Biology subjects

Hatton, C.

Publications and source records attributed to Hatton, C..

8 recordsLinked to original sources

bioRxiv2026

Pathogenesis and immune responses to Eurasian avian like H1N1 and influenza D virus in pigs.

Eurasian avian like H1N1 (EAavH1N1) and influenza D viruses (IDV) with their ongoing evolution and zoonotic potential are a serious threat to animal and human health. Using experimental infection of pigs, we characterized and compared their pathogenesis, and immune responses. EAavH1N1 induced rapid viral clearance, early immune activation, including robust systemic and mucosal antibody responses and increased IFN{gamma} and TNF production. This heightened immune response was associated with more severe pathology of the upper and lower respiratory tract. In contrast, IDV infection resulted in prolonged viral shedding and higher viral titres, with delayed and attenuated cellular immune responses. Single cell transcriptomic analysis of lung further indicated early and persistent suppression of antiviral and innate immune pathways during IDV infection. These findings demonstrate that EAavH1N1 and IDV exhibit distinct viral kinetics, immune activation profiles, and lung responses, providing insight into differences in transmission dynamics, disease severity, and immune control among influenza virus types in swine.

immunology↗

bioRxiv2025

Post-infection pig and ferret antisera show similar antigenic profiles for human influenza A(H1N1pdm09) viruses

BackgroundMonitoring antigenic drift in human influenza A viruses is essential for vaccine strain selection and ensuring protection against circulating strains. Antigenic drift is traditionally assessed using ferret antisera, which provide monospecific responses, and human vaccinee sera, which reflect exposure to multiple antigens. In this study we evaluated the pig as an alternative source of antisera to study antigenic drift compared to immune responses in ferrets and humans. We included seasonal influenza A(H1N1pdm09) human viruses that had shown different antigenic characteristics when using ferret or human antisera. MethodsPairs of pigs were inoculated with six human A(H1N1)pdm09 viruses circulating between 2019 and 2023, a period of marked antigenic drift. Pig and ferret antisera were analysed by hemagglutination inhibition (HI) and virus neutralization (VN) assays. ResultsPigs were successfully infected with all strains, shedding virus and producing antibody responses, confirming their susceptibility to human influenza A viruses. Antigenic reactivity of pig antisera was qualitatively comparable to ferret antisera in both HI and VN assays, although maximum homologous antibody titres were significantly higher in ferrets. The antisera raised against viruses in circulation in 2019 and before, exempified by A/Guangdong-Maonan/SWL1536/2019, clade 5a.1, were clearly differentiated by both ferret and pig antisera from those in clade 5a.2 and its derivatives that became predominant. ConclusionsFerrets and pigs showed comparable responses and both distinguished clade 5a.1 from clade 5a.2. However, neither model recognised antigenically drifted variants from 2019-2022, including subclades 5a.2-C, 5a.2a-C.1/C.1.9, and .5a.2a.1-C.1.1/D, which were distinguishable using human post-vaccination antisera.

immunology↗

bioRxiv2024

MOZ and HBO1 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia

NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML) and drive leukemogenesis through liquid-liquid phase separation-mediated nuclear condensate formation. However, the composition and consequences of NUP98 FO-associated condensates are incompletely understood. Here we show that MYST family histone acetyltransferase (HAT) complex proteins including MOZ/KAT6A, HBO1/KAT7, and the common MOZ/HBO1 complex subunit BRPF1 associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of Moz and Hbo1 impairs NUP98-r cell fitness. MOZ/HBO1 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, MOZ/HBO1 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r AML. SIGNIFICANCE STATEMENTMOZ and HBO1 associate with NUP98 fusion oncoprotein condensates to drive leukemogenesis. Inhibition of their histone acetyltransferase activity is an effective therapeutic strategy in NUP98-rearranged leukemias, including those resistant to Menin inhibition. Moreover, combined MOZ/HBO1 and Menin inhibition is synergistic, supporting clinical translation to improve outcomes of NUP98 FO-driven leukemias.

cancer biology↗

bioRxiv2024

High-throughput diversification of protein-ligand surfaces to discover chemical inducers of proximity

Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry1,2. While rational design strategies can expedite the discovery of heterobifunctional CIPs, monovalent, molecular glue-like CIPs have relied predominantly on serendipity3. Envisioning a prospective approach to discover molecular glues for a pre-selected target, we hypothesized that pre-existing ligands could be systematically decorated with chemical modifications to empirically discover protein-ligand surfaces that are tuned to cooperatively engage another protein interface. Here, we used sulfur(VI)-fluoride exchange (SuFEx)-based high-throughput chemistry (HTC) to install 3,163 structurally diverse chemical building blocks onto ENL and BRD4 ligands and then screened the crude products for degrader activity. This revealed dHTC1, a potent, selective, and stereochemistry-dependent degrader of ENL. It recruits CRL4CRBN to ENL through an extended interface of protein-protein and protein-ligand contacts, but only after pre-forming the ENL:dHTC1 complex. We also characterized two structurally distinct BRD4 degraders, including dHTC3, a molecular glue that selectively dimerizes the first bromodomain of BRD4 to SCFFBXO3, an E3 ligase not previously accessible for chemical rewiring. Altogether, this study introduces HTC as a facile tool to discover new CIPs and actionable cellular effectors of proximity pharmacology.

biochemistry↗

bioRxiv2024

Crystal structure of a bacterial photoactivated adenylate cyclase determined at room temperature by serial femtosecond crystallography

