Biology subjects

Haslam, S.

Publications and source records attributed to Haslam, S..

4 recordsLinked to original sources

bioRxiv2026

Early AAV9-mediated SLC9A6 gene replacement preserves cerebellar structure and motor function in the shaker rat model of Christianson syndrome

Christianson syndrome (CS) is an X-linked neurodevelopmental and neurodegenerative disorder caused by SLC9A6 loss of function, resulting in NHE6 deficiency and epilepsy, intellectual disability, cerebellar atrophy, and ataxia. Following on our prior gene replacement therapeutic development, we preclinically evaluated AAV9-mediated SLC9A6 gene replacement in the context of promoter selection, dosing, and treatment timing. Intracerebroventricular delivery of neuronal-targeted gene replacement at 1 x 10^11 vector genomes (vg) produced substantial improvements in motor coordination and preserved cerebellar volume, quantified through structural MRI. Early postnatal treatment prevented the development of gait ataxia throughout the longitudinal assessment period, statistically indistinguishable from wildtype controls, with molecular analyses demonstrating restored NHE6 expression and preservation of cerebellar markers. Interestingly, later treatments at timepoints corresponding to early neurodegenerative stages yielded strong initial effects, but these effects were largely lost over time, with half-life modelling demonstrating the need for early treatment. This conflicted with more persistent motor benefit shown in prior work with an engineered capsid, suggesting the need to consider the interaction between treatment timing and capsid-specific tropism and/or persistence. Finally, we built models capable of accurately predicting motor coordination from several protein markers. These findings will impact therapeutic development for CS, with relevance across neurodevelopmental genetic disorders.

neuroscience↗

bioRxiv2026

The canine respiratory epithelium is a permissive ecosystem for influenza interspecies transmission and emergence

The outcome of virus spillover ranges from dead-end infections to pandemics and is underpinned by host-pathogen interactions as well as evolutionary and epidemiological processes. The emergence of novel influenza A viruses (IAVs) has been associated with reassortment events involving multiple species, highlighting the importance of reservoir and intermediate hosts in viral emergence. Highly pathogenic H5N1 IAVs of the 2.3.4.4b genotype have caused a panzootic affecting a broad range of mammals. The role of dogs--arguably the most popular companion animal and a natural host of IAVs--in the ecology of IAVs under this new zooepidemiological scenario is unknown. To address this, we characterised the glycome of the dog respiratory epithelium, infected canine tracheal explants with multiple IAVs (including canine H3N2 and H3N8, equine H3N8, avian H3N8 and H5N1, swine H1N1, human H1N1 and H3N2, and bovine H5N1 viruses), and determined their cellular tropism. We show that the respiratory tract of dogs presents abundant sialylated glycans known to act as IAV receptors. Further, most IAVs (including 2.3.4.4b viruses) infected and replicated in dog tracheas, targeting mainly ciliated cells. Serological testing showed evidence of influenza spillover infections in dogs from the UK. Overall, our results show that the canine respiratory tract can provide a suitable environment for the generation of new IAVs. Given the multi-host contact networks of dogs in nature, they could act as recipients, bridging hosts, and/or mixing vessels for multiple IAV lineages, playing a central role in the ecology of influenza emergence.

microbiology↗

bioRxiv2020

High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria

In both sickle cell disease (SCD) and malaria, red blood cells (RBCs) are phagocytosed in the spleen, but receptor-ligand pairs mediating uptake have not been identified. Here, we report that patches of high mannose N-glycans (Man5-9GlcNAc2), expressed on diseased or oxidized RBC surfaces, bind the mannose receptor (CD206) on phagocytes to mediate clearance. Extravascular haemolysis in SCD correlates with high mannose glycan levels on RBCs. Infection of RBCs with Plasmodium falciparum expose surface mannose N-glycans on healthy RBCs, which occurred at significantly higher levels on RBCs from subjects with sickle cell trait compared to those lacking haemoglobin S. The glycans were associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans, a novel response to cellular stress, is the first molecular mechanism common to both the pathogenesis of SCD and resistance to severe malaria in sickle cell trait.

immunology↗

bioRxiv2019

Choice of host cell line is essential for the functional glycosylation of the fragment crystallizable (Fc) region of human IgG1 inhibitors of influenza B viruses

Antibodies are glycoproteins that carry a conserved N-linked carbohydrate attached to the Fc, whose presence and fine structure profoundly impacts on their in vivo immunogenicity, pharmacokinetics and functional attributes. The host cell line used to produce IgG has a major impact on this glycosylation, as different systems express different glycosylation enzymes and transporters that contribute to the specificity and heterogeneity of the final IgG-Fc glycosylation profile. Here we compare two panels of glycan-adapted IgG1-Fc mutants expressed in either the HEK 293-F or CHO-K1 systems. We show that the types of N-linked glycans between matched pairs of Fc mutants vary significantly, and in particular with respect to sialylation. These cell line effects on glycosylation profoundly influence the ability of the engineered Fcs to interact with either human or pathogen receptors. For example, we describe Fc mutants that potently disrupted influenza B-mediated agglutination of human erythrocytes when expressed in CHO-K1 but not in HEK 293-F cells.

immunology↗