrophic gastritis resulted in greater bacterial abundance and equally high diversity compared to normal stomachs. Pathway analysis suggested that glucose-6-phospahte1-dehydrogenase and D-lactate dehydrogenase were over represented in H. pylori-induced atrophic gastritis versus autoimmune atrophic gastritis, and that both these groups showed increases in fumarate reductase.\n\nConclusionAutoimmune and H. pylori-induced atrophic gastritis were associated with different gastric microbial profiles. PPI treated patients showed relatively few alterations in the gastric microbiota compared to healthy subjects.\n\nSIGNIFICANCE OF THIS STUDY 1. What is already known about this subject?O_LISome conditions which result in reduced gastric acid secretion and hypochlorhydria are associated with an increased risk of gastric tumourigenesis.\nC_LIO_LIThis risk is different in patients with H. pylori-induced atrophic gastritis, autoimmune atrophic gastritis and chronic proton pump inhibitor use.\nC_LIO_LIHypochlorhydria and H. pylori infection cause alterations in the composition of the gastric microbiota.\nC_LI\n\n2. What are the new findings?O_LIWe used 16S rRNA sequencing to characterise the microbiota in gastric corpus biopsies from a well characterised cohort of patients.\nC_LIO_LIThe gastric microbiota was different in patients who were hypochlorhydric as a result of H. pylori-induced atrophic gastritis, autoimmune atrophic gastritis and proton pump inhibitor use.\nC_LIO_LIBiochemical pathways associated with gastric carcinogenesis such as the fumarate reductase pathway were predicted to be altered in patients with atrophic gastritis.\nC_LI\n\n3. How might it impact on clinical practice in the foreseeable future?O_LIUnderstanding how the microbiota that colonise the hypochlorhydric stomach influence gastric carcinogenesis may ultimately permit stratification of patients subsequent tumour risk.\nC_LIO_LIInterventions that alter the composition of the gastric microbiome in hypochlorhydric patients with atrophic gastritis should be tested to investigate whether they alter the subsequent risk of developing gastric malignancy.\nC_LI

microbiology↗