OaPAC is a recently discovered blue-light using flavin adenosine dinucleotide (BLUF) photoactivated adenylate cyclase from the cyanobacterium Oscillatoria acuminata that uses adenosine triphosphate and translates the light signal into the production of cyclic adenosine monophosphate. Here, we report the crystal structures of the enzyme in the absence of its natural substrate determined from room temperature serial crystallography data collected at both an X-ray free electron laser and a synchrotron and we compare them with the cryo macromolecular crystallography structures obtained at a synchrotron by us and others. These results reveal slight differences in the structure of the enzyme due to data collection at different temperatures and X-ray sources. We further investigate the effect of the Y6 mutation in the blue-light using flavin adenosine dinucleotide domain, a mutation which results in a rearrangement of the hydrogen-bond network around the flavin and a notable rotation of the side-chain of the critical Q48 residue. These studies pave the way for ps - ms time-resolved serial crystallography experiments at X-ray free electron lasers and synchrotrons in order to determine the early structural intermediates and correlate them with the well-studied ps - ms spectroscopic intermediates. SynopsisStructures of the dark-adapted state of a photoactivated adenylate cyclase are determined from serial crystallography (SX) data collected at room temperature at an X-ray free electron laser (XFEL) and a synchrotron and are compared with cryo macromolecular crystallography (MX) synchrotron structures obtained by us and others. These structures of the wild-type enzyme in combination with the cryo MX synchrotron structure of a light-sensor domain mutant provide insight into the hydrogen bond network rearrangement upon blue-light illumination and pave the way for the determination of structural intermediates of the enzyme by time-resolved SX.

biophysics↗

bioRxiv2021

Mouse models of NADK2 deficiency analyzed for metabolic and gene expression changes to elucidate pathophysiology

NADK2 encodes the mitochondrial isoform of NAD Kinase, which phosphorylates nicotinamide adenine dinucleotide (NAD). Rare recessive mutations in human NADK2 are associated with a syndromic neurological mitochondrial disease that includes metabolic changes such as hyperlysinemia and 2,4 dienoyl CoA reductase (DECR) deficiency. However, the full pathophysiology resulting from NADK2 deficiency is not known. Here we describe two chemically-induced mouse mutations in Nadk2, S326L and S330P, which cause a severe neuromuscular disease and shorten lifespan. The S330P allele was characterized in detail and shown to have marked denervation of neuromuscular junctions by 5 weeks of age and muscle atrophy by 11 weeks of age. Cerebellar Purkinje cells also showed progressive degeneration in this model. Transcriptome profiling on brain and muscle was performed at early and late disease stages. In addition, metabolomic profiling was performed on brain, muscle, liver, and spinal cord at the same ages. Combined transcriptomic and metabolomic analyses identified hyperlysinemia, DECR deficiency, and generalized metabolic dysfunction in Nadk2 mutant mice, indicating relevance to the human disease. We compared findings from the Nadk model to equivalent RNAseq and metabolomic datasets from a mouse model of infantile neuroaxonal dystrophy, caused by recessive mutations in Pla2g6. This enabled us to identify disrupted biological processes that are common between these mouse models of neurological disease, such as translation, and those processes that are gene-specific such as glycolysis and acetylcholine binding. These findings improve our understanding of the pathophysiology of both Nadk2 and Pla2g6 mutations, as well as pathways common to neuromuscular/neurodegenerative diseases.

genetics↗

bioRxiv2021

Prion-like α-synuclein pathology in the brains of infants: Krabbe disease as a novel seed-competent α-synucleinopathy

Krabbe disease (KD) is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene which causes accumulation of the toxic sphingolipid psychosine. GALC variants are associated with increased risk of Lewy body diseases (LBD), an umbrella term for age-associated neurodegenerative diseases in which the protein -synuclein aggregates into Lewy bodies. To explore whether -synuclein in KD has pathological similarities to that in LBD, we compared post-mortem KD tissue to that of infant control cases and identified alterations to -synuclein localisation and expression of modifications associated with LBD. To determine whether -synuclein in KD displayed pathogenic properties associated with LBD we evaluated its seeding capacity using the real-time quaking-induced conversion assay. Strikingly, seeded aggregation of -synuclein resulted in the formation of fibrillar aggregates similar to those observed in LBD, confirming the prion-like capacity of KD-derived -synuclein. These observations constitute the first report of prion-like -synuclein in the brain tissue of infants and challenge the putative view that -synuclein pathology is merely an age-associated phenomenon, instead suggesting it can result from alterations to biological processes such as sphingolipid homeostasis. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in LBD.

pathology↗

bioRxiv2018

Evidence for phospholipid export from the gram-negative inner membrane: time to rethink the Mla pathway?

The Mla pathway is believed to be involved in maintaining the asymmetrical Gram-negative outer membrane via retrograde phospholipid transport. The pathway is composed of 3 components: the outer membrane MlaA-OmpC/F complex, a soluble periplasmic protein, MlaC, and the inner membrane ATPase, MlaFEDB complex. Here we solve the crystal structure of MlaC in its phospholipid free closed apo conformation, revealing a novel pivoting {beta}-sheet mechanism which functions to open and close the phospholipid-binding pocket. Using the apo form of MlaC we provide evidence that the Mla pathway functions in an anterograde rather than a retrograde direction by showing the inner membrane MlaFEDB machinery exports phospholipids and transfers them to MlaC in the periplasm. We confirm that the lipid export process occurs through the MlaD component of the MlaFEDB complex. This lipid export process is shown to be independent of ATP. Our data provides, for the first time, evidence of an apparatus for lipid export to the outer membrane.

biophysics↗