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- Immunology
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.
A Murine Model of Trypanosoma brucei-Induced Myocarditis and Cardiac Dysfunction
Crilly et al., Microbiology Spectrum. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11792545
Trypanosoma brucei is a protozoan parasite that causes human and animal African trypanosomiases, HAT and AAT, respectively. Cardiac symptoms are commonly reported in HAT patients, and intracardiac parasites with accompanying myocarditis have been observed in both natural hosts and animal models for T. brucei infection. A clinically relevant, reproducible murine model for T. brucei–associated cardiomyopathy is currently unavailable. The researchers developed a 7- to 10-week-old C57Bl/6J male and female mouse model for T. brucei infection that demonstrates myocarditis, elevated serum levels of NT-proBNP, and electrocardiographic abnormalities, recapitulating the clinical features of infection. The results demonstrate the importance of interstitial space in T. brucei colonization and provide a relevant, reproducible murine model to investigate the pathogenesis and potential therapeutics of T. brucei-mediated heart damage. Supported by ORIP (T32OD011089, S10OD026859), NCI, and NIA.
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.
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.
Placental Gene Therapy in Nonhuman Primates: A Pilot Study of Maternal, Placental, and Fetal Response to Non-Viral, Polymeric Nanoparticle Delivery of IGF1
Wilson et al., Molecular Human Reproduction. 2024.
https://academic.oup.com/molehr/article/30/11/gaae038/7876288#493719584
This study investigates a novel nanoparticle-mediated gene therapy approach for addressing fetal growth restriction (FGR) in pregnant female nonhuman primates. Using polymer-based nanoparticles delivering a human insulin-like growth factor 1 (IGF1) transgene, the therapy targets the placenta via ultrasound-guided injections. Researchers evaluated maternal, placental, and fetal responses by analyzing tissues, immunomodulatory proteins, and hormones (progesterone and estradiol). Findings highlight the potential of IGF1 nanoparticles to correct placental insufficiency by enhancing fetal growth, providing a groundbreaking advancement for in utero treatments. This research supports further exploration of nonviral gene therapies for improving pregnancy outcomes and combating FGR-related complications. Supported by ORIP (P51OD011106) and NICHD.
Neutralizing Antibody Response to SARS‐CoV‐2 Bivalent mRNA Vaccine in SIV‐Infected Rhesus Macaques: Enhanced Immunity to XBB Subvariants by Two‐Dose Vaccination
Faraone, Journal of Medical Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38528837/
Researchers have shown that mRNA vaccination is less effective for people with advanced or untreated HIV infection, but data on the efficacy of mRNA vaccination against SARS-CoV-2 in this population are limited. Using rhesus macaques (sex not specified) with simian immunodeficiency virus (SIV), investigators examined the neutralizing antibody (nAb) response to SARS-CoV-2 vaccination. They found that administration of the bivalent vaccine alone can generate robust nAb titers against Omicron subvariants. Additionally, dams that received antiretroviral therapy had lower nAb titers than untreated dams. Overall, these findings highlight the need for further investigations into the nAb response in people with HIV. Supported by ORIP (P51OD011104), NCI, NIAID, NICHD, and NIMH.
Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy
Racine et al., Journal of Immunology. 2024.
Myocarditis has emerged as a relatively rare but often lethal autoimmune complication of checkpoint inhibitor (ICI) cancer therapy, and significant mortality is associated with this phenomenon. Investigators developed a new mouse model system that spontaneously develops myocarditis. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, the treatment accelerates skeletal muscle myositis. The team performed characterization of cardiac and skeletal muscle T cells using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies. Supported by ORIP (U54OD020351, U54OD030187), NCI, NIA, NIDDK, and NIGMS.
Deep Analysis of CD4 T Cells in the Rhesus CNS During SIV Infection
Elizaldi et al., PLOS Pathogens. 2023.
https://pubmed.ncbi.nlm.nih.gov/38060615/
Systemic HIV infection results in chronic inflammation that causes lasting damage to the central nervous system (CNS), despite long-term antiretroviral therapy (ART). Researchers studied neurocognitive outcomes in male and female rhesus macaques infected with simian immunodeficiency virus (SIV) using an ART regimen simulating suboptimal adherence; one group received no ART, and the other received ART with periodic interruptions. Using single-cell transcriptomic profiling, the researchers also identified molecular programs induced in the brain upon infection. They found that acute infection led to marked imbalance in the CNS CD4/CD8 T‑cell ratio, which persisted into the chronic phase. The studies provide insight into the role of CD4 T cells in the CNS during HIV infection. Supported by ORIP (P51OD011107, K01OD023034), NIA, NIAID, and NCI.
IL-21-IgFc Immunotherapy Alters Transcriptional Landscape of Lymph Node Cells Leading to Enhanced Flu Vaccine Response in Aging and SIV Infection
Pallikkuth et al., Aging Cell. 2023.
https://pubmed.ncbi.nlm.nih.gov/37712598/
Aging is associated with increased risk of seasonal flu disease burden and serious flu-related complications, particularly for people with HIV. In this study, investigators aimed to elucidate the immunomodulation following flu vaccination in aging male and female rhesus macaques infected with simian immunodeficiency virus (SIV). Their results suggest that IL-21 treatment at the time of flu vaccination modulates the inductive lymph node germinal center activity to reverse SIV-associated immune dysfunction. The authors identified IL-21 as a potential candidate molecule for immunotherapy to enhance flu vaccine responses in affected populations. Further studies could examine the overall benefit of IL-21 immunotherapy on mucosal lung immunity and protection against infection. Supported by ORIP (R24OD010947), NIA, and NIAID.
Very-Long-Chain Fatty Acids Induce Glial-Derived Sphingosine-1-Phosphate Synthesis, Secretion, and Neuroinflammation
Chung et al., Cell Metabolism. 2023.
https://pubmed.ncbi.nlm.nih.gov/37084732/
Very-long-chain fatty acids (VLCFAs) are the most abundant fatty acids in myelin. During age‑associated degeneration of myelin, glia are exposed to increased levels of VLCFAs. Investigators previously described a novel phenotype in patients that harbors a novel variant in the peroxisomal enzyme ACOX1. Here, they report that that glial loss of ACOX1 leads to an increase of VLCFAs, which results in a concomitant increase in sphingosine-1-phosphate (S1P). They found that suppressing S1P function attenuates the pathological phenotypes caused by excess VLCFAs. This work suggests that lowering of VLCFAs and S1P could be applied as a treatment avenue for multiple sclerosis. Supported by ORIP (R24OD022005, R24OD031447, P40OD018537), NINDS, and NICHD