ORCID Profile
0000-0001-9579-6408
Current Organisations
Fondazione IRCCS Istituto Nazionale dei Tumori
,
University of New South Wales
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Publisher: Wiley
Date: 14-05-2022
DOI: 10.1002/JMV.27832
Publisher: Elsevier BV
Date: 06-2020
Publisher: Springer Science and Business Media LLC
Date: 27-08-2019
DOI: 10.1007/S00125-019-4942-X
Abstract: The incidence of type 1 diabetes has increased since the mid-twentieth century at a rate that is too rapid to be attributed to genetic predisposition alone. While the disease can occur at any age, mounting evidence from longitudinal cohort studies of at-risk children indicate that type 1 diabetes associated autoantibodies can be present from the first year of life, and that those who develop type 1 diabetes at a young age have a more aggressive form of the disease. This corroborates the hypothesis that environmental exposures in early life contribute to type 1 diabetes risk, whether related to maternal influences on the fetus during pregnancy, neonatal factors or later effects during infancy and early childhood. Studies to date show a range of environmental triggers acting at different time points, suggesting a multifactorial model of genetic and environmental factors in the pathogenesis of type 1 diabetes, which integrally involves a dialogue between the immune system and pancreatic beta cells. For ex le, breastfeeding may have a weak protective effect on type 1 diabetes risk, while use of an extensively hydrolysed formula does not. Additionally, exposure to being overweight pre-conception, both in utero and postnatally, is associated with increased risk of type 1 diabetes. Epidemiological, clinical and pathological studies in humans support a role for viral infections, particularly enteroviruses, in type 1 diabetes, but definitive proof is lacking. The role of the early microbiome and its perturbations in islet autoimmunity and type 1 diabetes is the subject of investigation in ongoing cohort studies. Understanding the interactions between environmental exposures and the human genome and metagenome, particularly across ethnically erse populations, will be critical for the development of future strategies for primary prevention of type 1 diabetes.
Publisher: MDPI AG
Date: 19-01-2022
DOI: 10.3390/V14020185
Abstract: Whole-genome sequencing of viral isolates is critical for informing transmission patterns and for the ongoing evolution of pathogens, especially during a pandemic. However, when genomes have low variability in the early stages of a pandemic, the impact of technical and/or sequencing errors increases. We quantitatively assessed inter-laboratory differences in consensus genome assemblies of 72 matched SARS-CoV-2-positive specimens sequenced at different laboratories in Sydney, Australia. Raw sequence data were assembled using two different bioinformatics pipelines in parallel, and resulting consensus genomes were compared to detect laboratory-specific differences. Matched genome sequences were predominantly concordant, with a median pairwise identity of 99.997%. Identified differences were predominantly driven by ambiguous site content. Ignoring these produced differences in only 2.3% (5/216) of pairwise comparisons, each differing by a single nucleotide. Matched s les were assigned the same Pango lineage in 98.2% (212/216) of pairwise comparisons, and were mostly assigned to the same phylogenetic clade. However, epidemiological inference based only on single nucleotide variant distances may lead to significant differences in the number of defined clusters if variant allele frequency thresholds for consensus genome generation differ between laboratories. These results underscore the need for a unified, best-practices approach to bioinformatics between laboratories working on a common outbreak problem.
Publisher: Research Square Platform LLC
Date: 18-11-2020
DOI: 10.21203/RS.3.RS-105996/V1
Abstract: Accumulating evidence supports the high prevalence of co-infections among Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) patients, and their potential to worsen the clinical outcome of COVID-19. However, there are few data on Southern Hemisphere populations, and most studies to date have investigated a narrow spectrum of viruses using targeted qRT-PCR. Here we assessed respiratory viral co-infections among SARS-CoV-2 patients in Australia, through respiratory virome characterization. Nasopharyngeal swabs of 92 SARS-CoV-2-positive cases were sequenced using pan-viral hybrid-capture and the Twist Respiratory Virus Panel. In total, 8% of cases were co-infected, with rhinovirus (6%) or influenzavirus (2%). Twist capture also achieved near-complete sequencing ( % coverage, -fold depth) of the SARS-CoV-2 genome in 95% of specimens with Ct . Our results highlight the importance of assessing all pathogens in symptomatic patients, and the dual-functionality of Twist hybrid-capture, for SARS-CoV-2 whole-genome sequencing without licon generation and the simultaneous identification of viral co-infections with ease.
