Publications
243 results found
Bennett PR, Brown RG, MacIntyre DA, 2020, Vaginal microbiome in preterm rupture of membranes, Obstetrics and Gynecology Clinics of North America, Vol: 47, Pages: 503-521, ISSN: 0889-8545
MacIntyre D, Bennett P, 2020, Chapter 3 - Microbial signatures of preterm birth, The Human Microbiome in Early Life Implications to Health and Disease, Publisher: Academic Press, ISBN: 9780128180976
Preterm birth remains the primary cause of death in children under the age of 5 years worldwide. A causal relationship between infection and preterm birth has long been recognized. However, recent applications of molecular-based profiling techniques have provided new insights into the relationship between specific bacterial compositions of the lower reproductive tract and subsequent preterm birth risk. In this chapter, we investigate evidence for “microbial signatures” of preterm birth and examine mechanisms by which shifts in microbiome composition could contribute to an infectious etiology of preterm birth. Despite high levels of heterogeneity between studies, vaginal depletion of Lactobacillus spp. and high-diversity communities enriched for potentially pathogenic bacteria are frequently associated with preterm birth, whereas Lactobacillus spp. dominant communities appear to confer protection against preterm birth, particularly when dominated by Lactobacillus crispatus. Strategies focused toward promoting optimal microbial signatures during pregnancy may help reduce rates of preterm birth and improve maternal and neonatal outcomes.
Paraskevaidi M, Cameron SJS, Whelan E, et al., 2020, Laser-assisted rapid evaporative ionisation mass spectrometry (LA-REIMS) as a metabolomics platform in cervical cancer screening, EBioMedicine, Vol: 60, ISSN: 2352-3964
BackgroundThe introduction of high-risk human papillomavirus (hrHPV) testing as part of primary cervical screening is anticipated to improve sensitivity, but also the number of women who will screen positive. Reflex cytology is the preferred triage test in most settings but has limitations including moderate diagnostic accuracy, lack of automation, inter-observer variability and the need for clinician-collected sample. Novel, objective and cost-effective approaches are needed.MethodsIn this study, we assessed the potential use of an automated metabolomic robotic platform, employing the principle of laser-assisted Rapid Evaporative Ionisation Mass Spectrometry (LA-REIMS) in cervical cancer screening.FindingsIn a population of 130 women, LA-REIMS achieved 94% sensitivity and 83% specificity (AUC: 91.6%) in distinguishing women testing positive (n = 65) or negative (n = 65) for hrHPV. We performed further analysis according to disease severity with LA-REIMS achieving sensitivity and specificity of 91% and 73% respectively (AUC: 86.7%) in discriminating normal from high-grade pre-invasive disease.InterpretationThis automated high-throughput technology holds promise as a low-cost and rapid test for cervical cancer screening and triage. The use of platforms like LA-REIMS has the potential to further improve the accuracy and efficiency of the current national screening programme.
Bonnardel F, Haslam SM, Dell A, et al., 2020, Proteome-wide prediction of bacterial carbohydrate-binding proteins as a tool for understanding commensal and pathogen colonisation of the vaginal microbiome, Publisher: Nature Research
<jats:title>Abstract</jats:title><jats:p>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.</jats:p>
Bayar E, Bennett PR, Chan D, et al., 2020, The pregnancy microbiome and preterm birth, Springer Seminars in Immunopathology, Vol: 42, Pages: 487-499, ISSN: 1863-2297
Preterm birth is a global health concern and continues to contribute to substantial neonatal morbidity and mortality despite advances in obstetric and neonatal care. The underlying aetiology is multi-factorial and remains incompletely understood. In this review, the complex interplay between the vaginal microbiome in pregnancy and its association with preterm birth is discussed in depth. Advances in the study of bacteriology and an improved understanding of the human microbiome have seen an improved awareness of the vaginal microbiota in both health and in disease.
