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Functional Differences Between Rodent and Human PD-1 Linked to Evolutionary Divergence
Masubuchi et al., Science Immunology. 2025.
https://pubmed.ncbi.nlm.nih.gov/39752535/
Programmed cell death protein 1 (PD-1), an immune checkpoint receptor, regulates immunity against cancer. Rodent models (e.g., mice) do not exhibit the same response rates and immune-related adverse effects to PD-1 blocking drugs as patients with cancer. Only 59.6% amino acid sequence identity is conserved in human PD-1 (hu PD-1) and mouse PD-1 (mo PD-1). Researchers used mouse tumor models, coculture assays, and biophysical assays to determine key functional and biochemical differences between hu PD-1 and mo PD-1. HuPD-1 demonstrates stronger suppressive activity of interleukin-2 secretion and CD69 expression than mo PD-1 because of the ectodomain and intracellular domain, but not the transmembrane domain. Analysis of rodent evolution demonstrated that other inhibitory immunoreceptors were positively selected or had selection intensification over PD-1. Understanding the conservation and divergence of PD-1 signaling at the molecular level in humans compared with mice is needed to properly translate preclinical data to clinical therapeutics. Supported by ORIP (S10OD026929), NCI, and NIA.
Plural Molecular and Cellular Mechanisms of Pore Domain KCNQ2 Encephalopathy
Abreo et al., eLife. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11703504
This study investigates the cellular and molecular mechanisms underlying KCNQ2 encephalopathy, a severe type of early-onset epilepsy caused by mutations in the KCNQ2 gene. Researchers describe a case study of a child with a specific KCNQ2 gene mutation, G256W, and found that it disrupts normal brain activity, leading to seizures and developmental impairments. Male and female Kcnq2G256W/+ mice have reduced KCNQ2 protein levels, epilepsy, brain hyperactivity, and premature deaths. As seen in the patient study, ezogabine treatment rescued seizures in mice, suggesting a potential treatment avenue. These findings provide important insights into KCNQ2-related epilepsy and highlight possible therapeutic strategies. Supported by ORIP (U54OD020351, S10OD026804, U54OD030187), NCI, NHLBI, NICHD, NIGMS, NIMH, and NINDS.
Matrikine Stimulation of Equine Synovial Fibroblasts and Chondrocytes Results in an In Vitro Osteoarthritis Phenotype
Gagliardi et al., Journal of Orthopaedic Research. 2025.
https://pubmed.ncbi.nlm.nih.gov/39486895
Advancements in therapy development for osteoarthritis (OA) currently are limited due to a lack of physiologically relevant in vitro models. This study aimed to understand the effect of matrikine stimulation, using human recombinant fibronectin fragment containing domains 7–10 (FN7–10), on equine synovial fibroblasts and chondrocytes. Inflammatory cytokines, chemokines, and matrix degradation genes in equine synovial fibroblasts and chondrocytes were significantly altered in response to FN7–10 stimulation; marked upregulation was observed in interleukin-6 (IL-6), IL-4, IL-10, matrix metalloproteinase 1 (MMP1), MMP3, MMP13, CCL2/MCP1, and CXCL6/GCP-2 gene expression. Only IL-6 protein production was significantly increased in media isolated from cells stimulated with FN7–10. These results support the potential use of equine synovial fibroblasts and chondrocytes—employing FN7–10—as representative in vitro models to study OA. Supported by ORIP (T32OD011130) and NIAMS.
Engineered Bacteria That Self-Assemble Bioglass Polysilicate Coatings Display Enhanced Light Focusing
Sidor et al., PNAS. 2024.
https://pubmed.ncbi.nlm.nih.gov/39656206
Organisms in nature have evolved to create multifunctional structures with advanced optical properties that can be used to design new optical materials. Researchers created constructs containing the enzyme silicatein, derived from sea sponges, and the outer membrane protein A (OmpA) to engineer Escherichia coli bacteria to express surface-level silicatein enzymes. Using Rhodamine123 staining and transmission electron microscopy, results showed that engineered E. coli expressing OmpA-silicatein displayed polysilicate encapsulation with smooth, nonruffled cell borders compared with wild-type E. coli. Light-scattering analysis demonstrated that engineered E. coli create photonic nanojets that are brighter than wild-type E. coli. This study serves as proof of concept that cells can be engineered for potential utilization as tunable photonic components. Supported by ORIP (S10OD030296) and NIGMS.
SHIV Remission in Macaques With Early Treatment Initiation and Ultra Long-Lasting Antiviral Activity
Daly et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/39632836
Antiretroviral therapy (ART) suppresses HIV and simian immunodeficiency virus (SIV) replication but cannot eliminate reservoirs of long-lived infected cells that enable rebound after discontinuation of ART. These researchers hypothesized that ART designed to have long-lasting activity and penetrate tissue reservoirs would be optimized against HIV or SIV remission. Macaques were treated with a four-drug regimen (i.e., oral emtricitabine/tenofovir alafenamide and long-acting cabotegravir/rilpivirine) designed to improve dosing of immune cells, with or without the immune-activating drug vesatolimod (VES), after the onset of SIV viremia. The animals were monitored for 1 year with treatment and 2 additional years following treatment discontinuation. Durable viral suppression was observed in all animals treated with the optimized ART regimen with or without VES. These results will inform novel HIV treatment regimens with long-lasting antiviral activity in humans. Supported by ORIP (P40OD028116).
