Biology subjects

Moore, P.

Publications and source records attributed to Moore, P..

16 recordsLinked to original sources

bioRxiv2026

Cell Cycle Regulation of Merkel Cell Polyomavirus Replication and Genome Inheritance in Single Cells

Merkel cell polyomavirus (MCV) establishes a near-ubiquitous, asymptomatic infection in humans but on rare occasions drives Merkel cell carcinoma, an aggressive skin cancer. How MCV replication is coordinated with host cell-cycle progression, and how this coordination shapes infected-cell fate, has remained unresolved. Here we combine reporter virus live-cell imaging, pharmacologic cell-cycle perturbation, flow cytometry, and single-cell transcriptomics to examine MCV replication dynamics. VP1 late gene expression occurs almost exclusively during late S or G2, is associated with prolonged G2 arrest, and frequently culminates in cell death. Strikingly, cells that divide before virus replication give rise to daughter cells that synchronously initiate viral replication and VP1 expression, revealing mitotic inheritance of silent viral genomes, a pattern seen for viruses with a known latency lifecycle. Single-cell RNA sequencing further identifies a transient antiviral and inflammatory response that is subsequently suppressed in surviving, cell cycle arrested cells. These findings define the cell-cycle logic, inheritance, and host consequences of MCV replication at single-cell resolution.

cell biology↗

bioRxiv2025

Foraging ecology drives viral community structure in New Zealand's aquatic birds

Wild migratory birds play a major role in the global spread of viruses, yet the diversity, host range and transmission patterns of viruses harboured by migratory species in Aotearoa/New Zealand remain largely unknown. This knowledge gap is critical given New Zealands position along major migratory flyways spanning Oceania, Antarctica and east Asia, where understanding viral diversity is key to assessing the risk of viral introductions such as highly pathogenic avian influenza virus and viral dispersal across these regions. To address this, we conducted the first large-scale metatranscriptomic survey of wild birds from New Zealand and its subantarctic islands, collecting 1,348 samples from 31 host species spanning four avian orders. We identified 118 avian viruses from 17 families, including 107 novel species, greatly expanding our knowledge of avian viral diversity. Viral communities differed significantly by host order and foraging behaviour, with scavenger birds harbouring more diverse viromes than non-scavengers. Although no HPAI subtypes were detected, we recovered a low-pathogenic avian influenza A/H1N9 virus from red knots (Calidris canutus) and a divergent tobanivirus from Auckland Island teal (Anas aucklandica), the first putative avian member of the Tobaniviridae. Notably, we detected 12 mammalian-associated viruses, primarily in scavenger birds, including Hedgehog hepatovirus, Rabbit haemorrhagic disease virus 2, and sea lion astroviruses, with mammalian host reads confirming their dietary origin. This study establishes the first virome baseline for New Zealands migratory birds, highlighting the ecological role of foraging in shaping viral communities and improving regional preparedness for HPAI and other emerging avian pathogens.

microbiology↗

bioRxiv2025

Neuroprotective Parkinson's Disease Therapeutic: Transition Metal Dichalcogenide Nanoflower Treatments Alleviate Pathological Cell Stress

Parkinsons disease (PD) is triggered by irreversible degeneration of dopaminergic neurons in the midbrain, hypothalamus, and thalamus. Although the underlying molecular etiology of these pathological processes remains unclear, progressive aggregation of alpha-synuclein (-syn) and mitochondrial dysfunction are two expected mechanisms implicated in neuronal degeneration. Accumulating evidence indicates that transition metal dichalcogenide (TMD) nanoflowers (NFs), a novel class of nanomaterials, can restore mitochondrial health by the activation of mitochondrial biogenesis. However, therapeutic potential of TMD NFs in PD remains unclear. The current study investigates the neuroprotective properties of molybdenum disulfide (MoS2) and molybdenum diselenide (MoSe2) nanoflowers (NFs) in neurons and astrocytes exposed to -syn aggregates. It was found that MoS2 and MoSe2 suppressed -syn-induced unfolded protein response (UPR) in the endoplasmic reticulum, and upregulated autophagy and exocytosis of -syn fibrils. TMD NFs also reversed -syn-induced damage of cell mitochondria, simultaneously stimulating mitochondrial biogenesis. As a result, a drastic decrease in ROS levels in both neurons and astrocytes was observed. These results show that MoS2 or MoSe2 NFs could fully rescue neurons and astrocytes from the cytotoxic effects of -syn fibrils. Neuroprotective properties of these novel nanomaterials were further explored in Caenorhabditis elegans that overexpress -syn. Nematodes that received NFs experienced a drastic reduction in the amount of aggregated -syn which resulted in a significant increase in C. elegans lifespan. These findings indicated that MoS2 or MoSe2 NFs could be used as novel therapeutic to decelerate the progression of PD.

