ORCID Profile
0000-0002-4764-3519
Current Organisation
University of Queensland
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Publisher: MDPI AG
Date: 07-03-2022
DOI: 10.20944/PREPRINTS202203.0101.V1
Abstract: The COVID-19 pandemic is the biggest public health threat facing the globe today. Multiple vaccines have been approved, however the emergence of viral variants such as the recent Omicron, raises the possibility of booster doses to achieve adequate protection. In Brazil, the CoronaVac (Sinovac) vaccine was used, however it& rsquo s important to assess the immune response to this vaccine over time. This study aimed to monitor the anti-SARS-CoV-2 antibody responses in those immunized with CoronaVac and SARS-CoV-2 infected in iduals. S les were collected between August 2020 and August 2021. Within the vaccinated cohort, some in iduals had history of infection by SARS-CoV-2 prior to immunization and others not. We analyzed RBD-specific and neutralizing- antibodies. Anti-RBD antibodies were detected in both cohorts, with a peak between 45-90 days post infection or vaccination, followed by a steady decline over time. In those with previous history of COVID-19, a higher, longer, more persistent response was observed. This trend was mirrored in the neutralization assays, where infection followed by immunization resulted in higher, longer lasting responses which were conditioned on the presence of levels of RBD antibodies right before the vaccination. This supports the necessity of booster doses of CoronaVac in due course to prevent serious disease.
Publisher: Springer Science and Business Media LLC
Date: 08-06-2021
DOI: 10.1038/S41467-021-23779-5
Abstract: The current COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We demonstrate that despite the large size of the viral RNA genome (~30 kb), infectious full-length cDNA is readily assembled in vitro by a circular polymerase extension reaction (CPER) methodology without the need for technically demanding intermediate steps. Overlapping cDNA fragments are generated from viral RNA and assembled together with a linker fragment containing CMV promoter into a circular full-length viral cDNA in a single reaction. Transfection of the circular cDNA into mammalian cells results in the recovery of infectious SARS-CoV-2 virus that exhibits properties comparable to the parental virus in vitro and in vivo. CPER is also used to generate insect-specific Casuarina virus with ~20 kb genome and the human pathogens Ross River virus (Alphavirus) and Norovirus (Calicivirus), with the latter from a clinical s le. Additionally, reporter and mutant viruses are generated and employed to study virus replication and virus-receptor interactions.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-01-2021
Abstract: Flaviviruses are a group of RNA viruses that include the human pathogens dengue virus, Zika virus, and West Nile virus. The envelope protein (E) on the virus surface has been the target of vaccine development, but problems have arisen with antibodies against E, leading to enhanced infection. Now, Modhiran et al. and Biering et al. describe two different antibodies that bind to the flavivirus NS1 protein and prevent it from disrupting epithelial cells, which is associated with severe disease. Both antibodies cross-react with multiple flavivirus NS1 proteins. The antibodies reduce viremia and increase survival in mouse models of flavivirus disease. Both papers include structures of NS1 bound to an antibody, which give insight into the protective mechanism. Science , this issue p. 190 , p. 194
Publisher: Cold Spring Harbor Laboratory
Date: 19-05-2021
DOI: 10.1101/2021.05.18.444753
Abstract: Zika virus (ZIKV) is a re-emerging pathogenic flavivirus, which causes microcephaly in infants and poses a continuing threat to public health. ZIKV, like all other flaviviruses, produces highly abundant noncoding RNA known as subgenomic flaviviral RNA (sfRNA). Herein we utilized wild-type and mutant ZIKV defective in production of sfRNA to elucidate for the first time how production of sfRNA affects all aspects of ZIKV pathogenesis. We found that in mouse pregnancy model of infection sfRNA is required for trans-placental dissemination of ZIKV and subsequent infection of fetal brain. Using human brain organoids, we showed that sfRNA promotes apoptosis of neural progenitor cells leading to profound cytopathicity and disintegration of organoids. We also found by transcriptome profiling and gene network analysis that in infected human placental cells sfRNA inhibits multiple antiviral pathways and promotes apoptosis with STAT1 identified as a key shared factor linking these two interconnected sfRNA activities. We further showed for the first time that sfRNA inhibits phosphorylation and nuclear translocation of STAT1 by a novel mechanism which involves binding to and stabilizing viral protein NS5. This allows accumulation of NS5 at the levels required for efficient inhibition of STAT1 phosphorylation. Thus, we elucidated the molecular mechanism by which ZIKV sfRNA exerts its functions in vertebrate hosts and discovered a co-operation between viral noncoding RNA and a viral protein as a novel strategy employed by viruses to counteract antiviral responses.
Publisher: Springer Science and Business Media LLC
Date: 18-03-2019
Publisher: MDPI AG
Date: 28-04-2022
Abstract: The COVID-19 pandemic is the biggest public health threat facing the world today. Multiple vaccines have been approved however, the emergence of viral variants such as the recent Omicron raises the possibility of booster doses to achieve adequate protection. In Brazil, the CoronaVac (Sinovac, Beijing, China) vaccine was used however, it is important to assess the immune response to this vaccine over time. This study aimed to monitor the anti-SARS-CoV-2 antibody responses in those immunized with CoronaVac and SARS-CoV-2 infected in iduals. S les were collected between August 2020 and August 2021. Within the vaccinated cohort, some in iduals had a history of infection by SARS-CoV-2 prior to immunization, while others did not. We analyzed RBD-specific and neutralizing-antibodies. Anti-RBD antibodies were detected in both cohorts, with a peak between 45–90 days post infection or vaccination, followed by a steady decline over time. In those with a previous history of COVID-19, a higher, longer, more persistent response was observed. This trend was mirrored in the neutralization assays, where infection, followed by immunization, resulted in higher, longer lasting responses which were conditioned on the presence of levels of RBD antibodies right before the vaccination. This supports the necessity of booster doses of CoronaVac in due course to prevent serious disease.