Publisher: Informa UK Limited
Date: 12-04-2023
Publisher: MDPI AG
Date: 16-07-2021
DOI: 10.3390/MICROORGANISMS9071519
Abstract: For over a century, viruses have left a long trail of evidence implicating them as frequent suspects in the development of type 1 diabetes. Through vigorous interrogation of viral infections in in iduals with islet autoimmunity and type 1 diabetes using serological and molecular virus detection methods, as well as mechanistic studies of virus-infected human pancreatic β-cells, the prime suspects have been narrowed down to predominantly human enteroviruses. Here, we provide a comprehensive overview of evidence supporting the hypothesised role of enteroviruses in the development of islet autoimmunity and type 1 diabetes. We also discuss concerns over the historical focus and investigation bias toward enteroviruses and summarise current unbiased efforts aimed at characterising the complete population of viruses (the “virome”) contributing early in life to the development of islet autoimmunity and type 1 diabetes. Finally, we review the range of vaccine and antiviral drug candidates currently being evaluated in clinical trials for the prevention and potential treatment of type 1 diabetes.
Publisher: MDPI AG
Date: 24-08-2021
DOI: 10.3390/IJMS22179129
Abstract: Background: Rural/remote blood collection can cause delays in processing, reducing PBMC number, viability, cell composition and function. To mitigate these impacts, blood was stored at 4 °C prior to processing. Viable cell number, viability, immune phenotype, and Interferon-γ (IFN-γ) release were measured. Furthermore, the lowest protective volume of cryopreservation media and cell concentration was investigated. Methods: Blood from 10 in iduals was stored for up to 10 days. Flow cytometry and IFN-γ ELISPOT were used to measure immune phenotype and function on thawed PBMC. Additionally, PBMC were cryopreserved in volumes ranging from 500 µL to 25 µL and concentration from 10 × 106 cells/mL to 1.67 × 106 cells/mL. Results: PBMC viability and viable cell number significantly reduced over time compared with s les processed immediately, except when stored for 24 h at RT. Monocytes and NK cells significantly reduced over time regardless of storage temperature. S les with h of RT storage had an increased proportion in Low-Density Neutrophils and T cells compared with s les stored at 4 °C. IFN-γ release was reduced after 24 h of storage, however not in s les stored at 4 °C for h. The lowest protective volume identified was 150 µL with the lowest density of 6.67 × 106 cells/mL. Conclusion: A s le delay of 24 h at RT does not impact the viability and total viable cell numbers. When long-term delays exist ( d) total viable cell number and cell viability losses are reduced in s les stored at 4 °C. Immune phenotype and function are slightly altered after 24 h of storage, further impacts of storage are reduced in s les stored at 4 °C.
Publisher: MDPI AG
Date: 23-06-2021
DOI: 10.20944/PREPRINTS202106.0574.V1
Abstract: For over a century, viruses have left a long trail of evidence implicating them as frequent suspects in the development of type 1 diabetes. Through vigorous interrogation of viral infections in in iduals with islet autoimmunity and type 1 diabetes using serological and molecular virus detection methods, and mechanistic studies of virus infected human pancreatic & beta -cells, the prime suspects have been narrowed down to predominantly human enteroviruses. Here we provide a comprehensive overview of evidence supporting the hypothesised role of enteroviruses in the development of islet autoimmunity and type 1 diabetes. We also discuss concerns over the historical focus and investigation bias toward enteroviruses, and summarise current unbiased efforts aimed at characterising the complete population of viruses (the & virome& ) contributing early in life to the development of islet autoimmunity and type 1 diabetes. Finally, we review the range of vaccine and antiviral drug candidates currently being evaluated in clinical trials for the prevention and potential treatment of type 1 diabetes.
