Search bioRxiv⌕ Search

Biology subjects

Hall, J. L.

Publications and source records attributed to Hall, J. L..

10 recordsLinked to original sources

Wild wood mouse gut microbiota are influenced by captivity and cross-fostering

Background Wild and laboratory animals harbour profoundly different gut microbiota, but how microbiomes shift between these states, and the relative roles of captivity, microbial history, and host identity in shaping that shift, remain unclear. Here, we developed a unique wood mouse (Apodemus sylvaticus) system comprising free-living mice (Wild:As), a wild-derived colony maintained in captivity for over a decade (Wild-like:As), and a second colony that we generated from the Wild-like:As mice by caesarean rederivation and cross-fostering to laboratory Mus musculus (Lab-like:As). We compared these three Apodemus cohorts with conventional laboratory Mus musculus (Lab:Mm) to ask how microbial diversity, community composition, and functional potential vary across a spectrum of wild-to-laboratory conditions. Results We found that alpha diversity varied substantially among cohorts but showed no consistent wild-to-laboratory trend: Shannon diversity was higher in Lab:Mm and Lab-like:As than in Wild:As and Wild-like:As mice, whereas phylogenetic diversity was similarly high in both the Wild:As and Lab:Mm groups. Community composition more closely reflected cohort histories. Despite over a decade in captivity, Wild-like:As mice remained most similar to Wild:As conspecifics, whereas Lab-like:As mice shifted strongly away from Wild-like:As and toward, but remained distinct from, Lab:Mm mice. The clearest wild-to-laboratory pattern emerged in microbiome consistency: core ASVs (present in [≥]90% of individuals) increased from 9 in Wild:As to 46 in Wild-like:As, 72 in Lab-like:As, and 138 in Lab:Mm mice. Predicted functional potential revealed a further distinction between taxonomic and functional patterns: Wild:As and Wild-like:As microbiomes did not differ significantly, whereas Lab-like:As shifted toward the Lab:Mm state despite remaining taxonomically distinct. Conclusions Together, these results show that laboratory-associated microbiomes do not emerge through simple loss of wild microbial diversity, but through broader reorganisation of community composition, consistency, and predicted functional potential reflecting microbial history and host context. The persistent Wild-like and Lab-like microbiome states within Apodemus provide a powerful experimental system for future timely work testing how microbiome history influences host physiology, resilience, and responses to environmental challenges.

microbiology↗

A Natural qE- and qZ-Deficient Alga Retains Functional Plant-Like and Chlorophycean Violaxanthin De-Epoxidases

Photosynthetic organisms protect themselves from excess light through non-photochemical quenching (NPQ), a process that safely dissipates excess light energy as heat. Current understanding of NPQ is largely drawn from a few model systems, leaving it unclear how universal NPQ mechanisms are across the green lineage. We characterize the slow, sustained NPQ of the green alga, Auxenochlorella protothecoides x symbiontica (UTEX 250-A). The Auxenochlorella genome lacks Light-Harvesting Complex Stress Related (LHCSR), one of the two proteins required for the fast energy-dependent quenching (qE) component of NPQ. Mutants lacking the Photosystem II Subunit S (PSBS)-like gene (psbsl1) in Auxenochlorella had no effect on NPQ, indicating this alga lacks canonical qE. We identified two candidate enzymes associated with zeaxanthin-dependent quenching (qZ), which has slower kinetics: a plant-type Violaxanthin De-Epoxidase (VDE) and an algal-type Chlorophycean Violaxanthin De-Epoxidase (CVDE). High light did not trigger the expected conversion of violaxanthin to zeaxanthin, a pigment change that is a hallmark of qZ. Mutants lacking VDE (vde1), CVDE (cvde1), or both enzymes (vde1 cvde1) still displayed slow, reversible NPQ. However, when the Auxenochlorella VDE1 and CVDE1 were expressed in a VDE-deficient mutant of Nicotiana benthamiana, both enzymes restored zeaxanthin production and NPQ, confirming they are catalytically functional de-epoxidases. Together, these results reveal an alga that retains two functional, evolutionarily distinct xanthophyll-cycle enzymes yet does not rely on typical xanthophyll pigment dynamics for photoprotection. This points to a biological function that is decoupled from de-epoxidase activity, highlighting unexplored diversity in green algal photoprotection.

