Selected Grantee Publications
- 608 results found
Mutant Prion Protein Enhances NMDA Receptor Activity, Activates PKC, and Triggers Rapid Excitotoxicity in Mice
Lin et al., The Journal of Clinical Investigation. 2025.
https://pubmed.ncbi.nlm.nih.gov/40185484
This study examined how a mutant form of a prion protein (PrPC) linked to Alzheimer’s disease can harm neurons, one type of brain cell. The team used genetically modified male and female mice and showed that changes in PrPC disrupt neuronal communication and lead to overactivation of Nmethyl-d-aspartate (NMDA) receptors in the brain, which are important for neuronal signaling. Mice experienced seizures and damage to neurons that are important for memory. The findings suggest that PrPC triggers toxic chain reactions in the brain and that these reactions play a key role in neurodegeneration. This discovery may ultimately help scientists better understand the mechanisms behind neurodegenerative diseases. Supported by ORIP (T32OD017863, S10OD023527) NCI, NHLBI, NIA, and NINDS.
Sperm Derived H2AK119ub1 is Required for Embryonic Development in Xenopus laevis
Francois-Campion et al., Nature Communications. 2025.
https://pubmed.ncbi.nlm.nih.gov/40188103
Previous research shows that exposure of males to various environmental factors can affect offspring by modifying the genetic material in sperm. Epigenetics—changes in gene expression that occur without altering the DNA sequence—plays an important role in how embryos develop. DNA is wrapped around groups of histones, a type of structural support protein that regulate DNA compaction and gene expression. DNA compaction can be regulated by modifications to histones—including the attachment of ubiquitin molecules. Researchers studied the role of a particular ubiquitin modification to histones, H2AK119ub1, in embryo development of Xenopus laevis (African clawed frog). The results showed that sperm-derived H2AK119ub1 instructs egg factor–mediated remodeling of the DNA contributed by the sperm and is required for embryonic development. Supported by ORIP (R24OD031956).
Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Mutation Reduces Endothelial TDP-43 and Causes Blood–Brain Barrier Defects
Cheemala et al., Science Advances. 2025.
https://pubmed.ncbi.nlm.nih.gov/40238886
Mutations in the TARDBP gene, which encodes nuclear protein TAR DNA-binding protein 43 (TDP-43), are linked to neurodegenerative diseases, such as familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This study showed that TDP-43 is reduced in brain endothelial cells (ECs) of male and female mice with this mutation—leading to blood–brain barrier (BBB) disruption and causing inflammation, protein buildup, and cognitive issues—mimicking key features of neurodegeneration. These findings suggest that endothelial TDP-43 loss contributes directly to BBB breakdown and disease pathology in ALS-FTD. Supported by ORIP (U54OD020351), NCI, NHLBI, NIA, and NINDS.
Synaptic Dysregulation in a Mouse Model of GRIN2D Developmental and Epileptic Encephalopathy
Teoh et al., Brain. 2025.
https://pubmed.ncbi.nlm.nih.gov/40200555
Researchers studied a gain-of-function mutation, V667l, in the GRIN2D gene, which is linked to severe developmental delays and epilepsy in children. Using a mouse model carrying the V664I variant (both sexes used), findings showed that the mutation caused early-onset seizures, abnormal brain activity, and learning impairments. Functional analysis demonstrated increased synaptic activity, notably in inhibitory GABAergic interneurons, leading to heightened hippocampal excitability. These findings highlight how this mutation alters excitatory and inhibitory neuronal signaling in the brain, supporting precision genetic therapy as a promising treatment strategy for patients with mutations in the GRIN2D gene. Supported by ORIP (U54OD020351), NCI, NIA, NICHD, NIMH, and NINDS.
IL-15/IL-15Ra Synergies with IL-12 to Induce Functional CD8 T Cells and NK Cells During Chronic SHIV Infection
Govindaraj et al., AIDS Research and Human Retroviruses. 2025.
https://pubmed.ncbi.nlm.nih.gov/39041621
Cytokines are key mediators of immune regulation—orchestrating communication between immune cells and shaping the immune landscape during diseases. Researchers investigated whether combining the cytokine treatments interleukin 15 (IL-15)/IL-15Rα and IL-12 would enhance antiviral immunity during chronic simian/human immunodeficiency virus (SHIV) infection. Results indicate that in vitro combination therapy treatment led to an expansion of virus-fighting immune cells (CD8 T and natural killer cells) from uninfected and chronically infected male rhesus macaques with SHIV, compared to single treatment (IL-15/IL-15Rα). Combination treatment also reduced the expression of CCR5, a key receptor that HIV uses to enter and infect CD4 T cells, limiting the number of viral targets. These findings suggest that combined IL-15/IL-15Rα plus IL-12 treatment could strengthen immune defenses and reduce viral spread, supporting its potential use in future therapies for chronic viral infections and cancer. Supported by ORIP (P51OD011132, U42OD011023) and NIAID.
