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.
Whole-Genome Sequences of Six Borrelia recurrentis Strains Obtained via PacBio Sequencing
Gaber et al., Microbiology Resource Announcements. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11895452
The spirochetal bacterium Borrelia recurrentis causes louse-borne relapsing fever (LBRF), which leads to significant morbidity and mortality in several African countries. Previous sequencing studies of B. recurrentis demonstrated discrepancies and did not accurately define the antigenic variation system. In this study, researchers used long-read PacBio technology to conduct whole-genome sequencing of six B. recurrentis strains that had been isolated from LBRF patients earlier. The resulting sequences of each genome included one linear chromosome and five linear plasmids, whose average size was 1,284,895 bp, with the mean GC content being 27.5%. Supported by ORIP (T32OD011083) and NIAID.
Structures of Respiratory Syncytial Virus G Bound to Broadly Reactive Antibodies Provide Insights into Vaccine Design
Juarez et al., Scientific Reports. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11906780
Respiratory syncytial virus (RSV) is one of the leading causes of severe lower respiratory infection in both infants and older adults. RSV viral entry and modulation of the host immunity is mediated by attachment glycoprotein RSV G binding to the chemokine receptor CX3CR1. Antibodies isolated from RSV-exposed individuals have shown great promise in host protection. Researchers using an ORIP-funded electron microscope, in conjunction with X-ray crystallography, have solved the structure of these antibodies bound to the RSV G protein and identified a novel dual antibody binding region. The presence of dual antibody binding sites indicates the potential to elicit antibody responses that resist virus escape. These findings will help develop next-generation RSV prophylactics and provide insight for new concepts in vaccine design. Supported by ORIP (S10OD027012, S10OD025097), NIAID, NHGRI, and NIGMS.
Senescent-like Microglia Limit Remyelination Through the Senescence Associated Secretory Phenotype
Gross et al., Nature Communications. 2025.
https://www.nature.com/articles/s41467-025-57632-w
Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease in which immune cells infiltrate the central nervous system and promote deterioration of myelin and neurodegeneration. The capacity to regenerate myelin in the central nervous system diminishes with age. In this study, researchers used 2- to 3-month-old (young), 12-month-old (middle-aged), and 18- to 22-month-old (aged) C57BL/6 male and female mice. Results showed an upregulation of the senescence marker P16ink4a (P16) in microglial and macrophage cells within demyelinated lesions. Notably, treatment of senescent cells using genetic and pharmacological senolytic methods leads to enhanced remyelination in young and middle-aged mice but fails to improve remyelination in aged mice. These results suggest that therapeutic targeting of senescence-associated secretory phenotype components may improve remyelination in aging and MS. Supported by ORIP (R24OD036199), NIA, NINDS, and NIMH.
Quorum Sensing LuxR Proteins VjbR and BabR Jointly Regulate Brucella abortus Survival During Infection
Caudill et al., Journal of Bacteriology. 2025.
https://pubmed.ncbi.nlm.nih.gov/40013834
Brucella abortus is a zoonotic bacterial pathogen that causes brucellosis, a persistent chronic infection that is globally endemic. B. abortus uses quorum sensing to escape immune clearance attempts, regulate virulence, and cause persistent infection within hosts. B. abortus quorum sensing system comprises two LuxR proteins, VjbR and BabR, as well as two signals, dodecanoyl (C12 AHL) and 3-oxododecanoyl (3-OXO-C12 AHL) homoserine lactone. Using chronic infection 6- to 7-week-old C57Bl/6 and BALB/c male and female mouse models, researchers found that the ΔvjbRΔbabR double-deletion strain was attenuated compared with single mutants. These results demonstrate that both quorum sensing proteins, VjbR and BabR, coordinate to maintain survival. This study helps further characterize the Brucella quorum sensing systems and indicates that further attention should be given to the joint interactions between VjbR and BabR in controlling virulence. Supported by ORIP (T32OD028239) and NIAID.
A New Drosophila melanogaster Research Resource: CRISPR-Induced Mutations for Clonal Analysis of Fourth Chromosome Genes
Weasner et al., G3 (Bethesda). 2025.
https://pubmed.ncbi.nlm.nih.gov/39804955
The fruit fly, Drosophila melanogaster, shares approximately 60% of its genes with human homologs and is an excellent model organism for studying mechanisms underlying human health and disease. However, the fourth chromosome of this organism is challenging to study because of the lack of genetic resources. This study presents a new resource—the Fourth Chromosome Resource Project—for studying the fourth chromosome of the fruit fly and expanding the understanding of gene function and disease mechanisms. Using gene editing approaches, researchers generated and characterized 119 mutations in 62 fourth chromosome genes, including 84 predicted null alleles and 29 in-frame deletions. Phenotypic assessments included tests for lethality, sterility, and visible traits. Many stable mutant stocks were submitted into public repositories in the United States and Japan for research purposes. Supported by ORIP (P40OD018537, R24OD028242) and NHGRI.
