Biology subjects

Elliott, N. M.

Publications and source records attributed to Elliott, N. M..

4 recordsLinked to original sources

bioRxiv2026

Sex-Dependent Effects of Creatine Hydrochloride on Neuroinflammation, Neuronal Survival, and Inhibitory Synaptic Remodeling Following Traumatic Brain Injury in Mice.

Despite traumatic brain injury (TBI) being a leading cause of death and disability in the United States, there is currently no FDA-approved medication that can prevent, heal, or reverse brain damage caused by TBI. TBI is caused by primary and secondary brain damage resulting in loss of neurons, astrocytic gliosis, and microglial activation which culminate in complex neurological disorders. The goal of the current study was to investigate the neuroprotective potential for Creatine Hydrochloride (C-HCl) supplementation following TBI in wild-type mice. Four C-HCl supplementation paradigms were examined including both 7 day pre-injury and 14-day post-injury treatments consisting of the following: 1) water/water, 2) water/C-HCl (100 mg/kg), 3) C-HCl (100 mg/kg)/C-HCl (100 mg/kg), 4) C-HCl (100 mg/kg)/C-HCl (450 mg/kg). Following controlled cortical impact (CCI) injury at a parietal location, measures of tissue and cellular (neuronal and glial) damage were assessed at 14 days post-injury (dpi). At 14 dpi, there were no significant effects on gross anatomical cavitation, tissue loss, third ventricle expansion, or systemic fluid biomarkers with any treatment group, though female mice exhibited larger baseline lesion boundaries overall compared to male mice. However, microstructural evaluation revealed a profound and sex-dependent effect of C-HCl supplementation in the hippocampus with female mice showing reduced neuroinflammation and male mice displaying reduced neurodegeneration (Fluoro-Jade C staining of neurons) across the CA1 and dentate gyrus (DG) compared to placebo control. Furthermore, mice receiving C-HCl pre-injury followed by high-dose C-HCl post-injury demonstrated distinct remodeling of inhibitory circuits to restore network balance with males significantly modifying presynaptic machinery via vesicular GABA transport (VGAT puncta) in the DG, whereas females reinforced postsynaptic architectural framing through scaffolding elements (gephyrin puncta) in both the CA1 and DG. These results suggest C-HCl supplementation holds promise as a neuroprotective therapeutic strategy for TBI. Crucially, the molecular mechanisms utilized to achieve this brain cell homeostasis are radically distinct between the sexes, females benefit primarily via upstream glial stabilization, while males derive protection via direct downstream neuronal survival. These outcomes highlight a critical requirement for sex-stratified profiling in translational pipelines for neurometabolic interventions for TBI. Ultimately, these data indicate that C-HCl successfully counteracts chronic secondary injury cascades, mitigating neurodegeneration, dampening neuroinflammation, and remodeling inhibitory circuitry to prevent post-traumatic network hyperexcitability.

neuroscience↗

bioRxiv2025

Pancreatic tumor microenvironment reprogramming via alloantigen-expressing virotherapy elicits tumor rejection and improves immunotherapy response

Pancreatic ductal adenocarcinoma (PDAC), the most common malignant type of pancreatic cancer, is characterized by a dense desmoplastic stroma, low neoantigen burden, and a highly immunosuppressive tumor microenvironment (TME), which severely limit cytotoxic T-cell infiltration and the efficacy of immune therapies. Here, we present a novel strategy harnessing acute transplant rejection mechanisms by employing a recombinant oncolytic rVMG vector engineered to express the murine H-2Kk MHC class I alloantigen (rVMG-H-2Kk), thereby inducing tumor-specific antigenic mismatch responses. In vitro, rVMG-H-2Kk exhibited strong replication and cytolytic activity while inducing cell surface expression of both H-2Kk and endogenous H-2Kb, in addition to upregulation of antigen presentation genes ({beta}2-microglobulin, Tap1, and Tapbp). In two independent immunocompetent PDAC models, intratumoral and systemic delivery of rVMG-H-2Kk delayed tumor progression and prolonged survival. Multiplex immunohistochemistry and immunophenotyping revealed substantial TME remodeling, marked by increased effector T-cell infiltration, regulatory T-cell depletion, and reduced fibrosis. Spatial transcriptomics further showed compartment-specific immune activation and epithelial metabolic reprogramming, corroborating with enhanced tumor immunogenicity. Despite these effects, rVMG-H-2Kk also induced compensatory immunosuppressive pathways, including upregulation of antiviral response genes and immune checkpoint receptors such as PDL-2. Importantly, combination therapy with rVMG-H-2Kk and murine checkpoint blockade (anti-PD-1 and anti-CTLA-4) drastically improved survival than checkpoint blockade alone. Strikingly, surviving mice resisted tumor rechallenge, indicating the establishment of durable antitumor memory. Collectively, these findings establish rVMG-H-2Kk as a novel immunotherapeutic platform capable of converting immune-cold tumors into immune-hot, sensitizing tumors to immune checkpoint inhibitors, and establishing durable antitumor immunity in PDAC. One Sentence SummaryOncolytic virus-based delivery of an alloantigen improves antitumor immunity and synergizes with immune checkpoint inhibitors in pancreatic cancer. Significance statementDelivery of murine alloantigens via an engineered oncolytic vesiculovirus, combined with immune checkpoint blockade, overcomes immunosuppressive barriers and establishes durable antitumor immunity in PDAC.

