Biology subjects

Abdullahi, A.

Publications and source records attributed to Abdullahi, A..

8 recordsLinked to original sources

bioRxiv2025

COVID-19 vaccination induces cross-neutralisation of sarbecoviruses related to SARS-CoV-2

Close relatives of SARS-CoV-1 and SARS-CoV-2 continue to circulate in wildlife, posing an ongoing threat of zoonotic spillover. While vaccination played a key role in controlling the COVID-19 pandemic, variants of concern (VOC) with immune evasive substitutions emerged on multiple occasions, causing widespread breakthrough infections. The combined threats of zoonosis and newly emerging VOCs, coupled with the potential for recombination, underscore the need to assess the breadth of existing vaccine-mediated protection. Here, we investigate a cohort of older individuals (median age 68.5 years) for the potential of cross-neutralisation against Omicron lineage VOC and animal sarbecoviruses induced by four COVID-19 vaccine doses. Despite the recent use of a bivalent mRNA vaccine dose (encoding spike from Wu-1 and omicron), we observed that neutralisation of Omicron lineage VOCs such as BA.1 and BA.2 were reduced compared to SARS-CoV-2 Wu-1, suggesting an imprinted immune response from pre-Omicron lineage viruses. Similarly, both SARS-CoV-1 and a SARS-CoV-1-related bat CoV were neutralised less efficiently than SARS-CoV-2 Wu-1. Unexpectedly, however, we observed that two animal SARS-CoV-2-related viruses, BANAL-20-52 (from bats) and a pangolin-CoV, were more sensitive to serum neutralising antibodies than SARS-CoV-2 Wu-1 itself. These surprising findings suggest that vaccine-mediated adaptive immunity may provide efficient cross-protection against certain animal sarbecoviruses.

microbiology↗

bioRxiv2024

Nasopharyngeal specific selection and emergence of SARS-CoV-2 spike fusion peptide mutation P812S during chronic infection

Omicron emergence represented a seismic event in the COVID-19 pandemic, demonstrating what was essentially antigenic shift in a virus that cannot reassort its genome as influenza can. Understanding the success of Omicron is essential, and yet we have little understanding of the biological underpinnings of its ability to accommodate diverse mutations and bring together deleterious mutations to generate a highly successful new serotype. Persistent SARS-CoV-2 infections are a likely source of new variants and may provide valuable insight into past and future evolutionary trajectories, in particular those involving allosteric interactions that defy genotype to phenotype prediction. Here we observe upper airway specific evolution of SARS-CoV-2 demonstrating fusion peptide (FP) domain mutation S:P812S adjacent to the S2 cleavage site that emerged during a chronic infection in an immunocompromised individual. Indeed, this mutation had previously emerged in an ancestral B lineage as well as the delta variant lineage and transmitted successfully in populations globally, though remains uncharacterised. P812S in spike pseudotyped virus particles did not impact entry efficiency across cell lines expressing endogenous ACE2 and TMPRSS2. However, efficiency of spike cleavage at S1/S2 was reduced and molecular dynamics simulation demonstrated altered S1/S2 loop conformations that possibly impacted furin mediated cleavage. Consistent with impaired S1/S2 cleavage, and reminiscent of Omicron BA.1, cell-cell fusogenicity was severely impaired by introduction of P812S. The mutation also introduced significant perturbations to the FP region and also affected protomer-protomer packing. P812S conferred evasion of a neutralising monoclonal antibody targeting the fusion peptide, consistent with significant structural rearrangements in the FP region. Finally, P812S bearing viruses showed evasion of polyclonal neutralising antibodies in sera from vaccinated individuals at 32{degrees}C (simulating upper respiratory tract) and to a lesser extent at 37{degrees}C. Thus we report a novel mutational adaptation to the upper airway allowing enhanced immune evasion to fusion peptide targeting neutralising antibodies that also incurs a defect in ability to induce syncytia. These data shed light on the balance between upper airway adaptation/immune evasion by SARS-CoV-2, ability to induce syncytia formation, and disease severity given the established link between syncytia and severe COVID-19.

immunology↗

bioRxiv2023

A detailed characterisation of drug resistance during darunavir/ritonavir (DRV/r) monotherapy highlights a high barrier to the emergence of resistance mutations in protease but identifies alternative pathways of resistance