Suppressing APOE4-Induced Neural Pathologies by Targeting the VHL-HIF Axis
Jiang et al., PNAS. 2025.
https://pubmed.ncbi.nlm.nih.gov/39874294
The ε4 variant of human apolipoprotein E (APOE4) is a major genetic risk factor for Alzheimer’s disease and increases mortality and neurodegeneration. Using Caenorhabditis elegans and male APOE-expressing mice, researchers determined that the Von Hippel-Lindau 1 (VHL-1) protein is a key modulator of APOE4-induced neural pathologies. This study demonstrated protective effects of the VHL-1 protein; the loss of this protein reduced APOE4-associated neuronal and behavioral damage by stabilizing hypoxia-inducible factor 1 (HIF-1), a transcription factor that protects against cellular stress and injury. Genetic VHL-1 inhibition also mitigated cerebral vascular injury and synaptic damage in APOE4-expressing mice. These findings suggest that targeting the VHL–HIF axis in nonproliferative tissues could reduce APOE4-driven mortality and neurodegeneration. Supported by ORIP (R24OD010943, R21OD032463, P40OD010440), NHGRI, NIA, and NIGMS.
Dysregulation of mTOR Signalling Is a Converging Mechanism in Lissencephaly
Zhang et al., Nature. 2025.
https://pubmed.ncbi.nlm.nih.gov/39743596
Lissencephaly (smooth brain) is a rare genetic condition, with such symptoms as epilepsy and intellectual disability and a median life expectancy of 10 years. This study reveals that reduced activity of the mTOR pathway may be a common cause of lissencephaly. Researchers used laboratory-grown brain models (organoids) and sequencing and spectrometry techniques to identify decreased mTOR activation in two types of lissencephaly disorders: p53-induced death domain protein 1 and Miller–Dieker lissencephaly syndrome. Pharmacological activation of mTOR signaling with a brain-selective mTORC1 activator molecule, NV-5138, prevented and reversed the morphological and functional defects in organoids. These findings suggest that mTOR dysregulation contributes to the development of lissencephaly spectrum disorders and highlight a potential druggable pathway for therapy. Supported by ORIP (S10OD018034, S10OD019967, S10OD030363), NCATS, NHGRI, NICHD, NIDA, NIGMS, NIMH, and NINDS.
Systematic Ocular Phenotyping of 8,707 Knockout Mouse Lines Identifies Genes Associated With Abnormal Corneal Phenotypes
Vo et al., BMC Genomics. 2025.
https://pubmed.ncbi.nlm.nih.gov/39833678
Corneal dysmorphologies (CDs) are a group of acquired but predominantly genetically inherited eye disorders that cause progressive vision loss and can be associated with systemic abnormalities. This study aimed to identify candidate CD genes in humans by looking at knockout mice with targeted deletions of orthologous genes that exhibited statistically significant corneal abnormalities. Analysis of data from 8,707 knockout mouse lines identified 213 candidate CD genes; 176 (83%) genes have not been implicated previously in CD. Bioinformatic analyses implicated candidate genes in several signaling pathways (e.g., integrin signaling pathway, cytoskeletal regulation by Rho GTPase, FAS signaling pathway), which are potential therapeutic targets. Supported by ORIP (U42OD011175, R03OD032622, UM1OD023221), NEI, and NHGRI.
Liver-Specific Transgenic Expression of Human NTCP In Rhesus Macaques Confers HBV Susceptibility on Primary Hepatocytes
Rust et al., PNAS. 2025.
https://pubmed.ncbi.nlm.nih.gov/39937851
This study establishes the first transgenic nonhuman primate model for hepatitis B virus (HBV). Male and female rhesus macaques were engineered to express the human HBV receptor, NTCP (hNTCP), specifically in the liver. Researchers used PiggyBac transposon technology to introduce a liver-specific NTCP transgene into embryos, which were then implanted into surrogate females. The resulting offspring expressed hNTCP in hepatocytes and demonstrated high susceptibility to HBV infection. This model overcomes the species-specific limitations of HBV research, providing a powerful tool for studying HBV biology and evaluating HBV treatments in a clinically relevant model system. Supported by ORIP (P51OD011092), NIDA, and NIAID.