Selected Grantee Publications
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.
Effect of Omeprazole on Esophageal Microbiota in Dogs Detected Using a Minimally Invasive Sampling Method
Handa et al., Journal of Veterinary Internal Medicine. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11864821
Omeprazole alters the esophageal microbiome (EM) of humans and has associated effects. The changes and subsequent recovery of the EM in 3- to 6-year-old dogs after omeprazole treatment were assessed using the esophageal string test (EST). All 10 dogs tolerated the EST without adverse effects, and the EST retrieved sufficient biofluid to characterize the EM. Diversity analysis revealed no significant alterations in alpha (Observed species, Shannon and Simpson indices) and beta diversity (Bray‐Curtis) across the time points after omeprazole administration. Thus, omeprazole therapy was not observed to alter the EM of healthy dogs in this study. The application of EST in dogs illustrates its use as a minimally invasive tool for investigating the role of EM in esophageal health and disease in dogs. Supported by ORIP (K01OD030515).
De Novo and Inherited Variants in DDX39B Cause a Novel Neurodevelopmental Syndrome
Booth et al., Brain. 2025.
https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf035/8004980?login=true
DDX39B is a core component of the TRanscription-EXport (TREX) super protein complex. Recent studies have highlighted the important role of TREX subunits in neurodevelopmental disorders. Researchers describe a cohort of six individuals (male and female) from five families with disease-causing de novo missense variants or inherited splice-altering variants in DDX39B. Three individuals in the cohort are affected by mild to severe developmental delay, hypotonia, history of epilepsy or seizure, short stature, skeletal abnormalities, variable dysmorphic features, and microcephaly. Using a combination of patient genomic and transcriptomic data, in silico modeling, in vitro assays, and in vivo Drosophila and zebrafish models, this study implicates disruption of DDX39B in a novel neurodevelopmental disorder called TREX-complex-related neurodevelopmental syndrome. Supported by ORIP (U54OD030165).
Preclinical Use of a Clinically-Relevant scAAV9/SUMF1 Vector for the Treatment of Multiple Sulfatase Deficiency
Presa et al., Communications Medicine. 2025.
https://pubmed.ncbi.nlm.nih.gov/39870870
This study evaluates a gene therapy strategy using an adeno-associated virus (AAV)/SUMF1 vector to treat multiple sulfatase deficiency (MSD), a rare and fatal lysosomal storage disorder caused by mutations in the SUMF1 gene. Researchers delivered the functional gene to male and female Sumf1 knockout mice either neonatally or after symptom onset. Neonatal treatment via cerebral spinal fluid extended survival up to 1 year, alleviated MSD symptoms, and restored normal behavior and cardiac and visual function without toxicity. Treated tissues showed widespread SUMF1 expression and enzymatic activity. These findings support the translational potential of this gene replacement therapy for clinical use in MSD patients. Supported by ORIP (U42OD010921, U54OD020351, U54OD030187) and NCI.
Single-Cell Transcriptomics Predict Novel Potential Regulators of Acute Epithelial Restitution in the Ischemia-Injured Intestine
Rose et al., American Journal of Physiology-Gastrointestinal and Liver Physiology. 2025.
https://pubmed.ncbi.nlm.nih.gov/39853303
Following ischemia in the small intestine, early barrier restoration relies on epithelial restitution to reseal the physical barrier and prevent sepsis. Pigs share a similar gastrointestinal anatomy, physiology, and microbiota with humans. Researchers used neonatal and juvenile, 2- to 6-week-old male and female Yorkshire cross pigs to determine upstream regulators of restitution. Single-cell sequencing of ischemia-injured epithelial cells demonstrated two sub-phenotypes of absorptive enterocytes, with one subset presenting a restitution phenotype. Colony-stimulating factor-1 (CSF1) was the only predicted upstream regulator expressed in juvenile jejunum compared with neonatal jejunum. An in vitro scratch wound assay using IPEC-J2 cells showed that BLZ945, a colony-stimulating factor 1 receptor antagonist, inhibited restitution. Ex vivo ischemia-injured neonatal pig jejunum treated with exogenous CSF1 displayed increased barrier function. This study could inform future research focused on developing novel therapeutics for intestinal barrier injury in patients. Supported by ORIP (T32OD011130, K01OD028207), NCATS, NICHD, and NIDDK.
