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Transcriptomic Analysis of Skeletal Muscle Regeneration Across Mouse Lifespan Identifies Altered Stem Cell States
Walter et al., Nature Aging. 2024.
https://pubmed.ncbi.nlm.nih.gov/39578558
Age-related skeletal muscle regeneration dysfunction is poorly understood. Using single-cell transcriptomics and high-resolution spatial transcriptomics, researchers evaluated factors contributing to age-related decline in skeletal muscle regeneration after injury in young, old, and geriatric male and female mice (5, 20, and 26 months old). Eight immune cell types were identified and associated with age-related dynamics and distinct muscle stem cell states specific to old and geriatric tissue. The findings emphasize the role of extrinsic and intrinsic factors, including cellular senescence, in disrupting muscle repair. This study provides a spatial and molecular framework for understanding regenerative decline and cellular heterogeneity in aging skeletal muscle. Supported by ORIP (F30OD032097), NIA, NIAID, NIAMS, NICHD, and NIDA.
Amphiphilic Shuttle Peptide Delivers Base Editor Ribonucleoprotein to Correct the CFTR R553X Mutation in Well-Differentiated Airway Epithelial Cells
Kulhankova et al., Nucleic Acids Research. 2024.
https://academic.oup.com/nar/article/52/19/11911/7771564?login=true
Effective translational delivery strategies for base editing applications in pulmonary diseases remain a challenge because of epithelial cells lining the intrapulmonary airways. The researchers demonstrated that the endosomal leakage domain (ELD) plays a crucial role in gene editing ribonucleoprotein (RNP) delivery activity. A novel shuttle peptide, S237, was created by flanking the ELD with poly glycine-serine stretches. Primary airway epithelia with the cystic fibrosis transmembrane conductance regulator (CFTR) R533X mutation demonstrated restored CFTR function when treated with S237-dependent ABE8e-Cas9-NG RNP. S237 outperformed the S10 shuttle peptide at Cas9 RNP delivery in vitro and in vivo using primary human bronchial epithelial cells and transgenic green fluorescent protein neonatal pigs. This study highlights the efficacy of S237 peptide–mediated RNP delivery and its potential as a therapeutic tool for the treatment of cystic fibrosis. Supported by ORIP (U42OD027090, U42OD026635), NCATS, NHGRI, NHLBI, NIAID, NIDDK, and NIGMS.
Comparison of the Immunogenicity of mRNA-Encoded and Protein HIV-1 Env-ferritin Nanoparticle Designs
Mu et al., Journal of Virology. 2024.
https://journals.asm.org/doi/10.1128/jvi.00137-24
Inducing broadly neutralizing antibodies (bNAbs) against HIV-1 remains a challenge because of immune system limitations. This study compared the immunogenicity of mRNA-encoded membrane-bound envelope (Env) gp160 to HIV-1 Env-ferritin nanoparticle (NP) technology in inducing anti-HIV-1 bNAbs. Membrane-bound mRNA encoding gp160 was more immunogenic than the Env-ferritin NP design in DH270 UCA KI mice, but at lower doses. These results suggest further analysis of mRNA design expression and low-dose immunogenicity studies are necessary for anti-HIV-1 bNAbs. Supported by ORIP (P40OD012217, U42OD021458) and NIAID.
Loss of Lymphatic IKKα Disrupts Lung Immune Homeostasis, Drives BALT Formation, and Protects Against Influenza
Cully et al., Immunohorizons. 2024.
https://pubmed.ncbi.nlm.nih.gov/39007717/
Tertiary lymphoid structures (TLS) have context-specific roles, and more work is needed to understand how they function in separate diseases to drive or reduce pathology. Researchers showed previously that lymph node formation is ablated in mice constitutively lacking IκB kinase alpha (IKKα) in lymphatic endothelial cells (LECs). In this study, they demonstrated that loss of IKKα in lymphatic endothelial cells leads to the formation of bronchus-associated lymphoid tissue in the lung. Additionally, they showed that male and female mice challenged with influenza A virus (IAV) exhibited markedly improved survival rates and reduced weight loss, compared with littermate controls. They concluded that ablating IKKα in this tissue reduces the susceptibility of the mice to IAV infection through a decrease in proinflammatory stimuli. This work provides a new model to explore the mechanisms of TLS formation and the immunoregulatory function of lung lymphatics. Supported by ORIP (T35OD010919), NHLBI, NIAID, and NIAMS.
Vaccination Induces Broadly Neutralizing Antibody Precursors to HIV gp41
Schiffner et al., Nature Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38816615
Primary immunogens that induce rare broadly neutralizing antibody (bnAb) precursor B cells are needed to develop vaccines against viruses of high antigenic diversity. 10E8-class bnAbs must possess a long, heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. Researchers developed germline-targeting epitope scaffolds with an affinity for 10E8-class precursors that exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens. Protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. This study showed that germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features. Supported by ORIP (P51OD011132, U42OD011023), NIAID, and NIGMS.
In Vitro and In Vivo Functions of SARS-CoV-2 Infection-Enhancing and Neutralizing Antibodies
Li et al., Cell. 2021.
https://doi.org/10.1016/j.cell.2021.06.021
Antibody-dependent enhancement of infection is a concern for clinical use of antibodies. Researchers isolated neutralizing antibodies against the receptor-binding domain (RBD) or N-terminal domain (NTD) of SARS-CoV-2 spike from COVID-19 patients. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific binding modes. RBD and NTD antibodies mediated both neutralization and infection enhancement in vitro. However, infusion of these antibodies into mice or macaques resulted in suppression of virus replication, demonstrating that antibody-enhanced infection in vitro does not necessarily predict enhanced infection in vivo. RBD-neutralizing antibodies having cross-reactivity against coronaviruses were protective against SARS-CoV-2, the most potent of which was DH1047. Supported by ORIP (P40OD012217, U42OD021458, S10OD018164), NIAID, NCI, NIGMS, and NIH Common Fund.