plant biology↗

Helminth coinfection facilitates gammaherpesvirus infection in the wood mouse Apodemus sylvaticus

Helminths are widespread parasites that can modulate host immunity, potentially increasing susceptibility to viral infections. However, evidence for these effects varies across systems and environments, and links between laboratory and wild populations remain unclear. We developed a tractable system using wood mice, Heligmosomoides spp. nematodes, and wood mouse herpes virus (WMHV) to bridge this gap. Combining laboratory and field experiments with population modelling, we examined how helminth infection, anthelmintic treatment and diet affect viral dynamics. Across lab and field data, helminth infection consistently increased WMHV risk, with stronger effects at higher worm burdens. Field results showed that anthelmintic treatment reduced viral infection, and laboratory experiments showed that improved nutrition mitigates helminth-induced increases in viral susceptibility. Our population-level modelling suggested that helminth burden-dependent facilitation can generate nonlinear effects on viral spread, dependent on helminth virulence. Our findings highlight the potential importance of helminths as facilitators of viral infections, and suggest that anthelmintic treatment may provide indirect benefits for viral control. We also show the value of integrating lab and field approaches on the same (or closely related) species, in particular the potential offered by the wood mouse - Heligmosomoides - WMHV system, to understand the drivers and consequences of host-helminth-viral interactions.

ecology↗

Environmental drivers of low vaccine responsiveness in a lab-to-wild rodent model

Vaccination is the most effective way to prevent infectious diseases and safeguard public health. Yet, most new vaccines fail in late clinical trials, and even estab-lished ones often underperform in populations apart from those in which they were initially tested. This can lead to reduced vaccine responsiveness, breakthrough infections, and prevent or delay herd immunity. While the causes of vaccine hypore-sponsiveness remain difficult to identify, quantify, and therefore address, numerous reports indicate a predominant role of environmental factors. This has notably been demonstrated by a reduction in the immunogenicity and efficacy of various vaccines when transitioning from urban to rural human populations. Here, we tested whether and, if so, how the environment can cause vaccine hyporesponsive-ness. We hypothesised that if the leading causes of vaccine hyporesponsiveness were environmental, then the reduced efficacy would be exacerbated when indi-viduals are under nutritional stress; specifically predicting that high quality diet supplementation would increase vaccine responsiveness. Finally, we predicted that parasitic helminth infection, which are more common in rural populations, would degrade vaccine responsiveness, e.g. due to their ability to suppress host immunity, and that anthelmintic treatment could rescue vaccine responsiveness in infected individuals. To test these hypotheses, we coupled lab and field experiments with structural causal modelling, and measured antibody responses of paired conspecific cohorts of laboratory-reared and wild wood mice (Apodemus sylvaticus) to a single or two doses of diphtheria toxoid vaccine formulated with alum; with and without diet supplementation. We found that vaccine-specific IgG1 antibodies were [~]47% lower in the wild wood mice compared to the laboratory reared population. We also demonstrate that, across both habitats (wild and lab), substantial variation in vaccine responsiveness was caused by diet. However, contrary to our predictions, this high quality dietary supplementation resulted in lower vaccine responsiveness. Further, once the effects of habitat, diet, and sex were adjusted for, increasing hel-minth infection burdens negatively affected vaccine-specific antibody production. Using counterfactual modelling, we show that targeting anthelmintic treatment at heavily infected individuals would have improved their vaccine responsiveness by 2 to 4-fold. Our results indicate that the wild environment and access to a high-quality diet play a dramatic role in shaping the immune systems response to immunisation. Further, we show that laboratory settings, even when using a genetic diverse, non-traditional model, may systematically overestimate vaccine performance by failing to capture natural environmental variability. Our study provides a robust, causally explicit modelling approach to disentangle and quantify the complex factors that drive vaccine responsiveness in focal populations. This framework offers a path-way for predicting vaccine performance across diverse populations and identifying targeted interventions to enhance immunisation outcomes in real-world settings.

systems biology↗

Comparative transcriptomics reveals an extracellular worm argonaute as an ancestral regulator of LTR retrotransposons.

