School of BioSciences - Research Publications

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    Altered visual function in a larval zebrafish knockout of neurodevelopmental risk gene
    Xie, J ; Jusuf, PR ; Bui, BV ; Dudczig, S ; Goodbourn, PT ( 2020-09-22)
    The human PDZK1 gene is located in a genomic susceptibility region for neurodevelopmental disorders. A genome-wide association study (GWAS) identified links between PDZK1 polymorphisms and altered visual contrast sensitivity, an endophenotype for schizophrenia and autism spectrum disorder. The PDZK1 protein is implicated in neurological functioning, interacting with synaptic molecules including post-synaptic density 95 (PSD-95), N-methyl-D-aspartate receptors (NMDAR), corticotropin-releasing factor receptor 1 (CRFR1) and serotonin 2A receptors. To elucidate the role of PDZK1, we generated pdzk1-knockout (pdzk1-KO) zebrafish using CRISPR/Cas-9 genome editing. Visual function of 7-day-old fish was assessed at behavioural and functional levels using the optomotor response (OMR) and scotopic electroretinogram (ERG). We also quantified retinal morphology and densities of PSD-95, NMDAR1, CRFR1 and serotonin in the synaptic inner plexiform layer at 7 days, 4 weeks and 8 weeks of age. Relative to wild-type, pdzk1-KO larvae showed spatial-frequency tuning functions with increased amplitude (likely due to abnormal gain control) and reduced ERG b-waves (suggestive of inner retinal dysfunction). However, these functional differences were not associated with gross synaptic or morphological retinal phenotypes. The findings corroborate a role for pdzk1 in visual function, and our model system provides a platform for investigating other genes associated with abnormal visual behaviour.
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    The novel Dbl homology/BAR domain protein, MsgA, of Talaromyces marneffei regulates yeast morphogenesis during growth inside host cells
    Weerasinghe, H ; Bugeja, HE ; Andrianopoulos, A ( 2018-11-29)
    Abstract Microbial pathogens have evolved many strategies to evade recognition by the host immune system, including the use of phagocytic cells as a niche within which to proliferate. Dimorphic pathogenic fungi employ an induced morphogenetic transition, switching from multicellular hyphae to unicellular yeast that are more compatible with intracellular growth. A switch to mammalian host body temperature (37°C) is a key trigger for the dimorphic switch. This study describes a novel gene, msgA, from the dimorphic fungal pathogen Talaromyces marneffei that controls cell morphology in response to host cues rather than temperature. The msgA gene is upregulated during murine macrophage infection, and deletion results in aberrant yeast morphology solely during growth inside macrophages. MsgA contains a Dbl homology domain, and a Bin, Amphiphysin, Rvs (BAR) domain instead of a Plekstrin homology domain typically associated with guanine nucleotide exchange factors (GEFs). The BAR domain is crucial in maintaining yeast morphology and cellular localisation during infection. The data suggests that MsgA does not act as a canonical GEF during macrophage infection and identifies a temperature independent pathway in T. marneffei that controls intracellular yeast morphogenesis.
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    Development of a transboundary model of livestock disease in Europe
    Bradhurst, R ; Garner, G ; Hóvári, M ; de la Puente, M ; Mintiens, K ; Yadav, S ; Federici, T ; Kopacka, I ; Stockreiter, S ; Kuzmanova, I ; Paunov, S ; Cacinovic, V ; Rubin, M ; Szilágyi, J ; Kókány, ZS ; Santi, A ; Sordilli, M ; Sighinas, L ; Spiridon, M ; Potocnik, M ; Sumption, K (Cold Spring Harbor Laboratory, 2021)
    Epidemiological models of notifiable livestock disease are typically framed at a national level and targeted for specific diseases. There are inherent difficulties in extending models beyond national borders as details of the livestock population, production systems and marketing systems of neighbouring countries are not always readily available. It can also be a challenge to capture heterogeneities in production systems, control policies, and response resourcing across multiple countries, in a single transboundary model. In this paper we describe EuFMDiS, a continental-scale modelling framework for transboundary animal disease, specifically designed to support emergency animal disease planning in Europe. EuFMDiS simulates the spread of livestock disease within and between countries and allows control policies to be enacted and resourced on per-country basis. It provides a sophisticated decision support tool that can be used to look at the risk of disease introduction, establishment and spread; control approaches in terms of effectiveness and costs; resource management; and post-outbreak management issues.
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    Post-outbreak surveillance strategies to support proof of freedom from foot-and-mouth disease
    Bradhurst, R ; Garner, G ; East, I ; Death, C ; Dodd, A ; Kompas, T ( 2021-04-28)
    Abstract Whilst emergency vaccination may help contain foot-and-mouth disease in a previously FMD-free country, its use complicates post-outbreak surveillance and the recovery of FMD-free status. A structured surveillance program is required that can distinguish between vaccinated and residually infected animals, and provide statistical confidence that the virus is no longer circulating in previously infected areas. Epidemiological models have been well-used to investigate the potential benefits of emergency vaccination during a control progam and when/where/whom to vaccinate in the face of finite supplies of vaccine and personnel. Less well studied are post-outbreak issues such as the management of vaccinated animals and the implications of having used vaccination during surveillance regimes to support proof-of-freedom. This paper presents enhancements to the Australian Animal Disease Model (AADIS) that allow comparisons of different post-outbreak surveillance sampling regimes for establishing proof-of-freedom from FMD. A case study is provided that compares a baseline surveillance sampling regime (derived from current OIE guidelines), with an alternative less intensive sampling regime. It was found that when vaccination was not part of the control program, a reduced sampling intensity significantly reduced the number of samples collected and the cost of the post-outbreak surveillance program, without increasing the risk of missing residual infected herds.
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    Characterization of Epidermal Bladder Cells in Chenopodium quinoa
    Otterbach, S ; Khoury, H ; Rupasinghe, T ; Mendis, H ; Kwan, K ; Lui, V ; Natera, S ; Klaiber, I ; Allen, N ; Jarvis, D ; Tester, M ; Roessner, U ; Schmöckel, S ( 2021-05-10)
    Chenopodium quinoa (quinoa) is considered a superfood, as it has favourable nutrient composition and is gluten free. Quinoa has high tolerance to several abiotic stresses, i.e. salinity, water deficit (drought) and cold. The tolerance mechanisms are yet to be elucidated. Quinoa has Epidermal Bladder Cells (EBCs) that densely cover the shoot surface, particularly the younger parts of the plant. Here, we report on the EBC’s primary and secondary metabolomes, as well as the lipidome in response to abiotic stresses. EBCs were isolated from plants after cold, heat, high-light, water deficit and salt treatments. We used untargeted Gas Chromatography-Mass Spectrometry (GC-MS) to analyse metabolites and untargeted and targeted Liquid Chromatography-MS (LC-MS) for lipids and secondary metabolite analyses. We identified 64 primary metabolites, including sugars, organic acids and amino acids, 19 secondary metabolites, including phenolic compounds, betanin and saponins and 240 lipids categorized in five groups including glycerolipids and phospholipids. Although we found only few changes in the metabolic composition of bladders in response to abiotic stresses, metabolites related with heat, cold and high-light treatments, but not salt stress, were changed significantly. Na concentrations were low in EBCs with all treatments, and approximately two orders of magnitude lower than K concentrations.
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    Reconstructing the early global dynamics of under-ascertained COVID-19 cases and infections
    Russell, T ; Russell, T ; Golding, N ; Hellewell, J ; Abbott, S ; Wright, L ; Pearson, C ; Pearson, C ; Zandvoort, KV ; Jarvis, C ; Gibbs, H ; Liu, Y ; Eggo, R ; Edmunds, J ; Kucharski, A ( 2020-07-08)

