Biology subjects

Sykes, L.

Publications and source records attributed to Sykes, L..

3 recordsLinked to original sources

bioRxiv2024

Lactobacillus crispatus S-layer proteins modulate innate immune response and inflammation in the lower female reproductive tract.

Lactobacillus species dominance of the vaginal microbiome is a hallmark of vaginal health. Pathogen displacement of vaginal lactobacilli drives innate immune activation and mucosal barrier disruption which increases the risks of STI acquisition and, in pregnancy, of preterm birth. Using cell reporter systems, we describe differential TLR mediated activation of the proinflammatory transcription factor NF-{kappa}B by vaginal pathogens and commensals. Vaginal Lactobacillus strains associated with optimal health were shown to selectively interact with anti-inflammatory innate immune receptors whereas species associated with suboptimal health including L. iners and Gardnerella vaginalis interacted with both pro- and anti-inflammatory receptors. Anti-inflammatory action of L. crispatus was regulated by surface layer protein (SLPs)-mediated shielding of TLR ligands and selective interaction with anti-inflammatory receptor, DC-SIGN. In pregnant women, cervicovaginal SLPs were predominately associated with Lactobacillus-enriched microbiota. These data offer new mechanistic insights into how vaginal microbiota modulate host immune response and influences risk of preterm birth.

microbiology↗

bioRxiv2020

Proteome-wide prediction of bacterial carbohydrate-binding proteins as a tool for understanding commensal and pathogen colonisation of the vaginal microbiome

Bacteria use protein receptors called lectins to anchor to specific host surface sugars. The role of lectins in the vaginal microbiome, and their involvement in reproductive tract pathophysiology is poorly defined. Here we establish a classification system based on taxonomy and protein 3D structure to identify 109 lectin classes. Hidden Markov Model (HMM) profiles for each class were used to search bacterial genomes, resulting in the prediction of >100 000 bacterial lectins available at unilectin.eu/bacteria. Genome screening of 90 isolates from 21 vaginal bacterial species showed that potential pathogens produce a larger variety of lectins than commensals indicating increased glycan-binding potential. Both the number of predicted bacterial lectins, and their specificities for carbohydrates correlated with pathogenicity. This study provides new insights into potential mechanisms of commensal and pathogen colonisation of the reproductive tract that underpin health and disease states.

bioinformatics↗

bioRxiv2020

Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by mutation of the psychiatric risk gene Cacna1c

Genetic variation in CACNA1C, which encodes the alpha-1 subunit of CaV1.2 L-type voltage-gated calcium channels, is strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. To translate genetics to neurobiological mechanisms and rational therapeutic targets, we investigated the impact of altered Cacna1c dosage on rat cognitive, synaptic and circuit phenotypes implicated by patient studies. We show that rats hemizygous for Cacna1c harbor marked impairments in learning to disregard non-salient stimuli, a behavioral change previously associated with psychosis. This behavioral deficit is accompanied by dys-coordinated network oscillations during learning, pathway-selective disruption of hippocampal synaptic plasticity, attenuated Ca2+ signaling in dendritic spines and decreased signaling through the Extracellular-signal Regulated Kinase (ERK) pathway. Activation of the ERK pathway by a small molecule agonist of TrkB/TrkC neurotrophin receptors rescued both behavioral and synaptic plasticity deficits in Cacna1c+/- rats. These results map a route through which genetic variation in CACNA1C can disrupt experience-dependent synaptic signaling and circuit activity, culminating in cognitive alterations associated with psychiatric disorders. Our findings highlight targeted activation of neurotrophin signaling pathways with BDNF mimetic drugs as a novel, genetically informed therapeutic approach for rescuing behavioral abnormalities in psychiatric disorder. One Sentence SummaryNeurotrophin receptor activation reveals that BDNF mimetic drugs have therapeutic potential to ameliorate genetic risk for psychiatric disorders.

neuroscience↗