Safeguarding the genome from non-self elements is essential for reproduction, development, and ageing. One of the major threats to genome integrity is Transposable Elements (TEs), which can be post-transcriptionally silenced through small RNAs (sRNAs) and argonaute proteins. Recent work suggests TE-derived sRNAs may also act as virulence factors in host-pathogen interactions. During infection, the intestinal parasite Heligmosomoides bakeri secretes a single argonaute protein (exWAGO) and a wide variety of TE-derived sRNAs. Although exWAGO is highly expressed, conserved, and secreted by parasitic nematodes, its function and sRNA guide preference remain unclear. Using comparative transcriptomics of the sRNAs bound to exWAGO within parasites of rodents, livestock and humans, and its orthologs in C. elegans, we found that exWAGO is capable of loading sRNAs produced from all classes of TEs in addition to some protein-coding and non-coding transcripts. However, our results suggest that the ancestral endogenous function of exWAGO was likely linked to LTR retrotransposon regulation. To understand how this relates to potential extracellular functions of exWAGO we also examined the sRNAs bound to exWAGO secreted by H. bakeri in both vesicular and non-vesicular forms. Extracellular exWAGO preferentially loads sRNA guides derived from non-autonomous and fragmented LTRs, suggesting the existence of adaptable reservoirs of regulatory sRNAs with potential roles in cross-species RNA communication. Together, our results show that exWAGO is part of an evolutionarily conserved pathway for LTR retrotransposon regulation, while preferentially utilising degenerated elements as sources of secreted sRNAs.

genomics↗

CT-induced disease generates epithelial cell-derived L-lactate that promotes Vibrio cholerae growth in the small intestine

Cholera toxin (CT) promotes Vibrio cholerae colonization by altering gut metabolism to favor pathogen growth. We have previously found that CT-induced disease leads to increased concentrations of L-lactate in the lumen of the small intestine during experimental cholera. Here, we show that CT-induced disease leads to the upregulation of mammalian lactate dehydrogenase A (LDHA), an enzyme that catalyzes the conversion of pyruvate to L-lactate, in small intestinal epithelial cells. In a suckling mouse model, the bacterial L-lactate dehydrogenase (LldD) conferred a fitness advantage to V. cholerae but not to the {Delta}ctxAB mutant incapable of producing CT. Finally, the fitness advantage conferred by LldD was significantly reduced in mice lacking epithelial-cell specific LDHA, demonstrating that epithelial-derived L-lactate is a major contributor to CT-dependent pathogen expansion. These findings identify L-lactate as a host-derived metabolite generated by intestinal epithelial cells produced during cholera disease that directly fuels V. cholerae growth during infection, uncovering a mechanism by which CT confers a fitness advantage to the pathogen during disease.

microbiology↗

CD33-CD45 Interaction Reveals a Mechanistic Link to Alzheimer's Disease Susceptibility

The innate immune gene CD33, encoding a myeloid inhibitory sialic acid-binding receptor, is associated with Alzheimers disease (AD) susceptibility. The AD-associated rs3865444CC risk variant reduces splicing of the sialic acid-binding domain and increases expression of the full-length (sialic acid-binding) CD33 isoform seven-fold compared to the rs3865444AA protective genotype. Here we identify CD45 as an immune cell-specific sialic acid-dependent cis CD33 binding partner, whose phosphatase activity is inhibited by CD33. Overexpression of CD33 or loss of CD45 contributes to impaired microglial clearance of amyloid beta and amyloid beta-induced loss of dendritic spines in microglial-neuronal co-cultures, aligning with a detrimental effect of CD33-mediated inhibition of CD45. CD33-CD45 interaction frequency was increased in monocytes from individuals with the rs3865444CC risk variant compared to rs3865444AA, as well as in AD compared to controls, independent of genotype. Furthermore, an interaction between CD33 and PTPRC (encoding CD45) gene expression in human brain tissue was associated with a pathological diagnosis of AD and global burden of AD pathology. Our findings thus establish a functional interaction between CD33 and CD45 relevant to AD susceptibility and systemic myeloid dysfunction in this disease.

neuroscience↗

CD33 and Clusterin Interact Biophysically and Genetically to Modulate Alzheimer Risk

