Biology subjects

Chappell, K. J.

Publications and source records attributed to Chappell, K. J..

4 recordsLinked to original sources

bioRxiv2026

Koala retrovirus dynamics in the Snowy Monaro, NSW

Koala Retrovirus (KoRV) is in transition from exogenous virus to endogenous element and shows distinct profiles between northern and southern koala populations. Northern animals carry high proviral copy numbers of endogenous KoRV-A and a range of exogenous subtypes, while southern koalas instead generally only possess degraded and recombinant versions of the virus. In this study we investigated the KoRV profiles of koalas in the Snowy Monaro (SM) region of southern NSW, which is at the intersection between northern and southern populations. We found that SM koalas have lower KoRV loads and proviral copy numbers than koalas from other northern populations. Plasma RNA subtype profiles were very consistent between individuals with all animals having KoRV-A at low relative abundance and high proportions of subtypes D and L. This pattern of subtype profiles is unique compared to other populations studied and suggests that KoRV-D and/or L may be endogenous in southern NSW or that KoRV-A is effectively suppressed in koalas from the region. Despite these unique profiles, in agreement with findings from other regions, higher KoRV loads were associated with C. pecorum shedding. Further, KoRV loads were temporally stable with no consistent changes found over time in koalas in the wild or koalas rescued from burnt habitat after fire and brought in for rehabilitation. Further studies into the role KoRV plays in disease susceptibility in southern NSW and into the endogenization status of KoRV-D/L will provide important insights into this model of retroviral endogenization and guide koala conservation efforts in the region.

microbiology↗

bioRxiv2026

Reanalysis of data from ten years of koala chlamydia vaccine trials reveals inherent bias and a lack of protective efficacy

Koalas within Australia are facing multiple threats from habitat loss, climate change and pervasive chlamydial disease. A safe and effective vaccine to protect koalas against chlamydia would be a welcome veterinary intervention to prevent this devastating disease which causes blindness, renal and reproductive pathology, infertility and mortality. However, over a decade of vaccine development and research trials has produced conflicting results, which vary from no observable indication of protective efficacy to a 64% reduction in chlamydia associated mortality. Given this discrepancy we conducted an independent analysis of data underpinning the highly cited publication demonstrating vaccine efficacy that was the basis for a permit for limited use in koalas. In doing so, we identified a substantial error in the way the data was encoded for analysis, which resulted in survival from birth to time of vaccination incorrectly being attributed to vaccination. After correction for this error, we show using the exact methods of the original authors that there was no significant difference in the survival or disease rate between vaccinated and unvaccinated koalas. Furthermore, we identified a substantial source of bias whereby animals with disease at their first health assessment were not excluded from the study and as those animals were generally not vaccinated, they were almost six times more likely to be included in the control group. Reanalysis including only koalas that were healthy on initial assessment and for which follow-up health assessments were performed, showed that vaccinated individuals were equally likely to contract disease or to die with disease; 18 of 143 vaccinated koalas (12.6%) developed disease and 3 (2.1%) died, compared to 63 of 439 control animals (14.4%) that developed disease and 11 (2.5%) that died. This study highlights the importance of randomised, observer blinded, placebo-controlled studies in veterinary settings to uphold scientific rigor and prevent stratification bias.

immunology↗

bioRxiv2023

HTLV-1 reverse transcriptase homology model provides structural basis for sensitivity to existing nucleoside/nucleotide reverse transcriptase inhibitors

The human T-lymphotropic virus type 1 (HTLV-1) infects millions of people globally and is endemic to various resource-limited regions. Infections persist for life and are associated with increased susceptibility to opportunistic infections and severe diseases including adult T cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy-tropical spastic paraparesis (HAM-TSP). No HTLV-1-specific anti-retrovirals have been developed and it is unclear whether existing anti-retrovirals developed for treatment of human immunodeficiency virus (HIV) have efficacy against HTLV-1. To understand the structural basis for therapeutic binding, homology modelling and machine learning were used to develop a structural model of the HTLV-1 reverse transcriptase. With this, molecular docking experiments using a panel of FDA-approved inhibitors of viral reverse transcriptases to assess their capacity for binding, and in turn, inhibition. Importantly, nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) but not non-nucleoside reverse transcriptase inhibitors (NNRTIs) were capable of binding the HTLV-1 reverse transcriptase, with similar affinity to HIV-1 reverse transcriptase. By strengthening the rationale for clinical testing of therapies such as tenofovir alafenamide, zidovudine, lamivudine, and azvudine for treatment of HTLV-1, this study has demonstrated the power of in silico structural biology approaches in drug design and therapeutic testing.

pharmacology and toxicology↗

bioRxiv2022

SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike-ACE2 receptor interaction

Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases of probable Parkinsons disease. As microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, here we interrogated whether SARS-CoV-2 can promote microglial NLRP3 inflammasome activation utilising a model of human monocyte-derived microglia. We identified that SARS-CoV-2 isolates can bind and enter microglia, triggering inflammasome activation in the absence of viral replication. Mechanistically, microglial NLRP3 could be both primed and activated with SARS-CoV-2 spike glycoprotein in a NF-{kappa}B and ACE2-dependent manner. Notably, virus- and spike protein-mediated inflammasome activation in microglia was significantly enhanced in the presence of -synuclein fibrils, which was entirely ablated by NLRP3-inhibition. These results support a possible mechanism of microglia activation by SARS-CoV-2, which could explain the increased vulnerability to developing neurological symptoms akin to Parkinsons disease in certain COVID-19 infected individuals, and a potential therapeutic avenue for intervention. SIGNIFICANCE STATEMENTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) principally affects the lungs, however there is evidence that the virus can also reach the brain and lead to chronic neurological symptoms. In this study, we examined the interaction SARS-CoV-2 with brain immune cells, by using an ex-vivo model of human monocyte-derived microglia. We identified robust activation of the innate immune sensor complex, NLRP3 inflammasome, in cells exposed to SARS-CoV-2. This was dependent on spike protein-ACE2 receptor interaction and was potentiated in the presence of -synuclein. We therefore identify a possible mechanism for SARS-CoV-2 and increased vulnerability to developing neurological dysfunction. These findings support a potential therapeutic avenue for treatment of SARS-CoV-2 driven neurological manifestations, through use of NLRP3 inflammasome or ACE2 inhibitors.

neuroscience↗