Publisher: Springer Science and Business Media LLC
Date: 09-12-2020
DOI: 10.1038/S41467-020-20075-6
Abstract: Viral whole-genome sequencing (WGS) provides critical insight into the transmission and evolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Long-read sequencing devices from Oxford Nanopore Technologies (ONT) promise significant improvements in turnaround time, portability and cost, compared to established short-read sequencing platforms for viral WGS (e.g., Illumina). However, adoption of ONT sequencing for SARS-CoV-2 surveillance has been limited due to common concerns around sequencing accuracy. To address this, here we perform viral WGS with ONT and Illumina platforms on 157 matched SARS-CoV-2-positive patient specimens and synthetic RNA controls, enabling rigorous evaluation of analytical performance. We report that, despite the elevated error rates observed in ONT sequencing reads, highly accurate consensus-level sequence determination was achieved, with single nucleotide variants (SNVs) detected at % sensitivity and % precision above a minimum ~60-fold coverage depth, thereby ensuring suitability for SARS-CoV-2 genome analysis. ONT sequencing also identified a surprising ersity of structural variation within SARS-CoV-2 specimens that were supported by evidence from short-read sequencing on matched s les. However, ONT sequencing failed to accurately detect short indels and variants at low read-count frequencies. This systematic evaluation of analytical performance for SARS-CoV-2 WGS will facilitate widespread adoption of ONT sequencing within local, national and international COVID-19 public health initiatives.
Publisher: InTech
Date: 29-08-2011
DOI: 10.5772/22686
Publisher: Public Library of Science (PLoS)
Date: 24-04-2012
Publisher: Springer Science and Business Media LLC
Date: 11-02-2019
DOI: 10.1038/S41598-018-38368-8
Abstract: Enteroviruses (EVs) are prime candidate environmental triggers of islet autoimmunity (IA), with potential as vaccine targets for type 1 diabetes prevention. However, the use of targeted virus detection methods and the selective focus on EVs by most studies increases the risk for substantial investigation bias and an overestimated association between EV and type 1 diabetes. Here we performed comprehensive virome-capture sequencing to examine all known vertebrate-infecting viruses without bias in 182 specimens (faeces and plasma) collected before or at seroconversion from 45 case children with IA and 48 matched controls. From .6 billion reads, 28 genera of viruses were detected and 62% of children (58/93) were positive for ≥1 vertebrate-infecting virus. We identified 129 viruses as differentially abundant between the gut of cases and controls, including 5 EV-A types significantly more abundant in the cases. Our findings further support EV’s hypothesised contribution to IA and corroborate the proposal that viral load may be an important parameter in disease pathogenesis. Furthermore, our data indicate a previously unrecognised association of IA with higher EV-A abundance in the gut of children and provide a catalog of viruses to be interrogated further to determine a causal link between virus infection and type 1 diabetes.
Publisher: Wiley
Date: 22-03-2018
DOI: 10.1002/RMV.1974
Abstract: Virus infections are implicated in the development of type 1 diabetes based on epidemiological, clinical, in vitro cell-based and molecular studies, and animal models. We reviewed the association between virus infections in pregnant women and development of islet autoimmunity or type 1 diabetes in their offspring. We performed a systematic review and meta-analysis, analysed using random effects models, of human studies from Medline and EMBASE without language restriction. Inclusion criteria were as follows: cohort and case-control studies measuring viral nucleic acid in blood, stool, urine, or tissue, or serological tests for viruses, in pregnant women whose offspring developed islet autoimmunity and/or type 1 diabetes. All studies required sufficient data to calculate odds ratios and 95% confidence intervals. The 10 studies (4 case control, 6 nested-case control) that met the eligibility criteria included 2992 participants (953 offspring, 2039 mothers), with varying study design. The 2 outcomes examined were islet autoimmunity (n = 466) and type 1 diabetes (n = 2526). Meta-analysis showed a significant association between virus infection during pregnancy and clinical type 1 diabetes during childhood (odds ratio 2·16, 95% CI 1·22-3·80 P = 0·008 heterogeneity X
Publisher: Springer Science and Business Media LLC
Date: 08-08-2018
DOI: 10.1038/S41598-018-30322-Y
Abstract: More than 100 different enterovirus (EV) genotypes infect humans and contribute to substantial morbidity. However, current methods for characterisation of full-length genomes are based on Sanger sequencing of short genomic regions, which are labour-intensive and do not enable comprehensive characterisation of viral populations. Here, we describe a simple and sensitive protocol for the lification and sequencing of near full-length genomes of human EV species using next generation sequencing. EV genomes were lified from 89% of s les tested, with C t values ranging between 15.7 and 39.3. These s les included 7 EV-A genotypes (CVA2, 5–7, 10, 16 and EV71), 19 EV-B genotypes (CVA9, CVB1-6, ECHO3, 4, 6, 7, 9, 11, 16, 18, 25, 29, 30, and EV69), 3 EV-C genotypes (CVA19 and PV2, 3) and 1 EV-D genotype (EV70). We characterised 70 EVs from 58 clinical stool s les and eight reference strains, with a minimum of 100X depth. We found evidence of co-infection in four clinical specimens, each containing two distinct EV genotypes (CVB3/ECHO7, CVB3/ECHO18 and ECHO9/30). Characterisation of the complete genome provided conclusive genotyping of EVs, which can be applied to investigate the intra-host virus evolution of EVs, and allows further identification and investigation of EV outbreaks.