Temperature-Dependent Alterations in the Proteome of the Emergent Fish Pathogen Edwardsiella piscicida
Jacobsen et al., Journal of Fish Diseases. 2024.
https://pubmed.ncbi.nlm.nih.gov/39304982
Reported outbreaks of Edwardsiella piscicida, a bacterial pathogen among cultured and wild fish, have been steadily increasing over the past decade in tandem with climate change–mediated increases in water temperatures. The capacity for this increasingly prevalent fish pathogen to infect and cause disease in mammals is important to understand. Researchers examined the role of temperature on the virulence of E. piscicida to understand its pathogenesis in the context of climate warming trends and better understand its zoonotic potential. Findings revealed downregulation of virulence-related proteins, such as flagellar and Type VI secretion system proteins, at colder temperatures. These findings highlight the potential environmental factors influencing the pathogen’s threat to aquaculture and public health. Supported by ORIP (S10OD026918, T32OD011147).
Extended Survival of 9- and 10-Gene-Edited Pig Heart Xenografts With Ischemia Minimization and CD154 Costimulation Blockade-Based Immunosuppression
Chaban et al., The Journal of Heart and Lung Transplantation. 2024.
https://pubmed.ncbi.nlm.nih.gov/39097214
Heart transplantations are severely constrained from the shortage of available organs derived from human donors. Xenotransplantation of hearts from gene-edited (GE) pigs is a promising way to address this problem. Researchers evaluated GE pig hearts with varying knockouts and human transgene insertions. Human transgenes are introduced to mitigate important physiological incompatibilities between pig cells and human blood. Using a baboon heterotopic cardiac transplantation model, one female and seven male specific-pathogen-free baboons received either a 3-GE, 9-GE, or 10-GE pig heart with an immunosuppression regimen targeting CD40/CD154. Early cardiac xenograft failure with complement activation and multifocal infarcts were observed with 3-GE pig hearts, whereas 9- and 10-GE pig hearts demonstrated successful graft function and prolonged survival. These findings show that one or more transgenes of the 9- and 10-GE pig hearts with CD154 blockade provide graft protection in this preclinical model. Supported by ORIP (U42OD011140) and NIAID.
Impaired Axon Initial Segment Structure and Function in a Model of ARHGEF9 Developmental and Epileptic Encephalopathy
Wang et al., PNAS. 2024.
https://www.pnas.org/doi/10.1073/pnas.2400709121
Researchers developed a mouse model carrying the G55A missense variant identified in ARHGEF9 patients with severe epilepsy and neurodevelopmental phenotypes. Using male Arhgef9G55A mice, this study examined behavioral, molecular, and electrophysiological phenotypes in the Arhgef9G55A model of developmental and epileptic encephalopathies (DEE). Researchers found that the G55A variant causes disruption of inhibitory postsynaptic organization and axon initial segment (AIS) architecture, leading to impairment of both synaptic transmission and action potential generation. The effects of Arhgef9G55A on neuronal function affect both intrinsic and synaptic excitability and preferentially impair AIS. These findings indicate a novel pathological mechanism of DEE and represent a unique example of a neuropathological condition converging from AIS dysfunctions. Supported by ORIP (U54OD020351, U54OD030187, U54OD020351, S10OD026974) and NINDS.
Fetal Bone Engraftment Reconstitutes the Immune System in Pigs With Severe Combined Immunodeficiency
Monarch et al., Lab Animal. 2024.
https://pubmed.ncbi.nlm.nih.gov/39289566/
A valuable preclinical model for studying immune-related pathologies is the severe combined immunodeficiency (SCID) pig through modification of recombination activating gene 2 (RAG2) and interleukin-2 receptor-γ (IL2RG). RAG2/IL2RG double knockout SCID pigs are hard to maintain for breeding and long-term studies because their life span is 8 weeks or less. The researchers investigated fetal allograft transplantation derived from immunocompetent pigs as a strategy for reconstituting the immune system of SCID pigs and promoting survival. Following fetal allograft, SCID pigs demonstrated increased levels of lymphocytes. SCID pigs that received the fetal allograft demonstrated improved body condition and extended life span compared with nonrecipient SCID littermates. This study demonstrates the potential use of fetal allograft transplantation to extend the life span of SCID pigs to breeding age to reduce the resources used to maintain this model for biomedical research. Supported by ORIP (U42OD011140, R21OD027062).
Impaired Skeletal Development by Disruption of Presenilin-1 in Pigs and Generation of Novel Pig Models for Alzheimer's Disease
Uh et al., Journal of Alzheimer's Disease. 2024.
https://pubmed.ncbi.nlm.nih.gov/39177593/
This study explored the effects of presenilin 1 (PSEN1) disruption on vertebral malformations in male and female PSEN1 mutant pigs. Researchers observed significant skeletal impairments and early deaths in pigs with a PSEN1 null mutation, mirroring phenotypes seen in mouse models of Alzheimer’s disease (AD). This porcine model provides valuable insights into pathological hallmarks of PSEN1 mutations in AD, offering a robust platform of therapeutic exploration. The findings establish pigs as an essential translational model for AD, enabling advanced studies on pathophysiology and treatment development for human skeletal and neurological conditions. Supported by ORIP (U42OD011140), NHLBI, NIA, NIAID.