neuroscience↗

bioRxiv2025

Lipodystrophy and recovery are mediated by the Wnt/lipogenesis axis during skin fibrosis.

Acquired lipodystrophy in the dermal white adipose tissue (DWAT) is a salient feature of skin fibrosis, and is followed by accumulation of extracellular matrix (ECM). Lipodystrophy syndromes, often associated with metabolic co-morbidities, are estimated to affect 1 in 20,000 people. We recently showed that fibrosis-associated lipodystrophy is dependent on sustained Wnt signaling, but the mechanism is unclear. Transcriptomic profiling of mature dermal adipocytes in vivo reveal that Wnt activation downregulates the de novo-lipogenesis (DNL) axis enzymes within 48 hours. We found that protein expression of Fatty Acid Synthase (FASN), a key DNL enzyme, is dependent on sustained Wnt activation in vitro and in vivo. In human systemic sclerosis, FASN mRNA is significantly downregulated during two years of disease. Remarkably, pharmacological inhibition of FASN enzyme during reversal from Wnt induced fibrosis impedes recovery of DWAT lipid content as well as ECM accumulation and topography. All together, we demonstrate that acquired lipodystrophy in the context of skin fibrosis is mediated by a new role of the Wnt-DNL axis. These findings underscore the importance of this pathway in lipodystrophy and fibrosis, opening new avenues for therapeutic targets in skin fibrosis.

cell biology↗

bioRxiv2025

Profiling a large HIV-1 elite neutralizer cohort reveals remarkable CD4bs bNAb for HIV-1 prevention and therapy

Administration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo. However, clinical use is challenged by broad envelope sequence diversity and rapid emergence of viral escape1-9. Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies (bNAbs) with highest potency and breadth for clinical application. From 831 expressed monoclonal antibodies, we identified 04_A06, a new VH1-2-encoded CD4 binding site bNAb with remarkable breadth and potency against extended multiclade pseudovirus panels (GeoMean IC50 = 0.059 {micro}g/ml, breadth = 98.5%, 332 virus strains). Moreover, 04_A06 was not susceptible to classic viral CD4bs escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed that antiviral activity is mediated by an unusually long 11-amino acid heavy chain insertion. This insertion facilitates inter-protomer contacts and interactions with highly conserved residues on the adjacent gp120 protomer. Finally, 04_A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody Mediated Prevention (AMP) trials (GeoMean IC50 = 0.082 {micro}g/ml, breadth = 98.4%, 191 virus strains) and in silico modeling for 04_A06LS predicted HIV-1 prevention efficacy of >93%. Thus, 04_A06 will provide unique opportunities for effective treatment and prevention strategies of HIV-1 infection.

immunology↗

bioRxiv2025

Influence of the broadly neutralizing antibody VRC01 on HIV breakthrough virus populations in antibody-mediated prevention trials