Publisher: Frontiers Media SA
Date: 12-02-2021
DOI: 10.3389/FMICB.2021.625136
Abstract: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been identified as the causative agent of coronavirus disease 2019 and is capable of human-to-human transmission and rapid global spread. The rapid emergence and global spread of SARS-CoV-2 has encouraged the establishment of a rapid, sensitive, and reliable viral detection and quantification methodology. Here, we present an alternative assay, termed immuno-plaque assay (iPA), which utilizes a combination of plaque assay and immunofluorescence techniques. We have extensively optimized the conditions for SARS-CoV-2 infection and demonstrated the great flexibility of iPA detection using several antibodies and dual-probing with two distinct epitope-specific antibodies. In addition, we showed that iPA could be utilized for ultra-high-throughput viral titration and neutralization assay within 24 h and is amenable to a 384-well format. These advantages will significantly accelerate SARS-CoV-2 research outcomes during this pandemic period.
Publisher: Cold Spring Harbor Laboratory
Date: 18-01-2023
DOI: 10.1101/2023.01.17.524329
Abstract: Aging is the primary risk factor for most neurodegenerative diseases, and recently coronavirus disease 2019 (COVID-19) has been associated with severe neurological manifestations that can eventually impact neurodegenerative conditions in the long-term. The progressive accumulation of senescent cells in vivo strongly contributes to brain aging and neurodegenerative co-morbidities but the impact of virus-induced senescence in the aetiology of neuropathologies is unknown. Here, we show that senescent cells accumulate in physiologically aged brain organoids of human origin and that senolytic treatment reduces inflammation and cellular senescence for which we found that combined treatment with the senolytic drugs dasatinib and quercetin rejuvenates transcriptomic human brain aging clocks. We further interrogated brain frontal cortex regions in postmortem patients who succumbed to severe COVID-19 and observed increased accumulation of senescent cells as compared to age-matched control brains from non-COVID-affected in iduals. Moreover, we show that exposure of human brain organoids to SARS-CoV-2 evoked cellular senescence, and that spatial transcriptomic sequencing of virus-induced senescent cells identified a unique SARS-CoV-2 variant-specific inflammatory signature that is different from endogenous naturally-emerging senescent cells. Importantly, following SARS-CoV-2 infection of human brain organoids, treatment with senolytics blocked viral retention and prevented the emergence of senescent corticothalamic and GABAergic neurons. Furthermore, we demonstrate in human ACE2 overexpressing mice that senolytic treatment ameliorates COVID-19 brain pathology following infection with SARS-CoV-2. In vivo treatment with senolytics improved SARS-CoV-2 clinical phenotype and survival, alleviated brain senescence and reactive astrogliosis, promoted survival of dopaminergic neurons, and reduced viral and senescence-associated secretory phenotype gene expression in the brain. Collectively, our findings demonstrate SARS-CoV-2 can trigger cellular senescence in the brain, and that senolytic therapy mitigates senescence-driven brain aging and multiple neuropathological sequelae caused by neurotropic viruses, including SARS-CoV-2.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-12-2022
Abstract: All flaviviruses, including Zika virus, produce noncoding subgenomic flaviviral RNA (sfRNA), which plays an important role in viral pathogenesis. However, the exact mechanism of how sfRNA enables viral evasion of antiviral response is not well defined. Here, we show that sfRNA is required for transplacental virus dissemination in pregnant mice and subsequent fetal brain infection. We also show that sfRNA promotes apoptosis of neural progenitor cells in human brain organoids, leading to their disintegration. In infected human placental cells, sfRNA inhibits multiple antiviral pathways and promotes apoptosis, with signal transducer and activator of transcription 1 (STAT1) identified as a key shared factor. We further show that the production of sfRNA leads to reduced phosphorylation and nuclear translocation of STAT1 via a mechanism that involves sfRNA binding to and stabilizing viral protein NS5. Our results suggest the cooperation between viral noncoding RNA and a viral protein as a novel strategy for counteracting antiviral responses.
Publisher: Springer Science and Business Media LLC
Date: 05-05-2020
DOI: 10.1038/S41467-020-16086-Y
Abstract: Flaviviruses, including Zika virus (ZIKV), utilise host mRNA degradation machinery to produce subgenomic flaviviral RNA (sfRNA). In mammalian hosts, this noncoding RNA facilitates replication and pathogenesis of flaviviruses by inhibiting IFN-signalling, whereas the function of sfRNA in mosquitoes remains largely elusive. Herein, we conduct a series of in vitro and in vivo experiments to define the role of ZIKV sfRNA in infected Aedes aegypti employing viruses deficient in production of sfRNA. We show that sfRNA-deficient viruses have reduced ability to disseminate and reach saliva, thus implicating the role for sfRNA in productive infection and transmission. We also demonstrate that production of sfRNA alters the expression of mosquito genes related to cell death pathways, and prevents apoptosis in mosquito tissues. Inhibition of apoptosis restored replication and transmission of sfRNA-deficient mutants. Hence, we propose anti-apoptotic activity of sfRNA as the mechanism defining its role in ZIKV transmission.
No related grants have been discovered for Morgan Freney.