    Background

    Asymptomatic or subclinical SARS-CoV-2 infections are often unreported, which means that confirmed case counts may not accurately reflect underlying epidemic dynamics. Understanding the level of ascertainment (the ratio of confirmed symptomatic cases to the true number of symptomatic individuals) and undetected epidemic progression is crucial to informing COVID-19 response planning, including the introduction and relaxation of control measures. Estimating case ascertainment over time allows for accurate estimates of specific outcomes such as seroprevalence, which is essential for planning control measures.

    Methods

    Using reported data on COVID-19 cases and fatalities globally, we estimated the proportion of symptomatic cases (i.e. any person with any of fever >= 37.5°C, cough, shortness of breath, sudden onset of anosmia, ageusia or dysgeusia illness) that were reported in 210 countries and territories, given those countries had experienced more than ten deaths. We used published estimates of the baseline case fatality ratio (CFR), which was adjusted for delays and under-ascertainment, then calculated the ratio of this baseline CFR to an estimated local delay-adjusted CFR to estimate the level of under-ascertainment in a particular location. We then fit a Bayesian Gaussian process model to estimate the temporal pattern of under-ascertainment.

    Results

    Based on reported cases and deaths, we estimated that, during March 2020, the median percentage of symptomatic cases detected across the 84 countries which experienced more than ten deaths ranged from 2.4% (Bangladesh) to 100% (Chile). Across the ten countries with the highest number of total confirmed cases as of 6th July 2020, we estimated that the peak number of symptomatic cases ranged from 1.4 times (Chile) to 18 times (France) larger than reported. Comparing our model with national and regional seroprevalence data where available, we find that our estimates are consistent with observed values. Finally, we estimated seroprevalence for each country. As of the 7th June, our seroprevalence estimates range from 0% (many countries) to 13% (95% CrI: 5.6% – 24%) (Belgium).

