Biology subjects

Henderson, C.

Publications and source records attributed to Henderson, C..

7 recordsLinked to original sources

bioRxiv2026

Developing and Characterizing a Murine Model of In Utero Transmission of Ebola Virus

Ebola virus (EBOV) disease (EVD) is a hemorrhagic disease caused by EBOV infection. EVD outcomes in pregnant women are similar to non-pregnant women however, EVD is associated with negative fetal outcomes in [~]99% of cases. There is a critical need for a tractable small animal model to study maternal/fetal transmission of EBOV. We utilized interferon /{beta} receptor knock out mice infected and authentic EBOV or the model virus, recombinant vesicular stomatitis virus encoding EBOV glycoprotein (rVSV/EBOV). Infection with either virus during late pregnancy resulted in placental infection and vertical transmission to the fetus within 2-3 days. Robust levels of maternal and fetal proinflammatory cytokines were evident by day 5 after EBOV infection. Within the placenta, trophoblasts and endothelial cells were viral antigen positive. Elimination of the endosomal receptor NPC1 in junctional zone trophoblasts reduced placental infection and virus transmission to the fetus. These studies establish an infectious model that provides EBOV trafficking and pathogenesis insights during pregnancy. TeaserThis model provides key insights into how viral trafficking and maternal immune responses drive adverse fetal outcomes during gestational Ebola virus infection.

microbiology↗

bioRxiv2025

Integrated management of Canada thistle (Cirsium arvense) in the Great Plains and Intermountain West using a biocontrol agent (Puccinia suaveolens)

Canada thistle [Cirsium arvense (L.) Scop.] is an invasive perennial plant that threatens agricultural landscapes and natural ecosystems worldwide. The extensive regenerative root system of Canada thistle complicates control efforts, with current strategies having limited success. Puccinia suaveolens (Pers.) Rostr (syn. Puccinia punctiformis (F. Strauss) Rohl), an obligate biotrophic rust fungus, has shown potential as a biological control agent by systemically infecting the root system, reducing root mass and shoot growth, and limiting vegetative regeneration; however, its efficacy when integrated with other control methods remains unclear. We conducted experiments from 2020 to 2022 at two sites in Colorado and Utah to evaluate P. suaveolens efficacy when applied alone and in combination with mowing, tillage, and herbicide. Treatments were applied in Fall (2020 and 2021), with monitoring of thistle stem density, vegetative cover, as well as P. suaveolens incidence before and after treatments through 2022. While P. suaveolens alone contributed to a decrease in thistle density, it was less effective compared to herbicide treatments, and its impact when integrated with mowing or tillage was inconsistent. Herbicide application (alone and when combined with P. suaveolens) generated the greatest immediate reduction in thistle stem density and vegetative cover, although it resulted in the greatest amount of bare ground exposure. Grass coverage present within treated plots varied significantly between treatments, ranging from 0-75%, with the highest percentage observed in herbicide treatments compared to control and tillage in both years. Forb cover remained below 10% across treatments and years. Although P. suaveolens continues to show promise as a biological control agent, further research is needed to improve efficacy, and optimize integration with other control strategies.

ecology↗

bioRxiv2025

A chemical screen identifies p38 MAPK inhibition as a candidate neuroprotective strategy for combinatorial SMA therapy

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by ubiquitous deficiency in the survival motor neuron (SMN) protein. The identification of effectors and modifiers of pathogenic events downstream of SMN deficiency is key to understanding disease mechanisms and broadening the range of targets for developing SMA therapies that can complement SMN upregulation. Here, we report a cell-based phenotypic screen for chemical modifiers of SMN biology that identified inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) as suppressors of proliferation defects induced by SMN deficiency in mouse fibroblasts. We further show that SMN deficiency induces p38 MAPK activation and that pharmacological inhibition of this pathway improves motor function in SMA mice through SMN-independent neuroprotective effects. Using a highly optimized p38 MAPK inhibitor (MW150) and a specific paradigm of combinatorial treatment in SMA mice, we observed synergistic enhancement of the phenotypic benefit induced by either MW150 or an SMN-inducing drug alone. By promoting survival of motor neurons, pharmacological inhibition of p38 MAPK synergizes with SMN induction and enables enhanced synaptic rewiring of motor neurons within sensory-motor spinal circuits, resulting in increased motor function, weight gain, and survival of SMA mice. Together, our studies identify the p38 MAPK pathway as a therapeutic target and MW150 as a candidate pharmacological approach for SMN-independent neuroprotection with clinical relevance for combination therapy in SMA.

neuroscience↗

bioRxiv2024

Cis-regulatory elements driving motor neuron-restricted viral payload expression within the mammalian spinal cord