In the HIV antibody mediated prevention (AMP) trials, the broadly neutralizing antibody VRC01 demonstrated protective efficacy against new diagnoses with susceptible HIV strains. To understand how VRC01 shaped breakthrough infections, we performed deep sequencing on 172 participants in the placebo and treatment arms, generating 63,444 gag-{Delta}pol (2.5 kb) and 53,088 rev-env-{Delta}nef (3 kb) sequences. Sequences were classified into transmitted founder lineages (TFLs), and infections with multiple distinct lineages were determined. Multilineage infections were detected in [~]38% of participants in both the African (HVTN 703/HPTN 081) and Americas/Europe (HVTN 704/HPTN 085) cohorts, regardless of placebo or treatment group, or cohort. The high levels of multilineage infections could be attributed to minor lineages (<5% abundance) identified in 20% of participants. Infection with VRC01 discordant viruses (IC80s >3-fold different) was observed in 40% of multilineage infections, with a trend toward greater intra-host neutralization differences with increasing VRC01 dose (Jonckheere-Terpstra test, p=0.072). In six VRC01 treated participants who acquired both sensitive (IC80<1{micro}g/ml) and resistant viruses (IC80>3{micro}g/ml), the sensitive lineages declined over time. Recombination was pervasive, observed in 63% of multilineage infections at the time of HIV diagnosis. In one treated participant infected with VRC01 discordant lineages, recombinant viruses preferentially inherited the resistance mutation (binomial p=0.004). In conclusion, our in-depth analysis of breakthrough viruses in the AMP trials revealed a high frequency of multilineage infections, including infections with viruses with different VRC01 sensitivities. This analysis also highlights the role of recombination in shaping intra-host viral evolution and facilitating escape from VRC01. SignificanceThis work advances our understanding of the diversity of initial viral infection and evolution and in vivo activity of broadly neutralizing antibodies (bNAbs). Deep sequencing revealed [~]38% of HIV acquisitions with multiple transmitted founder lineages, higher than previous studies. These occurrences were similar in the placebo and VRC01 groups. Viral recombination among post-acquisition variants was common under antibody selection and appeared to favor resistant sequences in the treatment group. These data suggest as with single antiviral therapy, passive and active immunization of bNAbs should be directed at multiple antigen targets of HIV-1.

molecular biology↗

bioRxiv2025

KDM5 demethylases suppress R-loop-mediated viral mimicry and DNA damage in breast cancer cells

Tumors with low expression of Interferon-Stimulated Genes (ISG) and Antigen Presentation (AP) genes respond relatively poorly to current immunotherapies. One of the early hallmarks of cancer is DNA hypomethylation in genomic repeat regions, resulting in the expression of normally silenced endogenous "viral" elements. Such epigenetic changes have the potential to augment anti-tumor immune responses as well as reduce tumor cell fitness through the generation of aberrant nucleic acid species (NAS) and consequent activation of NAS-sensing pathways. Therefore, tumor evolution should favor additional selective events that suppress NAS generation, possibly yielding specific therapeutic vulnerabilities. Here, we show that the Lysine Demethylase 5 (KDM5) family of epigenetic regulatory enzymes suppress R-loop formation in genomic repeat regions in cancer cells. We find that KDM5 inhibition in luminal breast cancer cells results in R-loop-mediated DNA damage, reduced cell fitness and an increase in ISG and AP signatures as well as cell surface Major Histocompatibility Complex (MHC) class I, mediated by RNA:DNA hybrid activation of the CGAS/STING pathway. KDM5 inhibition does not result in DNA damage or activation of the CGAS/STING pathway in normal breast epithelial cells, suggesting that KDM5 inhibitors may enable a wide therapeutic window in this setting, as compared to STING agonists or Type I Interferons. These findings provide new insights into the interplay between epigenetic regulation of genomic repeats, R-loop formation, innate immunity, and cell fitness in the context of cancer evolution and therapeutic vulnerability.

cancer biology↗

bioRxiv2024

Comparative analysis of iPSC-derived human kidney organoid and tubuloid models

BackgroundEpithelial kidney organoids (tubuloids) made from kidney biopsies, urine, or iPSC-derived kidney organoids offer new opportunities in experimental and clinical nephrology. Yet, we have limited knowledge of how tubuloid models differ from each other, from iPSC-derived kidney organoids and from the human kidney. New insight is required to guide model selection for studies in kidney physiology and disease. MethodsTubuloids were generated from adult nephrectomy samples (adult tubuloids n=3), iPSC-derived kidney organoids (iTubuloids n=3), and for the first time, from human fetal kidneys (fetal tubuloids n=3). Kidney organoid and tubuloid models were compared to each other and to adult human kidney using bulk RNA sequencing. Tubuloids were subject to hypoxic insults over three passages and profiled with RNA sequencing to assess cumulative injury and repair. ResultsExpression signatures of proximal and distal tubules were stronger in adult kidneys than any organoid or tubuloid model. Comparative analysis between the models revealed that iPSC-derived kidney organoids had the highest expression of proximal tubule markers, even though adult tubuloids were derived from mature kidneys. Collecting duct signatures were enriched in adult and fetal tubuloids. Adult tubuloids showed stronger signatures of ageing and inflammation, while fetal tubuloids had enhanced ureteric tip progenitor signatures. Over 80 genes linked to inherited disorders were expressed in all tubuloid cultures, while a further 54 were expressed at higher levels in either adult, fetal or iTubuloids. Tubuloids subject to a single hypoxic injury effectively recovered by the end of the passage, while iTubuloids exposed to hypoxia over three passages expressed markers of maladaptive repair. ConclusionsThis study provides new transcriptome-wide reference data to aid in the selection and optimization of disease modelling for the human kidney. It defines common and unique opportunities to model inherited disorders in adult, fetal and iTubuloid models and illustrates new potential to model repetitive injury in long-lived tubuloid cultures.