Tzafetas M, Mitra A, Paraskevaidi M, et al., 2020, The intelligent knife (iKnife) and its intraoperative diagnostic advantage for the treatment of cervical disease (vol 117, pg 7338, 2020), PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 117, Pages: 18892-18892, ISSN: 0027-8424
Rasheed ZBM, Lee YS, Kim SH, et al., 2020, Differential response of gestational tissues to TLR3 viral priming prior to exposure to bacterial TLR2 and TLR2/6 agonists, Frontiers in Immunology, Vol: 11, Pages: 1-27, ISSN: 1664-3224
Background: Infection/inflammation is an important causal factor in spontaneous preterm birth (sPTB). Most mechanistic studies have concentrated on the role of bacteria, with limited focus on the role of viruses in sPTB. Murine studies support a potential multi-pathogen aetiology in which a double or sequential hit of both viral and bacterial pathogens leads to a higher risk preterm labour. This study aimed to determine the effect of viral priming on bacterial induced inflammation in human in vitro models of ascending and haematogenous infection.Methods: Vaginal epithelial cells, and primary amnion epithelial cells and myocytes were used to represent cell targets of ascending infection while interactions between peripheral blood mononuclear cells (PBMCs) and placental explants were used to model systemic infection. To model the effect of viral priming upon the subsequent response to bacterial stimuli, each cell type was stimulated first with a TLR3 viral agonist, and then with either a TLR2 or TLR2/6 agonist, and responses compared to those of each agonist alone. Immunoblotting was used to detect cellular NF-κB, AP-1, and IRF-3 activation. Cellular TLR3, TLR2, and TLR6 mRNA was quantified by RT-qPCR. Immunoassays were used to measure supernatant cytokine, chemokine and PGE2 concentrations.Results: TLR3 (“viral”) priming prior to TLR2/6 agonist (“bacterial”) exposure augmented the pro-inflammatory, pro-labour response in VECs, AECs, myocytes and PBMCs when compared to the effects of agonists alone. In contrast, enhanced anti-inflammatory cytokine production (IL-10) was observed in placental explants. Culturing placental explants in conditioned media derived from PBMCs primed with a TLR3 agonist enhanced TLR2/6 agonist stimulated production of IL-6 and IL-8, suggesting a differential response by the placenta to systemic inflammation compared to direct infection as a result of haematogenous spread. TLR3 agonism generally caused increased m
Mitra A, MacIntyre D, Ntritsos G, et al., 2020, The vaginal microbiota associates with the regression of untreated cervical intraepithelial neoplasia 2 lesions, Nature Communications, Vol: 11, Pages: 1-13, ISSN: 2041-1723
Emerging evidence suggests associations between the vaginal microbiota (VMB) composition, human papillomavirus (HPV) infection, and cervical intraepithelial neoplasia (CIN); however, causal inference remains uncertain. Here, we use bacterial DNA sequencing from serially collected vaginal samples from a cohort of 87 adolescent and young women aged 16–26 years with histologically confirmed, untreated CIN2 lesions to determine whether VMB composition affects rates of regression over 24 months. We show that women with a Lactobacillus-dominant microbiome at baseline are more likely to have regressive disease at 12 months. Lactobacillus spp. depletion and presence of specific anaerobic taxa including Megasphaera, Prevotella timonensis and Gardnerella vaginalis are associated with CIN2 persistence and slower regression. These findings suggest that VMB composition may be a future useful biomarker in predicting disease outcome and tailoring surveillance, whilst it may offer rational targets for the development of new prevention and treatment strategies.
MacIntyre D, Beagley K, 2020, The immune system of the genitourinary tract, Principles of Mucosal Immunology, Publisher: Garland Science, ISBN: 9781000754490
The human genitourinary tract is characterized by a complex system of compartmentalized, highly integrated tissues, finely tuned hormonal regulation, and an immune system that has some similarities to, but also distinct differences from, the gastrointestinal immune system. Innate and adaptive immune defenses in the genitourinary tract influence, and are influenced by, the composition of commensal microbial communities, which provide a degree of protection against sexually transmitted diseases. The mucosal immune system in the female reproductive tract contains an array of protective mechanisms that are under hormonal control. Immune cell organization varies with tissue and stage of the menstrual cycle. Sex hormones also regulate immune-cell function in tissues of the female reproductive tract as the immune system faces the unique challenge of protecting tissues that are changing shape, thickness, and vascularity. The mucosal immune system in the male and female human reproductive tracts has evolved to meet the unique requirements of procreation and host defense against genital tract pathogens.