IL-21 and Anti-α4β7 Dual Therapy During ART Promotes Immunological and Microbiome Responses in SIV-Infected Macaques
Johnson et al., JCI Insight. 2025.
https://pubmed.ncbi.nlm.nih.gov/39903521
Despite combination antiretroviral therapy (ART), HIV causes persistent gut barrier dysfunction, immune depletion, and dysbiosis. This study examined the use of interleukin 21 (IL-21) and anti-α4β7 dual therapy to improve immune and gut health outcomes in simian immunodeficiency virus (SIV)–infected male and female rhesus macaques receiving ART. Both dual- and mono-treated animals preserved immune cells and reduced harmful inflammation in the gut. This therapy also boosted levels of helpful gut bacteria, Roseburia, which are associated with better health. The amount of virus stayed similar between groups after stopping treatment; however, animals given combination therapy showed signs of stronger immune protection. These findings support the potential of IL-21 and anti-α4β7 as adjunct therapies in HIV treatment. Supported by ORIP (P51OD011132, U42OD011023), NIAID, NIDA, and NIMH.
Persistent Innate Immune Dysfunction and ZIKV Replication in the Gastrointestinal Tract During SIV Infection in Pigtail Macaques
Tisoncik-Go et al., Frontiers in Immunology. 2025.
https://pubmed.ncbi.nlm.nih.gov/40103823
Mosquito-transmitted viral infections, including Zika virus (ZIKV), are widespread in areas where HIV is prevalent. The effects of co-infection with HIV and ZIKV remain poorly understood. Using a 4- to 11-year-old male and female nonhuman primate (NHP) model, researchers investigated the impact of simian immunodeficiency virus (SIV)—a virus that mimics human HIV—on ZIKV replication and disease development. The presence of ZIKV in the bloodstream was delayed and ZIKV was more persistent in the gastrointestinal tissues of SIV–ZIKV co-infected NHPs compared with SIV-negative, ZIKV-infected NHPs. This persistence was associated with changes in immune cell recruitment to the blood and tissues, impaired immunity to ZIKV, and sustained expression of genes related to inflammation and innate immune response. Collectively, these findings suggest that untreated SIV infection may promote inflammatory cellular responses and foster chronic immune activation, which contributes to prolonged ZIKV infection and persistence in the gastrointestinal tract. Supported by ORIP (P51OD010425, U42OD011123), NCATS, NIAID, and NIMH.
SIV Env RhmAbs + N-803 at ART Initiation Prolongs Viral Decay Without Disrupting Reservoir Establishment in SIV-Infected Infant Macaques
Farinre et al., PLoS Pathogens. 2025.
https://pubmed.ncbi.nlm.nih.gov/39792949
The latent viral reservoir—immune cells infected with HIV but not actively producing new virus particles—remains the major barrier to an HIV cure. For newborns with HIV infection, there is a unique opportunity to begin treatment within days to weeks after birth. Using 4-week-old male and female nonhuman primates, researchers evaluated whether early antiretroviral therapy (ART) combined with virus-targeting antibodies, with or without the immune-stimulating drug N-803, could curb formation of the viral reservoir. Results showed that ART plus these antibodies produced a faster initial drop in virus levels, whereas adding N-803 unexpectedly slowed this decline despite increasing immune cell activation. Similar amounts of remaining virus and comparable rebound times across groups suggest that the viral reservoir forms within days of infection and that clearing only actively infected cells early in ART is unlikely to prevent its establishment. This study supports continued research efforts that provide insight into interventions that may work in patients. Supported by ORIP (P51OD011132, U42OD011023) and NIAID.
MARCKS Protein Is a Potential Target in a Naturally Occurring Equine Model of Neutrophilic Asthma
Conley et al., Respiratory Research. 2025.
https://pubmed.ncbi.nlm.nih.gov/40176021
Asthma is a chronic inflammatory airway disease that affects millions of people worldwide. Horses spontaneously develop asthma similar to humans, making the equine model ideal for studying airway inflammation. This study revealed that Myristoylated Alanine Rich C Kinase Substrate (MARCKS) protein levels were elevated in immune cells (macrophages and neutrophils) of male and female horses. Blocking this protein reduced inflammatory responses in these cells, suggesting that MARCKS may play a key role in driving asthma symptoms. These findings suggest that the MARCKS protein could potentially be a therapeutic target to reduce inflammation in severe neutrophilic asthma cases. Supported by ORIP (T32OD011130).
Structural Mapping of Polyclonal IgG Responses to HA After Influenza Virus Vaccination or Infection
León et al., mBio. 2025.
https://pubmed.ncbi.nlm.nih.gov/39912630
Seasonal influenza viruses cause hundreds of thousands of deaths each year and up to a billion infections; under the proper circumstances, influenza A viruses with pandemic potential could threaten the lives of millions more. Many promising universal flu vaccine candidates currently focus on guiding immune responses to highly conserved epitopes on the central stem of the influenza hemagglutinin (HA) viral fusion protein. To support the further development of these stem-targeting vaccine candidates, researchers used negative stain electron microscopy to assess the prevalence of central stem-targeting antibodies in individuals (male and female) who were exposed to influenza antigens through traditional vaccination or natural infection during the 2018–2019 flu season. Results demonstrated humoral IgGs targeting highly conserved regions on both H1 and H3 subtype HAs found in both vaccinated and infected patients. Results from this study support the need for further characterization of protective responses toward conserved epitopes and provide a baseline for examining antibody responses. Supported by ORIP (K01OD036063) and NIAID.