molecular biology↗

bioRxiv2022

Polymorphisms in HIV-1 nef are associated with plasma concentration of biomarkers of endothelial activation

Infection with HIV is associated with an increased risk of cardiovascular disease (CVD), which may be mediated by the effect of the viral proteins, Nef and Tat, on inflammation and endothelial activation. The viral genes coding for Nef and Tat contain numerous polymorphisms, which we hypothesised may be differentially associated with endothelial activation. Therefore, our aim was to assess the association of these polymorphisms with endothelial activation and inflammation in subjects infected with HIV-1. The HIV-1 nef and tat genes were sequenced from clinical isolates from 31 and 34 patients, respectively. Plasma concentration of biomarkers of endothelial activation (intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelial leukocyte adhesion molecule-1 (E-selectin), monocyte chemoattractant protein-1 (MCP-1) and von Willebrand factor (vWF)), and biomarkers of inflammation (tumor necrosis factor- (TNF-), interleukin-6 (IL-6) and interleukin-8 (IL-8)), were measured. Analysis of HIV-1 nef gene sequences identified five polymorphisms (V16I, H40Y, T50A,H, S169N and H188Q,S) that were each significantly (p<0.05) associated with ICAM-1 plasma concentration. An additive effect of these variants on plasma ICAM-1 concentration (p=0.004 for trend), was observed. No significant associations were seen between Tat amino acid residues and plasma concentration of markers of endothelial activation and inflammation. These are the first human in vivo data that support the hypothesis that nef gene polymorphisms impact endothelial function. ImportanceCardiovascular disease (CVD) is a leading cause of mortality in adults living with HIV, which may in part be due to endothelial activation and inflammation caused by the viral proteins, Nef and Tat. However, there is no data from humans supporting the CVD-associated Nef and Tat hypothesis, and assays for accurately measuring Nef and Tat plasma concentrations are not currently available. Therefore, we hypothesized that polymorphisms in the nef and tat genes of clinical viral isolates may be associated with host plasma markers of endothelial activation and inflammation. Our results show that this was the case, with five nef polymorphisms showing both individual and additive association with plasma concentration of ICAM-1. The HIV-1 Tat gene, however, showed no significant association with plasma concentrations of markers of endothelial activation and inflammation. This is the first human study to directly link Nef to endothelial activation and to provide a possible screening tool i.e., nef genotyping, for identifying individuals at high risk of endothelial-based diseases.

biochemistry↗

bioRxiv2022

SARS-CoV-2 BA.4 infection triggers more cross-reactive neutralizing antibodies than BA.1

SARS-CoV-2 variants of concern (VOCs) differentially trigger neutralizing antibodies with variable cross-neutralizing capacity. Here we show that unlike SARS-CoV-2 Omicron BA.1, which triggered neutralizing antibodies with limited cross-reactivity, BA.4/5 infection triggers highly cross-reactive neutralizing antibodies. Cross-reactivity was observed both in the absence of prior vaccination and also in breakthrough infections following vaccination. This suggests that next-generation vaccines incorporating BA.4, which is spreading globally, might result in enhanced neutralization breadth.

immunology↗

bioRxiv2022

Fc effector activity and neutralization against SARS-CoV-2 BA.4 is compromised in convalescent sera, regardless of the infecting variant