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.
Targeting Pancreatic Cancer Cell Stemness by Blocking Fibronectin-Binding Integrins on Cancer-Associated Fibroblasts
Wu et al., Cancer Research Communications. 2025.
https://pubmed.ncbi.nlm.nih.gov/39785683
Cancer-associated fibroblasts (CAFs) stimulate the formation and progression of pancreatic adenocarcinoma (PDAC) through the generation of extracellular matrix (ECM). Researchers developed a bispecific antibody (bsAb) that targets α5β1 and αvβ3 integrins expressed on CAFs. Blockade using the bsAb resulted in reduced assembly of fibronectin and collagen fibers in vitro. An antifibrotic effect was observed when CAFs were plated for 72 hours prior to bsAb treatment; pre-deposited ECM was disrupted. Six- to 8-week-old female nu/nu mice treated with bsAb demonstrated fewer tumors and reduced tumor stiffness compared with those exposed to only CAFs co-injected with PDAC cells. These results support a potential novel PDAC therapeutic that targets CAF-mediated fibronectin assembly and ECM production. Supported by ORIP (K01OD030513) and NCI.
Transiently Boosting Vγ9+Vδ2+ γδ T Cells Early in Mtb Coinfection of SIV-Infected Juvenile Macaques Does Not Improve Mtb Host Resistance
Larson et al., Infection and Immunity. 2024.
https://pubmed.ncbi.nlm.nih.gov/39475292/
Children with HIV have a higher risk of developing tuberculosis (TB), which is caused by the bacterium Mycobacterium tuberculosis (Mtb). This study utilized juvenile Mauritian cynomolgus macaques to investigate whether enhancing Vγ9+Vδ2+ γδ T cells with zoledronate treatment could improve TB resistance in HIV–TB coinfection. Researchers found that although boosting these immune cells temporarily increased their presence, it did not enhance the macaques’ ability to fight Mtb infection. These findings suggest that solely targeting γδ T cells may not be an effective strategy for improving TB immunity in immunocompromised individuals. These insights are crucial for developing better treatments for HIV–TB coinfections. Supported by ORIP (K01OD033539, P51OD011106) and NIAID.
Aberrant Activation of Wound-Healing Programs within the Metastatic Niche Facilitates Lung Colonization by Osteosarcoma Cells
Reinecke et al., Clinical Cancer Research. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11739783/
The leading cause of deaths in the pediatric osteosarcoma is due to lung metastasis. A current clinical need is the development of therapies that disrupt the later stages of metastasis. Researchers used 6- to 8-week-old female C57BL/6 and CB17-SCID mice to understand how tumor cells disrupt the lung microenvironment to promote tumor growth. Single-cell RNA sequencing and spatial transcriptomics demonstrated osteosarcoma–epithelial cell interactions in a chronic state of wound healing in the lung. Nintedanib administration significantly disrupted metastatic progression compared with the vehicle control, demonstrating a potential novel therapeutic for combating osteosarcoma lung metastasis. Supported by ORIP (K01OD031811), NCI, and NCATS.
Response of Spontaneous Oral Tumors in Canine Cancer Patients Treated With Stereotactic Body Radiation Therapy (SBRT)
Gualtieri et al., Radiation Research. 2024.
https://pubmed.ncbi.nlm.nih.gov/39478420
This single-institution retrospective study assessed outcomes in 98 dogs with oral tumors after treatment with SBRT. Overall, progression-free survival (PFS) was 152 days, and median survival time (MST) was 270 days for dogs with oral malignant melanoma, squamous cell carcinoma, and soft tissue sarcoma following SBRT, with no significant differences among the groups. Shortened PFS and MST were associated with lymph node metastasis and the use of elective nodal irradiation. Adverse effects of SBRT were common within the study population and included organ toxicities (11.8%) and the formation of certain fistulas (28.4%). The authors concluded that the presence of these adverse effects warrants a re-evaluation of SBRT risk factors and protocols. Supported by ORIP (K01OD031809).