Selected Grantee Publications
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
Lipid Droplets and Peroxisomes Are Co-Regulated to Drive Lifespan Extension in Response to Mono-Unsaturated Fatty Acids
Papsdorf et al., Nature Cell Biology. 2023.
https://www.nature.com/articles/s41556-023-01136-6
Investigators studied the mechanism by which mono-unsaturated fatty acids (MUFAs) extend longevity. They found that MUFAs upregulated the number of lipid droplets in fat storage tissues of Caenorhabditis elegans, and increased lipid droplets are necessary for MUFA-induced longevity and predicted remaining lifespan. Lipidomics data revealed that MUFAs modify the ratio of membrane lipids and ether lipids, which leads to decreased lipid oxidation in middle-aged individuals. MUFAs also upregulate peroxisome number. A targeted screen revealed that induction of both lipid droplets and peroxisomes is optimal for longevity. This study opens new interventive avenues to delay aging. Supported by ORIP (S10OD025004, S10OD028536, P40OD010440), NIA, NCCIH, NIDDK, and NHGRI.
Tenth Aquatic Models of Human Disease Conference 2022 Workshop Report: Aquatics Nutrition and Reference Diet Development
Sharpton et al., Zebrafish. 2023.
https://pubmed.ncbi.nlm.nih.gov/38117219/
Standard reference diets (SRDs) for aquatic model organisms, vital for supporting scientific rigor and reproducibility, are yet to be adopted. At this workshop, the authors presented findings from a 7-month diet test study conducted across three aquatic research facilities: Zebrafish International Resource Center (University of Oregon), Kent and Sharpton laboratories (Oregon State University), and Xiphophorus Genetic Stock Center (Texas State University). They compared the effects of two commercial diets and a suggested zebrafish SRD on general fish husbandry, microbiome composition, and health in three fish species (zebrafish, Xiphophorus, and medaka), and three zebrafish wild-type strains. They reported outcomes, gathered community feedback, and addressed the aquatic research community's need for SRD development. Discussions underscored the influence of diet on aquatic research variability, emphasizing the need for SRDs to control cross-experiment and cross-laboratory reproducibility. Supported by ORIP (P40OD011021, R24OD011120, and R24OD010998) and NICHD.
Age-Associated DNA Methylation Changes in Xenopus Frogs
Morselli et al., Epigenetics. 2023.
https://www.tandfonline.com/doi/full/10.1080/15592294.2023.2201517
Age-associated changes in DNA methylation have not been characterized yet in amphibians, which include widely studied model organisms. Here the authors present clear evidence that the aquatic vertebrate species Xenopus tropicalis displays patterns of age-associated changes in DNA methylation. Whole-genome bisulfite sequencing profiles from skin samples of frogs representing young, mature, and old adults demonstrated that many of the methylation features and changes they observed are consistent with what is known in mammalian species, suggesting that the mechanism of age-related changes is conserved. The results of this study will allow researchers to leverage the unique resources available for Xenopus to study how DNA methylation relates to other hallmarks of aging. Supported by ORIP (P40OD010997, R24OD031956, R24OD030008) and NICHD.
Effects of Pulsatile Intravenous Follicle-Stimulating Hormone Treatment on Ovarian Function in Women With Obesity
Luu et al., Fertility and Sterility. 2023.
https://pubmed.ncbi.nlm.nih.gov/37276947/
By performing intravenous (IV) administration of pulsatile recombinant follicle-stimulating hormone (FSH), researchers established conditions for effective hypothalamic suppression in women with normal and high body mass index (BMI). In women with obesity, the treatment resulted in E2 and inhibin B levels comparable to those in normal-weight women. This work offers a potential strategy to mitigate some of the adverse effects of high BMI on fertility, assisted reproduction, and pregnancy outcomes. Supported by ORIP (K01OD026526), NIA, and NICHD.
A Defect in Mitochondrial Fatty Acid Synthesis Impairs Iron Metabolism and Causes Elevated Ceramide Levels
Dutta et al., Nature Metabolism. 2023.
https://pubmed.ncbi.nlm.nih.gov/37653044/
Human mitochondrial enoyl coenzyme A reductase (Mecr), required for the last step of mitochondrial fatty acid synthesis (mtFAS), is linked to pediatric-onset neurodegeneration, but with unknown mechanisms. Researchers investigated phenotypes of mecr mutants in Drosophila and human-derived fibroblasts. They found that loss of function of Mecr in the whole body resulted in a defect in Fe-S cluster biogenesis and increased iron levels, leading to elevated ceramide levels and lethality in flies. Similar elevated ceramide levels and impaired iron homeostasis were observed human-derived fibroblasts with Mecr deficiency. Neuronal loss of Mecr led to progressive neurodegeneration in flies. This study pointed out a mechanistic link between mtFAS and neurodegeneration through Mecr. Supported by ORIP (R24OD022005, R24OD031447), NICHD, and NINDS.
Intestinal Microbiota Controls Graft-Versus-Host Disease Independent of Donor–Host Genetic Disparity
Koyama et al., Immunity. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480848/
Allogeneic hematopoietic stem cell transplantation is a curative therapy for hematopoietic malignancies and non-malignant diseases, but acute graft-versus-host disease (GVHD) remains a serious complication. Specifically, severe gut GVHD is the major cause of transplant-related mortality. Here, the authors show that genetically identical mice, sourced from different vendors, had distinct commensal bacterial compositions, which resulted in significantly discordant severity in GVHD. These studies highlight the importance of pre-transplant microbiota composition for the initiation and suppression of immune-mediated pathology in the gastrointestinal tract, demonstrating the impact of non-genetic environmental determinants to transplant outcome. Supported by ORIP (S10OD028685), NIA, NCI, and NHLBI.
SALL1 Enforces Microglia-Specific DNA Binding and Function of SMADs to Establish Microglia Identity
Fixsen et al., Nature Immunology. 2023.
https://doi.org/10.1038/s41590-023-01528-8
Microglia function is thought to play a role in neurodevelopmental, psychiatric, and neurodegenerative diseases. Using knockout mice, investigators explored functional interactions between spalt-like transcription factor 1 (SALL1) and SMAD4, which demonstrated that interactions are mediated by a conserved microglia-specific SALL1 super-enhancer and result in direct activation of regulatory elements. The concerted interactions induce a microglia lineage determining program of gene expression. These findings indicate that expression of SALL1 and associated genes could contribute to phenotypes of aging and neurodegenerative diseases. Supported by ORIP (S10OD026929), NIA, NIMH, and NINDS.