Tzafetas M, Mitra A, Paraskevaidi M, et al., 2020, The intelligent-Knife (i-Knife) and its intraoperative diagnostic advantage for the treatment of cervical disease, Proceedings of the National Academy of Sciences of USA, Vol: 117, Pages: 7338-7346, ISSN: 0027-8424
Clearance of surgical margins in cervical cancer prevents the need for adjuvant chemoradiation and allows fertility preservation. In this study, we determined the capacity of the rapid evaporative ionization mass spectrometry (REIMS), also known as intelligent knife (iKnife), to discriminate between healthy, preinvasive, and invasive cervical tissue. Cervical tissue samples were collected from women with healthy, human papilloma virus (HPV) ± cervical intraepithelial neoplasia (CIN), or cervical cancer. A handheld diathermy device generated surgical aerosol, which was transferred into a mass spectrometer for subsequent chemical analysis. Combination of principal component and linear discriminant analysis and least absolute shrinkage and selection operator was employed to study the spectral differences between groups. Significance of discriminatory m/z features was tested using univariate statistics and tandem MS performed to elucidate the structure of the significant peaks allowing separation of the two classes. We analyzed 87 samples (normal = 16, HPV ± CIN = 50, cancer = 21 patients). The iKnife discriminated with 100% accuracy normal (100%) vs. HPV ± CIN (100%) vs. cancer (100%) when compared to histology as the gold standard. When comparing normal vs. cancer samples, the accuracy was 100% with a sensitivity of 100% (95% CI 83.9 to 100) and specificity 100% (79.4 to 100). Univariate analysis revealed significant MS peaks in the cancer-to-normal separation belonging to various classes of complex lipids. The iKnife discriminates healthy from premalignant and invasive cervical lesions with high accuracy and can improve oncological outcomes and fertility preservation of women treated surgically for cervical cancer. Larger in vivo research cohorts are required to validate these findings.
Grewal K, Lee YS, Smith A, et al., 2020, Euploid Miscarriage is Associated with <i>Lactobacillus</i> spp. Deplete Vaginal Microbial Composition and Local Inflammation., 67th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SPRINGER HEIDELBERG, Pages: 65A-65A, ISSN: 1933-7191
Budwig L, Brown R, Lee YS, et al., 2020, The Use of Peripheral Blood Neutrophil Counts in the Prediction of Funisitis Following Preterm Prelabour Rupture of Membranes., 67th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SPRINGER HEIDELBERG, Pages: 212A-212A, ISSN: 1933-7191
Hua R, Edey LF, O'Dea KP, et al., 2020, CCR2 mediates the adverse effects of LPS in the pregnant mouse, Biology of Reproduction, Vol: 102, Pages: 445-455, ISSN: 0006-3363
In our earlier work, we found that intrauterine (i.u.) and intraperitoneal (i.p.) injection of LPS (10-μg serotype 0111:B4) induced preterm labor (PTL) with high pup mortality, marked systemic inflammatory response and hypotension. Here, we used both i.u. and i.p. LPS models in pregnant wild-type (wt) and CCR2 knockout (CCR2-/-) mice on E16 to investigate the role played by the CCL2/CCR2 system in the response to LPS. Basally, lower numbers of monocytes and macrophages and higher numbers of neutrophils were found in the myometrium, placenta, and blood of CCR2-/- vs. wt mice. After i.u. LPS, parturition occurred at 14 h in both groups of mice. At 7 h post-injection, 70% of wt pups were dead vs. 10% of CCR2-/- pups, but at delivery 100% of wt and 90% of CCR2-/- pups were dead. Myometrial and placental monocytes and macrophages were generally lower in CCR2-/- mice, but this was less consistent in the circulation, lung, and liver. At 7 h post-LPS, myometrial ERK activation was greater and JNK and p65 lower and the mRNA levels of chemokines were higher and of inflammatory cytokines lower in CCR2-/- vs. wt mice. Pup brain and placental inflammation were similar. Using the IP LPS model, we found that all measures of arterial pressure increased in CCR2-/- but declined in wt mice. These data suggest that the CCL2/CCR2 system plays a critical role in the cardiovascular response to LPS and contributes to pup death but does not influence the onset of inflammation-induced PTL.