We report the results of structural, functional and genetic studies on the CD33 sialic acid- binding receptor that reveal how non-coding variants in CD33 alter risk for Alzheimers disease (AD). The full-length CD33M isoform, whose expression is upregulated by non-coding AD-risk alleles, preferentially forms dimers at the cell surface, where they interact with AD-related proteins (clusterin and A{beta}). This interaction induces CD33M inhibitory signalling and downregulates protective microglial functions including phagocytic removal of amyloid plaques. Human brain expression quantitative trait loci (eQTL) and causal mediation analyses confirm that quantitative interactions between CLU and CD33 genotypes modulate AD phenotypes and suggest that genotypes at these loci might be used to personalise future therapeutic approaches. Our work also highlights several other unexpected aspects of CD33 biology, including a soluble shed extracellular fragment of CD33M and a similar soluble secreted product arising from a truncating mutation in the CD33 extracellular domain (CD33M{Delta}4bp).

neuroscience↗

Ancient diversity in host-parasite interaction genes in a model parasitic nematode

Host-parasite interactions exert strong selection pressures on the genomes of both host and parasite. These interactions can lead to increased fitness of rare alleles, resulting in negative frequency-dependent selection, a form of balancing selection that is hypothesised to explain the high levels of polymorphism seen in many host immune and parasite antigen loci. Despite their economic and ecological importance, there is limited evidence for balancing selection in parasitism-relevant genes in parasitic nematodes. Here, we sequenced the genomes of several individuals of Heligmosomoides bakeri, a parasite of house mice that is a well-established model parasitic nematode, and Heligmosomoides polygyrus, a closely related parasite of wood mice. We combined our single nematode genome assemblies with chromatin conformation capture (Hi-C) libraries derived from pools of individuals to generate chromosome-level reference genomes for both species. Although H. bakeri is commonly referred to as H. polygyrus in the literature, their genomes show levels of divergence that are consistent with millions of years of independent evolution. We found that the H. bakeri genome, which we expected to be highly homozygous through inbreeding, contained hundreds of hyper-divergent haplotypes, similar to those recently reported in free-living nematodes. Within these haplotypes, we found an enrichment of protein families that interact with the host immune response, including protease inhibitors and transthyretin-related proteins. We also found that many of these haplotypes originated prior to the divergence between H. bakeri and H. polygyrus, suggesting that they have been maintained since the last common ancestor of the two species by long-term balancing selection. Together, our results suggest that selection pressures exerted on parasites by their hosts have led to unexpected modes and levels of genetic diversity in the genomes of these economically and ecologically important species.

evolutionary biology↗

Translating DNA origami Nanotechnology to Middle School, High School, and Undergraduate Laboratories

DNA origami is a rapidly emerging nanotechnology that enables researchers to create nanostructures with unprecedented geometric precision that have tremendous potential to advance a variety of fields including molecular sensing, robotics, and nanomedicine. Hence, many students could benefit from exposure to basic knowledge of DNA origami nanotechnology. However, due to the complexity of design, cost of materials, and cost of equipment, experiments with DNA origami have been limited mainly to research institutions in graduate level laboratories with significant prior expertise and well- equipped laboratories. This work focuses on overcoming critical barriers to translating DNA origami methods to educational laboratory settings. In particular, we present a streamlined protocol for fabrication and analysis of DNA origami nanostructures that can be carried out within a 2-hour laboratory course using low-cost equipment, much of which is readily available in educational laboratories and science classrooms. We focus this educational experiment module on a DNA origami nanorod structure that was previously developed for drug delivery applications. In addition to fabricating nanostructures, we demonstrate a protocol for students to analyze structures via gel electrophoresis using classroom-ready gel equipment. These results establish a basis to expose students to DNA origami nanotechnology and can enable or reinforce valuable learning milestones in fields such as biomaterials, biological engineering, and nanomedicine. Furthermore, introducing students to DNA nanotechnology and related fields can also have the potential to increase interest and future involvement by young students. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/508130v1_ufig1.gif" ALT="Figure 1"> View larger version (70K): org.highwire.dtl.DTLVardef@137f058org.highwire.dtl.DTLVardef@1843271org.highwire.dtl.DTLVardef@bc9b4org.highwire.dtl.DTLVardef@1e779af_HPS_FORMAT_FIGEXP M_FIG C_FIG

scientific communication and education↗