Publisher: Hindawi Limited
Date: 07-01-2020
DOI: 10.1111/PEDI.12952
Abstract: Microbial exposures in utero and early life shape the infant microbiome, which can profoundly impact on health. Compared to the bacterial microbiome, very little is known about the virome. We set out to characterize longitudinal changes in the gut virome of healthy infants born to mothers with or without type 1 diabetes using comprehensive virome capture sequencing. Healthy infants were selected from Environmental Determinants of Islet Autoimmunity (ENDIA), a prospective cohort of Australian children with a first-degree relative with type 1 diabetes, followed from pregnancy. Fecal specimens were collected three-monthly in the first year of life. Among 25 infants (44% born to mothers with type 1 diabetes) at least one virus was detected in 65% (65/100) of s les and 96% (24/25) of infants during the first year of life. In total, 26 genera of viruses were identified and >150 viruses were differentially abundant between the gut of infants with a mother with type 1 diabetes vs without. Positivity for any virus was associated with maternal type 1 diabetes and older infant age. Enterovirus was associated with older infant age and maternal smoking. We demonstrate a distinct gut virome profile in infants of mothers with type 1 diabetes, which may influence health outcomes later in life. Higher prevalence and greater number of viruses observed compared to previous studies suggests significant underrepresentation in existing virome datasets, arising most likely from less sensitive techniques used in data acquisition.
Publisher: MDPI AG
Date: 13-02-2023
DOI: 10.3390/V15020522
Abstract: Australia experienced widespread COVID-19 outbreaks from infection with the SARS-CoV-2 Delta variant between June 2021 and February 2022. A 17-nucleotide frameshift-inducing deletion in ORF7a rapidly became represented at the consensus level (Delta-ORF7aΔ17del) in most Australian outbreak cases. Studies from early in the COVID-19 pandemic suggest that frameshift-inducing deletions in ORF7a do not persist for long in the population therefore, Delta-ORF7aΔ17del genomes should have disappeared early in the Australian outbreak. In this study, we conducted a retrospective analysis of global Delta genomes to characterise the dynamics of Delta-ORF7aΔ17del over time, determined the frequency of all ORF7a deletions worldwide, and compared global trends with those of the Australian Delta outbreak. We downloaded all GISAID clade GK Delta genomes and scanned them for deletions in ORF7a. For each deletion we identified, we characterised its frequency, the number of countries it was found in, and how long it persisted. Of the 4,018,216 Delta genomes identified globally, 134,751 (~3.35%) possessed an ORF7a deletion, and ORF7aΔ17del was the most common. ORF7aΔ17del was the sole deletion in 28,014 genomes, of which 27,912 (~99.6%) originated from the Australian outbreak. During the outbreak, ~87% of genomes were Delta-ORF7aΔ17del, and genomes with this deletion were s led until the outbreak’s end. These data demonstrate that, contrary to suggestions early in the COVID-19 pandemic, genomes with frameshifting deletions in ORF7a can persist over long time periods. We suggest that the proliferation of Delta-ORF7aΔ17del genomes was likely a chance founder effect. Nonetheless, the frequency of ORF7a deletions in SARS-CoV-2 genomes worldwide suggests they might have some benefit for virus transmission.