Al-Memar M, Bobdiwala S, Fourie H, et al., 2020, The association between vaginal bacterial composition and miscarriage: a nested case-control study, BJOG: an International Journal of Obstetrics and Gynaecology, Vol: 127, Pages: 264-274, ISSN: 1470-0328
OBJECTIVE: To characterise vaginal bacterial composition in early pregnancy and investigate its relationship with first and second trimester miscarriages. DESIGN: Nested case-control study. SETTING: Queen Charlotte's and Chelsea Hospital, Imperial College Healthcare NHS Trust, London. POPULATION: 161 pregnancies; 64 resulting in first trimester miscarriage, 14 in second trimester miscarriage and 83 term pregnancies. METHODS: Prospective profiling and comparison of vaginal bacteria composition using 16S rRNA gene-based metataxonomics from 5 weeks gestation in pregnancies ending in miscarriage or uncomplicated term deliveries matched for age, gestation and body-mass index. MAIN OUTCOME MEASURES: Relative vaginal bacteria abundance, diversity and richness. Pregnancy outcomes defined as first or second trimester miscarriage, or uncomplicated term delivery. RESULTS: First trimester miscarriage associated with reduced prevalence of Lactobacillus spp.-dominated vaginal microbiota classified using hierarchical clustering analysis (65.6% vs. 87·7%; P=0·005), higher alpha diversity (mean Inverse Simpson Index 2.5 (95% confidence interval 1.8-3.0) vs. 1.5 (1.3-1.7), P=0·003) and higher richness 25.1 (18.5-31.7) vs. 16.7 (13.4-20), P=0·017), compared to viable pregnancies. This was independent of vaginal bleeding and observable before first trimester miscarriage diagnosis (P=0·015). Incomplete/complete miscarriage associated with higher proportions of Lactobacillus spp.-deplete communities compared to missed miscarriage. Early pregnancy vaginal bacterial stability was similar between miscarriage and term pregnancies. CONCLUSIONS: These findings associate the bacterial component of vaginal microbiota with first trimester miscarriage and indicate suboptimal community composition is established in early pregnancy. While further studies are required to elucidate the mechanism, vaginal bacterial composition may represent a modifiable risk factor fo
Jones BP, Saso S, L'Heveder A, et al., 2020, The vaginal microbiome in uterine transplantation, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 127, Pages: 230-238, ISSN: 1470-0328
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- Citations: 14
Pavagada S, Channon RB, Chang JYH, et al., 2019, Oligonucleotide-templated lateral flow assays for amplification-free sensing of circulating microRNAs (vol 55, pg 12451, 2019), CHEMICAL COMMUNICATIONS, Vol: 55, Pages: 13470-13470, ISSN: 1359-7345
Mitra A, Macintyre D, Lee Y, et al., 2019, CERVICAL INTRAEPITHELIAL NEOPLASIA IS ASSOCIATED WITH AN ALTERED VAGINAL MICROBIOME AND INNATE IMMUNE DISRUPTION, Publisher: BMJ PUBLISHING GROUP, Pages: A71-A71, ISSN: 1048-891X
Semertzidou A, MacIntyre D, Marchesi J, et al., 2019, CHARACTERISATION OF THE MICROBIOME ALONG THE FEMALE GENITAL TRACT AND RECTUM IN ENDOMETRIAL CANCER, Publisher: BMJ PUBLISHING GROUP, Pages: A363-A364, ISSN: 1048-891X
Mitra A, Macintyre D, Ntritsos G, et al., 2019, THE ROLE OF THE VAGINAL MICROBIOTA IN THE REGRESSION OF UNTREATED CIN2 LESIONS, Publisher: BMJ PUBLISHING GROUP, Pages: A37-A37, ISSN: 1048-891X
Tzafetas M, Mitra A, Lever S, et al., 2019, ONCOLOGICAL AND REPRODUCTIVE OUTCOMES AFTER FERTILITY-SPARING SURGERY IN WOMEN WITH CERVICAL CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS, Publisher: BMJ PUBLISHING GROUP, Pages: A76-A77, ISSN: 1048-891X
Tzafetas M, Mitra A, Kalliala I, et al., 2019, THE IKNIFE AND ITS APPLICATION FOR THE TREATMENT OF CERVICAL ABNORMALITIES, Publisher: BMJ PUBLISHING GROUP, Pages: A589-A589, ISSN: 1048-891X
Pavagada S, Channon RB, Chang JYH, et al., 2019, Oligonucleotide-templated lateral flow assays for amplification-free sensing of circulating microRNAs, Chemical Communications, Vol: 55, Pages: 12451-12454, ISSN: 1359-7345
Herein we demonstrate the first example of oligonucleotide-templated reaction (OTR) performed on paper, using lateral flow to capture and concentrate specific nucleic acid biomarkers on a test line. Quantitative analysis, using a low-cost benchtop fluorescence reader showed very high specificity down to the single nucleotide level and proved sensitive enough for amplification-free, on-chip, detection of endogenous concentrations of miR-150-5p, a recently identified predictive blood biomarker for preterm birth.