    Conclusions

    We found substantial under-ascertainment of symptomatic cases, particularly at the peak of the first wave of the SARS-CoV-2 pandemic, in many countries. Reported case counts will therefore likely underestimate the rate of outbreak growth initially and underestimate the decline in the later stages of an epidemic. Although there was considerable under-reporting in many locations, our estimates were consistent with emerging serological data, suggesting that the proportion of each country’s population infected with SARS-CoV-2 worldwide is generally low.

    Funding

    Wellcome Trust, Bill & Melinda Gates Foundation, DFID, NIHR, GCRF, ARC.
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    Estimating the true (population) infection rate for COVID-19: A Backcasting Approach with Monte Carlo Methods
    Phipps, S ; Grafton, Q ; Kompas, T ( 2020-05-18)

    ABSTRACT

    Differences in COVID-19 testing and tracing across countries, as well as changes in testing within each country overtime, make it difficult to estimate the true (population) infection rate based on the confirmed number of cases obtained through RNA viral testing. We applied a backcasting approach, coupled with Monte Carlo methods, to estimate a distribution for the true (population) cumulative number of infections (infected and recovered) for 15 countries where reliable data are available. We find a positive relationship between the testing rate per 1,000 people and the implied true detection rate of COVID-19, and a negative relationship between the proportion who test positive and the implied true detection rate. Our estimates suggest that the true number of people infected across our sample of 15 developed countries is 18.2 (5-95% CI: 11.9-39.0) times greater than the reported number of cases. In individual countries, the true number of cases exceeds the reported figure by factors that range from 1.7 (5-95% CI: 1.1-3.6) for Australia to 35.6 (5-95% CI: 23.2-76.3) for Belgium.
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    Health and Economic Costs of Early, Delayed and No Suppression of COVID-19: The Case of Australia
    Kompas, T ; Grafton, Q ; Che, TN ; Chu, L ; Camac, J (Cold Spring Harbor Laboratory, 2020-06-23)
    We compare the health and economic costs of early (actual), delayed and no suppression of COVID-19 infections in 2020 in Australia. Using a fit-for-purpose compartment model that we fitted from recorded data, a value of a statistical life year (VSLY) and an age-adjusted value of statistical life (A-VSL), we find: (1) the economic costs of no suppression are multiples more than for early suppression; (2) VSLY welfare losses of fatalities equivalent to GDP losses mean that for early suppression to not to be the preferred strategy requires that Australians prefer more than 12,500–30,000 deaths to the economy costs of early suppression, depending on the fatality rate; and (3) early rather than delayed suppression imposes much lower economy and health costs. We conclude that in high-income countries, like Australia, a ‘go early, go hard’ strategy to suppress COVID-19 results in the lowest estimated public health and economy costs.
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    Development of a free radical scavenging probiotic to mitigate coral bleaching
    Dungan, A ; Bulach, D ; Lin, H ; van Oppen, M ; Blackall, L (Cold Spring Harbor Laboratory, 2020-07-03)

    ABSTRACT

    Corals are colonized by symbiotic microorganisms that exert a profound influence on the animal’s health. One noted symbiont is a single-celled alga (from the family Symbiodiniaceae ), which provides the coral with most of its fixed carbon. During thermal stress, hyperactivity of photosynthesis results in a toxic accumulation of reactive oxygen species (ROS). If not scavenged by the antioxidant network, ROS may trigger a signaling cascade ending with the coral host and algal symbiont disassociating; this process is known as bleaching. Our goal was to construct a probiotic comprised of host-associated bacteria able to neutralize free radicals such as ROS. Using the coral model, the anemone Exaiptasia diaphana , and pure bacterial cultures isolated from the model animal, we identified six strains with high free radical scavenging ability belonging to the families Alteromonadaceae, Rhodobacteraceae, Flavobacteriaceae , and Micrococcaceae . In parallel, we established a “negative” probiotic consisting of genetically related strains with poor free radical scavenging capacities. From their whole genome sequences, we explored genes of interest that may contribute to their potential beneficial roles, which may help facilitate the therapeutic application of a bacterial probiotic. In particular, the occurrence of key pathways that are known to influence ROS in each of the strains has been inferred from the genomes sequences and are reported here.

    IMPORTANCE

    Coral bleaching is tightly linked to the production of reactive oxygen species (ROS), which accumulates to a toxic level in algae-harboring host cells leading to coral-algal dissociation. Interventions targeting ROS accumulation, such as the application of exogenous antioxidants, have shown promise for maintaining the coral-algal partnership. With the feasibility of administering antioxidants directly to corals being low, we aim to develop a probiotic to neutralize toxic ROS during a thermal stress event. This probiotic can be tested with corals or a coral model to assess its efficacy in improving coral resistance to environmental stress.