Publisher: Springer Science and Business Media LLC
Date: 16-02-2021
DOI: 10.1038/S41598-021-83642-X
Abstract: Accumulating evidence supports the high prevalence of co-infections among Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) patients, and their potential to worsen the clinical outcome of COVID-19. However, there are few data on Southern Hemisphere populations, and most studies to date have investigated a narrow spectrum of viruses using targeted qRT-PCR. Here we assessed respiratory viral co-infections among SARS-CoV-2 patients in Australia, through respiratory virome characterization. Nasopharyngeal swabs of 92 SARS-CoV-2-positive cases were sequenced using pan-viral hybrid-capture and the Twist Respiratory Virus Panel. In total, 8% of cases were co-infected, with rhinovirus (6%) or influenzavirus (2%). Twist capture also achieved near-complete sequencing ( 90% coverage, tenfold depth) of the SARS-CoV-2 genome in 95% of specimens with Ct 30. Our results highlight the importance of assessing all pathogens in symptomatic patients, and the dual-functionality of Twist hybrid-capture, for SARS-CoV-2 whole-genome sequencing without licon generation and the simultaneous identification of viral co-infections with ease.
Publisher: Elsevier BV
Date: 06-2023
Publisher: Wiley
Date: 30-12-2020
DOI: 10.1002/RMV.2209
Abstract: Viruses are postulated as primary candidate triggers of islet autoimmunity (IA) and type 1 diabetes (T1D), based on considerable epidemiological and experimental evidence. Recent studies have investigated the association between all viruses (the ‘virome’) and IA/T1D using metagenomic next‐generation sequencing (mNGS). Current associations between the early life virome and the development of IA/T1D were analysed in a systematic review and meta‐analysis of human observational studies from Medline and EMBASE (published 2000–June 2020), without language restriction. Inclusion criteria were as follows: cohort and case–control studies examining the virome using mNGS in clinical specimens of children ≤18 years who developed IA/T1D. The National Health and Medical Research Council level of evidence scale and Newcastle–Ottawa scale were used for study appraisal. Meta‐analysis for exposure to specific viruses was performed using random‐effects models, and the strength of association was measured using odds ratios (ORs) and 95% confidence intervals (CIs). Eligible studies (one case–control, nine nested case–control) included 1,425 participants (695 cases, 730 controls) and examined IA ( n = 1,023) or T1D ( n = 402). Meta‐analysis identified small but significant associations between IA and number of stool s les positive for all enteroviruses (OR 1.14, 95% CI 1.00–1.29, p = 0.05 heterogeneity χ 2 = 1.51, p = 0.68, I 2 = 0%), consecutive positivity for enteroviruses (1.55, 1.09–2.20, p = 0.01 χ 2 = 0.19, p = 0.91, I 2 = 0%) and number of stool s les positive specifically for enterovirus B (1.20, 1.01–1.42, p = 0.04 χ 2 = 0.03, p = 0.86, I 2 = 0%). Virome analyses to date have demonstrated associations between enteroviruses and IA that may be clinically significant. However, larger prospective mNGS studies with more frequent s ling and follow‐up from pregnancy are required to further elucidate associations between early virus exposure and IA/T1D.
Publisher: Wiley
Date: 15-02-2023
DOI: 10.1002/RMV.2429
Abstract: Among the environmental factors associated with type 1 diabetes (T1D), viral infections of the gut and pancreas has been investigated most intensely, identifying enterovirus infections as the prime candidate trigger of islet autoimmunity (IA) and T1D development. However, the association between respiratory tract infections (RTI) and IA/T1D is comparatively less known. While there are significant amounts of epidemiological evidence supporting the role of respiratory infections in T1D, there remains a paucity of data characterising infectious agents at the molecular level. This gap in the literature precludes the identification of the specific infectious agents driving the association between RTI and T1D. Furthermore, the effect of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infections on the development of IA/T1D remains undeciphered. Here, we provide a comprehensive overview of the evidence to date, implicating RTIs (viral and non‐viral) as potential risk factors for IA/T1D.