cancer biology↗

bioRxiv2025

Repeat Systemic Delivery of Cross-Neutralization Resistant Synthetic Vesiculoviruses Immunomodulates the Tumor Microenvironment

The clinical efficacy of systemic oncolytic virotherapy (OV) is constrained by the rapid development of neutralizing antibodies (nAbs), which prevent repeat systemic administration, a critical barrier to sustained anti-tumor immunity. Vesiculoviruses offer potent oncolytic and immunogenic potential. However, leveraging their serological diversity for repeat dosing remains unexplored. We generated a library of chimeric vesiculovirus vectors incorporating glycoproteins from less well characterized vesiculovirus species. We evaluated vector replication, infectivity, interferon (IFN) responses, and oncolysis in vitro, alongside assessments of neutralization resistance using patient sera, monoclonal antibodies, and in silico structural modeling. In vivo studies assessed tumor delivery, immune activation, and therapeutic efficacy following intravenous administration. The vesiculovirus library exhibited broad tumor infectivity, distinct IFN-stimulatory profiles, and variable oncolytic activity. Neutralization assays and computational modeling identified serological distinctness across vectors, driven by hypervariable glycoprotein epitopes, enabling evasion of cross-neutralizing antibodies. Tumor delivery and anti-tumor immunity were preserved despite humoral barriers. Incorporating tumor-associated antigens (TAAs) further amplified anti-tumor responses, even in the context of anti-viral memory. Sequential administration of distinct vesiculovirus vectors induced robust immune activation and improved survival in a B16-OVA-IFNAR-/- model. Our findings establish a glycoprotein-diverse vesiculovirus platform capable of overcoming humoral immunity, enabling repeat intravenous dosing and sustained engagement of the tumor microenvironment. This strategy advances the field of oncolytic virotherapy by addressing a major translational barrier and lays the groundwork for future clinical studies integrating multi-vector, multi-dose immunovirotherapy with immune checkpoint blockade. One Sentence SummaryA glycoprotein-engineered vesiculovirus platform circumvents neutralizing antibodies, enabling repeat intravenous dosing and sustained anti-tumor immunity in preclinical models.

molecular biology↗

bioRxiv2022

Multi-modal Efficacy of a Chimeric Vesiculovirus Expressing the Morreton Glycoprotein in Sarcoma

Vesiculoviruses are attractive oncolytic virus (OV) platforms due to their rapid replication, genome with appreciable transgene capacity, broad tropism, limited pre-existing immunity, and type I interferon response gradient between malignant and normal cells. We developed a synthetic chimeric virus (VMG) expressing the glycoprotein (G) from Morreton virus (MorV) with remaining genes from vesicular stomatitis virus (VSV). VMG exhibited in vitro efficacy in cell proliferation and cell death assays across a broad range of sarcoma subtypes and across multiple species. Notably, all cell lines tested showed ability of VMG to yield productive infections with rapid replication kinetics. Pilot safety evaluations of VMG in immunocompetent, non-tumor bearing mice showed absence of toxicity with intranasal doses as high as 1e10 TCID50. VMG resulted in tumor reduction in vivo in an immunodeficient subcutaneous Ewing sarcoma model at doses as low as 2e5 TCID50. In the immune competent murine syngeneic fibrosarcoma model, while no tumor inhibition was achieved with VMG, there was a robust induction of CD8+ T cells suggestive of potential for combination approaches with immunomodulatory agents such as immune checkpoint inhibitors. The studies described herein establish the potential for VMG as a novel oncolytic virotherapy platform with multi-modal anti-tumor effects in sarcoma.

immunology↗