The SARS-CoV-2 Omicron BA.1 variant, which exhibits high level neutralization resistance, has since evolved into several sub-lineages including BA.4 and BA.5, which have dominated the fifth wave of infection in South Africa. Here we assessed the sensitivity of BA.4 to neutralization and antibody dependent cellular cytotoxicity (ADCC) in convalescent donors infected with four previous variants of SARS-CoV-2, as well as in post-vaccination breakthrough infections (BTIs) caused by Delta or BA.1. We confirm that BA.4 shows high level resistance to neutralization, regardless of the infecting variant. However, breakthrough infections, which trigger potent neutralization, retained activity against BA.4, albeit at reduced titers. Fold reduction of neutralization in BTIs was lower than that seen in unvaccinated convalescent donors, suggesting maturation of neutralizing responses to become more resilient against VOCs in hybrid immunity. BA.4 sensitivity to ADCC was reduced but remained detectable in both convalescent donors and in BTIs. Overall, the high neutralization resistance of BA.4, even to antibodies from BA.1 infections, provides an immunological mechanism for the rapid spread of BA.4 immediately after a BA.1-dominated wave. Furthermore, although ADCC activity against BA.4 was reduced, residual activity may nonetheless contribute to the protection from disease.

immunology↗

bioRxiv2021

Neutralizing antibodies elicited by the Ad26.COV2.S COVID-19 vaccine show reduced activity against 501Y.V2 (B.1.351), despite protection against severe disease by this variant.

The emergence of SARS-CoV-2 variants, such as 501Y.V2, with immune evasion mutations in the spike has resulted in reduced efficacy of several COVID-19 vaccines. However, the efficacy of the Ad26.COV2.S vaccine, when tested in South Africa after the emergence of 501Y.V2, was not adversely impacted. We therefore assessed the binding and neutralization capacity of n=120 South African sera (from Day 29, post-vaccination) from the Janssen phase 3 study, Ensemble. Spike binding assays using both the Wuhan-1 D614G and 501Y.V2 Spikes showed high levels of cross-reactivity. In contrast, in a subset of 27 sera, we observed significantly reduced neutralization of 501Y.V2 compared to Wuhan-1 D614G, with 22/27 (82%) of sera showing no detectable neutralization of 501Y.V2 at Day 29. These data suggest that even low levels of neutralizing antibodies may contribute to protection from moderate/severe disease. In addition, Fc effector function and T cells may play an important role in protection by this vaccine against 501Y.V2.

immunology↗

bioRxiv2021

Therapeutic effect of CT-P59 against SARS-CoV-2 South African variant

The global circulation of newly emerging variants of SARS-CoV-2 is a new threat to public health due to their increased transmissibility and immune evasion. Moreover, currently available vaccines and therapeutic antibodies were shown to be less effective against new variants, in particular, the South African (SA) variant, termed 501Y.V2 or B.1.351. To assess the efficacy of the CT-P59 monoclonal antibody against the SA variant, we sought to perform as in vitro binding and neutralization assays, and in vivo animal studies. CT-P59 neutralized B.1.1.7 variant to a similar extent as to wild type virus. CT-P59 showed reduced binding affinity against a RBD (receptor binding domain) triple mutant containing mutations defining B.1.351 (K417N/E484K/N501Y) also showed reduced potency against the SA variant in live virus and pseudovirus neutralization assay systems. However, in vivo ferret challenge studies demonstrated that a therapeutic dosage of CT-P59 was able to decrease B.1.351 viral load in the upper and lower respiratory tracts, comparable to that observed for the wild type virus. Overall, although CT-P59 showed reduced in vitro neutralizing activity against the SA variant, sufficient antiviral effect in B.1.351-infected animals was confirmed with a clinical dosage of CT-P59, suggesting that CT-P59 has therapeutic potential for COVID-19 patients infected with SA variant. HighlightsO_LICT-P59 significantly inhibit B.1.1.7 variant to a similar extent as to wild type virus C_LIO_LICT-P59 showed reduced potency against the B.1.351 variant in in vitro studies C_LIO_LITherapeutic dosage of CT-P59 showed in vivo neutralizing potency against B.1.351 in ferret challenge study. C_LI

microbiology↗

bioRxiv2021

Performance of generalist hemiparasitic Euphrasia across a phylogenetically diverse host spectrum