Spinal motor neuron (MN) dysfunction is the cause of a number of clinically significant movement disorders. Despite the recent approval of gene therapeutics targeting these MN-related disorders, there are no viral delivery mechanisms that achieve MN-restricted transgene expression. In this study, chromatin accessibility profiling of genetically defined mouse MNs was used to identify candidate cis-regulatory elements (CREs) capable of driving MN-selective gene expression. Subsequent testing of these candidates identified two CREs that confer MN-selective gene expression in the spinal cord as well as reduced off-target expression in dorsal root ganglia. Within one of these candidate elements, we identified a compact core transcription factor (TF)-binding region that drives MN-selective gene expression. Finally, we demonstrate that selective spinal cord expression of this mouse CRE is preserved in non-human primates. These findings suggest that the generation of cell-type-selective viral reagents, in which cell-type-selective CREs drive restricted gene expression, will be valuable research tools in mice and other mammalian species, with potentially significant therapeutic value in humans. SIGNIFICANCE STATEMENTMotor neurons transduce the motor outputs of nervous system activity to muscle and are the vulnerable neurons in a number of clinically significant degenerative conditions, including spinal muscular atrophy and amyotrophic lateral sclerosis. A recent strategy for treating motor neuron degenerative diseases has been to use viruses to introduce genes into motor neurons to inhibit the degenerative process. However, we still lack viral reagents that promote gene expression in motor neurons without potentially toxic off-target expression in other cell types. Our study identifies cis-regulatory elements capable of conferring motor neuron-selective transgene expression in a viral context. These findings have important implications for future gene therapeutics for motor neuron-related disorders.

neuroscience↗

bioRxiv2023

Scaling use of the rust fungus Puccinia punctiformis for biological control of Canada thistle (Cirsium arvense (L.) Scop.): First report on a U.S. statewide effort

Canada thistle (Cirsium arvense (L.) Scop., CT) is one of the worst weeds threatening temperate regions of the world. A host-specific rust fungus, Puccinia punctiformis (F. Strauss) Rohl., is known to cause systemic disease of CT, ultimately killing individuals and reducing stand densities. In 2013, it was demonstrated that fall inoculation of rosettes with coarsely ground leaves bearing P. punctiformis telia can successfully initiate epiphytotics. In the same year, a cooperative project between the Colorado Department of Agriculture and United States Department of Agriculture was initiated, in which CT patches across the state of Colorado (USA) were inoculated and tracked over subsequent years for changes in stem density. Here, we report our findings from 8 years (2014-2021) of monitoring effort. At most sites (N = 87), CT stem densities declined, from a mean ({+/-} SE) of 87.9 ({+/-} 6.5) stems to 44.7 ({+/-} 4.2). These declines however were spatially-autocorrelated, and likely attributable to local growing conditions, as mean annual daily maximum temperature and standard deviation of elevation, as well as climatic conditions around the times of both treatment and monitoring, were found to be important predictors of CT decline. Further, we observed that the amount of inoculum deployed, timing since last release, and method in which it was spread locally at a site were also associated with the magnitude of CT stem decline. These results are indicative of the value of P. punctiformis as a CT biological control agent. The name Cirsium arvense dieback (CADB) is proposed herein to describe the agriculturally important decline in CT stem densities attributable to this previously un-named systemic disease.

pathology↗

bioRxiv2022

Cysteine post-translational modifications regulate protein interactions of caveolin-3

Caveolae are small flask-shaped invaginations of the surface membrane which are proposed to recruit and co-localise signalling molecules. The distinctive caveolar shape is achieved by the oligomeric structural protein caveolin, of which three isoforms exist. Aside from the finding that caveolin-3 is specifically expressed in muscle, functional differences between the caveolin isoforms have not been rigorously investigated. Caveolin-3 is relatively cysteine-rich compared to caveolins 1 and 2, so we investigated its cysteine post-translational modifications. We find that caveolin-3 is palmitoylated at 6 cysteines and becomes glutathiolated following redox stress. We map the caveolin-3 palmitoylation sites to a cluster of cysteines in its C terminal membrane domain, and the glutathiolation site to an N terminal cysteine close to the region of caveolin-3 proposed to engage in protein interactions. Glutathiolation abolishes caveolin-3 interaction with heterotrimeric G protein alpha subunits. Our results indicate that a caveolin-3 oligomer contains up to 66 palmitates, compared to up to 33 for caveolin-1. The additional palmitoylation sites in caveolin-3 therefore provide a mechanistic basis by which caveolae in smooth and striated muscle can possess unique phospholipid and protein cargoes. These unique adaptations of the muscle-specific caveolin isoform have important implications for caveolar assembly and signalling.

cell biology↗

bioRxiv2022

Substrate topology and cognate immunity modulate antibacterial toxicity of Tae cell wall hydrolases

Members of the bacterial T6SS amidase effector (Tae) superfamily of toxins are delivered between competing bacteria to degrade cell wall peptidoglycan. Although Taes share a common substrate, they exhibit distinct antimicrobial potency across different competitor species. To investigate the molecular basis governing these differences, we quantitatively defined the functional determinants of Tae1 from Pseudomonas aeruginosa PAO1 using a combination of nuclear magnetic resonance (NMR) and a high-throughput in vivo genetic approach called deep mutational scanning (DMS). As expected, combined analyses confirmed the role of critical residues near the Tae1 catalytic center. Unexpectedly, DMS revealed substantial contributions to enzymatic activity from a much larger, ring-like functional hot spot extending around the entire circumference of the enzyme. Comparative DMS across distinct growth conditions highlighted how functional contribution of different surfaces is highly context-dependent, varying alongside composition of targeted cell walls. These observations suggest that Tae1 engages with the intact cell wall network through a more distributed three-dimensional interaction interface than previously appreciated, providing an explanation for observed differences in antimicrobial potency across divergent Gram-negative competitors. Further binding studies of several Tae1 variants with their cognate immunity protein demonstrate that requirements to maintain protection from Tae activity may be a significant constraint on the mutational landscape of tae1 toxicity in the wild. In total, our work reveals that Tae diversification has likely been shaped by multiple independent pressures to maintain interactions with binding partners that vary across bacterial species and conditions.

biochemistry↗