Publisher: Springer Science and Business Media LLC
Date: 14-11-2016
DOI: 10.1007/S11892-016-0819-2
Abstract: Since the discovery of the first mammalian microRNA (miRNA) more than two decades ago, a plethora of miRNAs has been identified in humans, now amounting to more than 2500. Essential for post-transcriptional regulation of gene networks integral for developmental pathways and immune response, it is not surprising that dysregulation of miRNAs is often associated with the aetiology of complex diseases including cancer, diabetes and autoimmune disorders. Despite massive expansion of small RNA studies and extensive investigation in erse disease contexts, the role of miRNAs in type 1 diabetes has only recently been explored. Key studies using human islets have recently implicated virus-induced miRNA dysregulation as a pivotal mechanism of β cell destruction, while the interplay between miRNAs, the immune system and β cell survival has been illustrated in studies using animal and cellular models of disease. The role of specific miRNAs as major players in immune system homeostasis highlights their exciting potential as therapeutics and prognostic biomarkers of type 1 diabetes.
Publisher: Springer International Publishing
Date: 2021
Publisher: Informa UK Limited
Date: 10-2012
DOI: 10.4161/PSB.21518
Publisher: American Diabetes Association
Date: 11-11-2015
DOI: 10.2337/DB15-0956
Abstract: Extensive research has identified enterovirus (EV) infections as key environmental triggers of type 1 diabetes. However, the underlying molecular mechanisms via which EVs contribute to the pathogenesis of type 1 diabetes remain unclear. Given that EVs dysregulate host microRNAs (miRNAs), which function as key regulators of β-cell biology, we investigated the impact of coxsackievirus B5 (CVB5) infection on the cellular expression of miRNAs within human islets. Using high-throughput quantitative PCR nanofluidics arrays, the expression of 754 miRNAs was examined in CVB5-infected human pancreatic islets. In total, 33 miRNAs were significantly dysregulated (≥ threefold difference) in the infected compared with control islets (P & 0.05). Subsequently, these differentially expressed miRNAs were predicted to target mRNAs of 57 known type 1 diabetes risk genes that collectively mediate various biological processes, including the regulation of cell proliferation, cytokine production, the innate immune response, and apoptosis. In conclusion, we report the first global miRNA expression profiling of CVB5-infected human pancreatic islets. We propose that EVs disrupt the miRNA-directed suppression of proinflammatory factors within β-cells, thereby resulting in an exacerbated antiviral immune response that promotes β-cell destruction and eventual type 1 diabetes.
Publisher: Oxford University Press (OUP)
Date: 16-01-2019
DOI: 10.1093/OFID/OFZ025
Abstract: The importance of gut bacteria in human physiology, immune regulation, and disease pathogenesis is well established. In contrast, the composition and dynamics of the gut virome are largely unknown particularly lacking are studies in pregnancy. We used comprehensive virome capture sequencing to characterize the gut virome of pregnant women with and without type 1 diabetes (T1D), longitudinally followed in the Environmental Determinants of Islet Autoimmunity study. In total, 61 pregnant women (35 with T1D and 26 without) from Australia were examined. Nucleic acid was extracted from serial fecal specimens obtained at prenatal visits, and viral genomes were sequenced by virome capture enrichment. The frequency, richness, and abundance of viruses were compared between women with and without T1D. Two viruses were more prevalent in pregnant women with T1D: picobirnaviruses (odds ratio [OR], 4.2 95% confidence interval [CI], 1.0–17.1 P = .046) and tobamoviruses (OR, 3.2 95% CI, 1.1–9.3 P = .037). The abundance of 77 viruses significantly differed between the 2 maternal groups (≥2-fold difference P & .02), including 8 Enterovirus B types present at a higher abundance in women with T1D. These findings provide novel insight into the composition of the gut virome during pregnancy and demonstrate a distinct profile of viruses in women with T1D.
Start Date: 2020
End Date: 2023
Funder: Juvenile Diabetes Research Foundation
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: Juvenile Diabetes Research Foundation International
View Funded ActivityStart Date: 2020
End Date: 2021
Funder: National Computational Infrastructure
View Funded Activity