O_LIGeneralist hemiparasites may attach to many different host species and experience complex parasite-host interactions. How these parasite-host interactions impact on the fitness of hemiparasitic plants remain largely unknown. C_LIO_LIWe used experimentally tractable eyebrights (Euphrasia, Orobanchaceae) to understand parasite-host interactions affecting the performance of a generalist hemiparasitic plant. Common garden experiments were carried out measuring Euphrasia performance across 45 diverse hosts and in different parasite-host combinations. C_LIO_LIWe showed that variation in hemiparasite performance could be attributed mainly to host species and host phylogenetic relationships ({lambda} = 0.82; 0.17-1.00 Cl). When this variation in performance is broken down temporally, annual host species cause earlier flowering, and lead to poorer performance late in the season. While Euphrasia species typically perform similarly on a given host species, some eyebrights show more specialised parasite-host interactions. C_LIO_LIOur results show that generalist hemiparasites only benefit from attaching to a limited, but phylogenetically divergent, subset of hosts. The conserved responses of divergent Euphrasia species suggest hemiparasite performance is affected by common host attributes. However, evidence for more complex parasite-host interactions show that a generalist hemiparasite can potentially respond to individual host selection pressures and may adapt to local host communities. C_LI

plant biology↗

bioRxiv2021

SARS-CoV-2 501Y.V2 (B.1.351) elicits cross-reactive neutralizing antibodies

Neutralization escape by SARS-CoV-2 variants, as has been observed in the 501Y.V2 (B.1.351) variant, has impacted the efficacy of first generation COVID-19 vaccines. Here, the antibody response to the 501Y.V2 variant was examined in a cohort of patients hospitalized with COVID-19 in early 2021 - when over 90% of infections in South Africa were attributed to 501Y.V2. Robust binding and neutralizing antibody titers to the 501Y.V2 variant were detected and these binding antibodies showed high levels of cross-reactivity for the original variant, from the first wave. In contrast to an earlier study where sera from individuals infected with the original variant showed dramatically reduced potency against 501Y.V2, sera from 501Y.V2-infected patients maintained good cross-reactivity against viruses from the first wave. Furthermore, sera from 501Y.V2-infected patients also neutralized the 501Y.V3 (P.1) variant first described in Brazil, and now circulating globally. Collectively these data suggest that the antibody response in patients infected with 501Y.V2 has a broad specificity and that vaccines designed with the 501Y.V2 sequence may elicit more cross-reactive responses.

immunology↗

bioRxiv2020

Development of early-stage type 1 diabetes in germ-free interleukin-10 deficient mice

Several experimental models demonstrate a role for gut microbiota in the progression of type 1 diabetes (T1D) in genetically prone hosts. While the association between disturbances in gut microbiota, or microbial dysbiosis, and complex immune diseases such as inflammatory bowel diseases (IBD) are well established, less is known about its role in T1D pathogenesis. In IBD-prone interleukin-10 deficient (IL-10 KO) mice, the absence of gut microbiota under germ-free (GF) conditions prevents IBD development. However, in aged GF IL-10 KO mice (>6-months of age), polyuria and pancreatic lymphocytic infiltration resembling T1D lesions was observed. Approximately 50% of male and female mice above 6-months of age develop pancreatic immune cell infiltration, as compared to none in conventionally-raised and fecal microbiota transplanted (FMT) IL-10 KO counterparts. Immunofluorescence staining of islet infiltrates was positive for adaptive and innate immunological markers, including lymphoid and myeloid cell markers, which typically characterize autoimmune T1D lesions. A subset of GF IL-10 KO mice was also positive for insulin autoantibodies (IAA), but the majority of mice did not become diabetic. Our findings of early stage lymphocytic infiltrates in the pancreas and IAA in the absence of overt diabetes in GF IL-10 KO mice embody the early stages of T1D pathogenesis. As such, we propose that the presence of gut microbiota play a protective role against immune infiltration in the pancreas of genetically prone hosts. Moreover, our model provides an opportunity to better understand the role of the microbiota in the early stages of immune pathogenesis and perhaps conceive the development of microbe-mediated prophylactic strategies to treat or even prevent T1D.

physiology↗