BackgroundMaintenance monotherapy with DRV/r has yielded variable outcomes and is not recommended. Trial samples offer valuable opportunities for detailed studies. We analysed samples from a 48-week trial in Cameroon to obtain a detailed characterisation of drug resistance. MethodsFollowing failure of NNRTI-based therapy and virological suppression on PI-based therapy, participants were assigned to receive either DRV/r (n=81) or TDF/3TC + LPV/r (n=39). PBMC from study entry underwent bulk protease and RT sequencing. Plasma collected at virological rebound (confirmed or last available HIV-1 RNA >60 copies/ml) underwent ultradeep protease and RT sequencing and bulk gag-protease sequencing. A site-directed mutant with T375A (p2/p7) was phenotypically characterised using a single-cycle assay. ResultsHIV-1 DNA analysis revealed NRTI and NNRTI resistance-associated mutations (RAMs) in 52/90 (57.8%) and 53/90 (58.9%) samples, respectively. In rebound HIV-1 RNA (DRV/r n=21; LPV/r n=2), prevalence was 9/23 (39.1%) and 10/23 (43.5%), respectively, with most RAMs occurring at frequencies [≥]15%. No DRV RAMs were found. Paired HIV-1 DNA and RNA sequences showed partial consistency in resistance patterns. Among 8 participants experiencing virological rebound on DRV/r (n=12 samples), all showed gag mutations associated with PI-exposure, including T375N, T375A (p2/p7), K436R (p7/p1), and mutations in p17, p24, p2 and p6. T375A conferred 10-fold DRV resistance and increased replication capacity. ConclusionsThe study highlights the high resistance barrier of DRV/r while identifying alternative pathways of DRV resistance through gag substitutions. During virological suppression, resistance patterns in HIV-1 DNA reflect treatment history, but due to technical and biological considerations, cautious interpretation is warranted.

microbiology↗

bioRxiv2022

Limited emergence of resistance to integrase strand inhibitors in HIV-experienced patients failing dolutegravir-based antiretroviral: Cross-sectional analysis from a Northeast Nigerian cohort

BackgroundOwing to high levels of resistance to previous first-line non-nucleoside reverse transcriptase inhibitors (NNRTI)-based antiretroviral therapy (ART), consolidated recommendations since 2019, from the WHO and others, have indicated that dolutegravir (DTG) is the preferred drug of choice for HIV treatment, globally. There is a paucity of resistance outcome data from non-B HIV subtypes circulating across West Africa. AimWe aimed to characterise the mutational profiles of HIV-positive patients from a small North-East Nigeria cohort, failing a DTG-based ART regimen. MethodsPlasma samples were collected and stored from 61 HIV-1 infected participants. Following failure of DTG-based ART, all samples were sequenced by Illumina whole-genome, ultra-deep sequencing. Sequencing was successful in (n=33) participants with median age of 40 years and median time on ART of 9 years. HIV-1 subtyping was performed using SNAPPy. Haplotype reconstruction and transmission were inferred using standard phylogenetic methods. ResultMost patients had mutational profiles that were reflective of prior exposure to first- and second-line ART including exposure to thymidine analogues, efavirenz and nevirapine. One patient had evidence of major INSTI DRMs (T66A, G118R, E138K and R263K), reducing efficacy of DTG. The participant was aged 18, infected with a subtype G virus and likely vertically infected. ConclusionThis study found low level resistance to DTG in the cohort, with one patient having high-level resistance to DTG and other INSTIs. Critical population level and long-term data on DTG outcomes are required to guide implementation and policy action across the region.

molecular biology↗

bioRxiv2021

SARS-CoV-2 Omicron spike mediated immune escape, infectivity and cell-cell fusion