Brown R, Chan D, Terzidou V, et al., 2019, Prospective observational study of vaginal microbiota pre- and post-rescue cervical cerclage, BJOG: An International Journal of Obstetrics and Gynaecology, Vol: 126, Pages: 916-925, ISSN: 1470-0328
ObjectiveTo investigate the relationship between vaginal microbiota composition and outcome of rescue cervical cerclage.DesignProspective observational study.SettingQueen Charlotte’s and Chelsea Hospital, LondonPopulationTwenty singleton pregnancies undergoing a rescue cervical cerclage.MethodsVaginal microbiota composition was analysed in women presenting with a dilated cervix and exposed fetal membranes before and 10 days following rescue cervical cerclage and correlated with clinical outcomes.Main outcome measuresComposition of vaginal bacteria characterised by culture independent next generation sequencing.Successful cerclage, defined as those resulting in the birth of a neonate discharged from hospital without morbidity.Unsuccessful cerclage, defined as procedures culminating in miscarriage, intrauterine death, neonatal death or significant neonatal morbidity.ResultsReduced Lactobacillus spp. relative abundance was observed in 40% of cases prior to rescue cerclage compared to 10% of gestational age matched controls (8/20, 40% vs 3/30, 10%, P=0.017). Gardnerella vaginalis was over-represented in women presenting with symptoms (3/7, 43% vs 0/13, 0%, P=0.03, LDA (log 10) and casesculminating in miscarriage (3/6, 50% vs 0/14, 0%, P=0.017). In the majority of cases (10/14, 71%) bacterial composition was unchanged following cerclage insertionand peri-operative interventions.ConclusionsReduced relative abundance of Lactobacillus spp. is associated with premature cervical dilatation, whereas high levels of Gardnerella vaginalis are associated with unsuccessful rescue cerclage cases. The insertion of a rescue cerclage does not affect the underlying bacterial composition in the majority of cases.
Rasheed ZBM, Lee YS, Bennett PR, et al., 2019, Priming of vaginal and amnion epithelial cells with a TLR3 agonist augments TLR2/TLR6 agonist response: a potential synergistic role of viruses and bacteria in preterm labour, Publisher: WILEY, Pages: 156-156, ISSN: 1470-0328
Grewal K, Lee Y, Smith A, et al., 2019, Lactobacillus-deplete vaginal microbiota composition is associated with chromosomally normal miscarriage, Publisher: WILEY, Pages: 29-29, ISSN: 1470-0328
Chan D, Lee YS, Ahmed S, et al., 2019, The vaginal microbiome influences the maternal local immune response in women who deliver preterm and at term, Publisher: WILEY, Pages: 165-166, ISSN: 1470-0328
Chan D, Lee YS, Teoh TG, et al., 2019, Maternal gut microbial-immune interactions during healthy pregnancy, Publisher: WILEY, Pages: 165-165, ISSN: 1470-0328
Rasheed ZBM, Martin CRS, Sullivan MHF, et al., 2019, The placenta exhibits selective immune response in an in vitro model of haematogenous multi-pathogen-induced preterm labour, Publisher: WILEY, Pages: 158-158, ISSN: 1470-0328
Brown RG, Al-Memar M, Marchesi JR, et al., 2019, Establishment of vaginal microbiota composition in early pregnancy and its association with subsequent preterm prelabour rupture of the fetal membranes, Translational Research, Vol: 207, Pages: 30-43, ISSN: 1931-5244
Vaginal bacterial community composition influences pregnancy outcome. Preterm prelabor rupture of the fetal membranes (PPROM), which precedes 30% of all spontaneous preterm births, is associated with high vaginal bacterial diversity prior to rupture. The point at which vaginal bacterial diversity is established before PPROM is unknown. In this study, we use metataxonomics to longitudinally characterize the vaginal bacterial composition from as early as 6 weeks of gestation in women at high (n = 38) and low (n = 22) risk of preterm birth who subsequently experience PPROM and in women delivering at term without complications (n = 36). Reduced Lactobacillus spp. abundance and high diversity was observed prior to PPROM in 20% and 26% of women at low and high risk of preterm births respectively, but in only 3% of women who delivered at term. PPROM was associated with instability of bacterial community structure during pregnancy and a shift toward higher diversity predominately occurring during the second trimester. This was characterized by increased relative abundance of potentially pathogenic species including Prevotella, Peptoniphilus, Streptococcus, and Dialister. This study identifies reduced Lactobacillus spp. abundance and increasing vaginal bacterial diversity as an early risk factor for PPROM and highlights the need for interventional studies designed to assess the impact of modifying vaginal bacterial composition for the prevention of preterm birth.
Chan D, Lee YS, Ahmed S, et al., 2019, Local and systemic immune responses in preterm and term pregnancies and their association with the vaginal microbiota, Publisher: WILEY, Pages: E128-E128, ISSN: 1470-0328
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