The SARS-CoV-2 Omicron BA.1 variant emerged in late 2021 and is characterised by multiple spike mutations across all spike domains. Here we show that Omicron BA.1 has higher affinity for ACE2 compared to Delta, and confers very significant evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralising antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralisation. Importantly, antiviral drugs remdesevir and molnupiravir retain efficacy against Omicron BA.1. We found that in human nasal epithelial 3D cultures replication was similar for both Omicron and Delta. However, in lower airway organoids, Calu-3 lung cells and gut adenocarcinoma cell lines live Omicron virus demonstrated significantly lower replication in comparison to Delta. We noted that despite presence of mutations predicted to favour spike S1/S2 cleavage, the spike protein is less efficiently cleaved in live Omicron virions compared to Delta virions. We mapped the replication differences between the variants to entry efficiency using spike pseudotyped virus (PV) entry assays. The defect for Omicron PV in specific cell types correlated with higher cellular RNA expression of TMPRSS2, and accordingly knock down of TMPRSS2 impacted Delta entry to a greater extent as compared to Omicron. Furthermore, drug inhibitors targeting specific entry pathways demonstrated that the Omicron spike inefficiently utilises the cellular protease TMPRSS2 that mediates cell entry via plasma membrane fusion. Instead, we demonstrate that Omicron spike has greater dependency on cell entry via the endocytic pathway requiring the activity of endosomal cathepsins to cleave spike. Consistent with suboptimal S1/S2 cleavage and inability to utilise TMPRSS2, syncytium formation by the Omicron spike was dramatically impaired compared to the Delta spike. Overall, Omicron appears to have gained significant evasion from neutralising antibodies whilst maintaining sensitivity to antiviral drugs targeting the polymerase. Omicron has shifted cellular tropism away from TMPRSS2 expressing cells that are enriched in cells found in the lower respiratory and GI tracts, with implications for altered pathogenesis.

microbiology↗

bioRxiv2019

Visualisation of ribosomes in Drosophila axons using Ribo-BiFC

Rates of protein synthesis and the number of translating ribosomes vary greatly between different cells in various cell states. The distribution of assembled, and potentially translating, ribosomes within cells can be visualised in Drosophila by using Bimolecular Fluorescence Complementation (BiFC) to monitor the interaction between tagged pairs of 40S and 60S ribosomal proteins (RPs) that are close neighbours across inter-subunit junctions in the assembled 80S ribosome. Here we describe transgenes that express two novel RP pairs tagged with Venus-based BiFC fragments that considerably increase the sensitivity of this technique that we termed Ribo-BiFC. This improved method should provide a convenient way of monitoring the local distribution of ribosomes in most Drosophila cells and we suggest that could be implemented in other organisms. We visualized 80S ribosomes in larval photoreceptors and in other neurons. Assembled ribosomes are most abundant in the various neuronal cell bodies, but they are also present along the lengths of axons and are concentrated in growth cones of larval and pupal photoreceptors. Surprisingly, there is relatively less puromycin incorporation in the distal portion of axons in the optic stalk, suggesting that some of the ribosomes that have started translation may not be engaged in elongation in axons that are still growing.

cell biology↗

bioRxiv2019

Aggregated and hyperstable damage-associated molecular patterns are released during ER stress to modulate immune function

Chronic ER stress occurs when protein misfolding in the ER lumen remains unresolved despite activation of the unfolded protein response. We have shown that traumatic injury such as a severe burn leads to chronic ER stress in vivo leading to systemic inflammation which can last for more than a year. The mechanisms linking chronic ER stress to systemic inflammatory responses is not clear. Here we show that induction of chronic ER stress leads to the release of known and novel damage-associated molecular patterns (DAMPs). The secreted DAMPs are aggregated and markedly protease resistant. ER stress-derived DAMPs activate dendritic cells which are then capable of polarizing naive T cells. Our findings indicate that induction of chronic ER stress may lead to the release of hyperstable DAMPs into the circulation resulting in persistent systemic inflammation and adverse outcomes.

cell biology↗

bioRxiv2018

Dorsal Hippocampus not always necessary in a Radial Arm Maze Delayed Win-shift Task

Spatial working memory is important for foraging and navigating the environment. However, its neural underpinnings remain poorly understood. The hippocampus, known for its spatial coding and involvement in spatial memory, is widely understood to be necessary for spatial working memory when retention intervals increase beyond seconds into minutes. Here, we describe new evidence that the dorsal hippocampus is not always necessary for spatial working memory for retention intervals of 8 minutes. Rats were trained to perform a delayed spatial win shift radial arm maze task (DSWS) with an 8-minute delay between study and test phases. We then tested whether bilateral inactivation of the dorsal hippocampus between the study and test phases impaired behavioral performance at test. Inactivation was achieved through a bilateral infusion of lidocaine. Performance following lidocaine was compared to control trials, in which, sterile phosphate buffered saline (PBS) was infused. Test performance did not differ between the lidocaine and PBS conditions, remaining high in each. To explore the possibility that this insensitivity to inactivation was a result of overtraining, a second cohort of animals received substantially less training prior to the infusions. In this second cohort, lidocaine infusions did significantly impair task performance. These data indicate that successful performance of a spatial win-shift task on the 8-arm maze need not always be hippocampally dependent.

neuroscience↗