Selected Grantee Publications
Persistence of a Skewed Repertoire of NK Cells in People With HIV-1 on Long-Term Antiretroviral Therapy
Anderko et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38551350
HIV-1 infection alters the natural killer (NK) cell phenotypic and functional repertoire. A rare population of FcRγ−NK cells exhibiting characteristics of traditional immunologic memory expands in people with HIV. In a longitudinal analysis during the first 4 years of antiretroviral therapy (ART), a skewed repertoire of cytokine unresponsive FcRγ−memory-like NK cells persisted in people with HIV, and surface expression of CD57 and KLRG1 increased, suggesting progression toward immune senescence. These traits were linked to elevated serum inflammatory biomarkers and increasing antibody titers to human cytomegalovirus (CMV), with human CMV viremia detected in approximately one-third of people studied during the first 4 years of ART. About 40% of people studied displayed atypical NK cell subsets, representing intermediate stages of NK-poiesis. These findings indicate that NK cell irregularities persist in people with HIV despite long-term ART. Supported by ORIP (P51OD011132, S10OD026799), NIAID, and NHLBI.
A Revamped Rat Reference Genome Improves the Discovery of Genetic Diversity in Laboratory Rats
de Jong, Cell Genomics. 2024.
https://www.cell.com/cell-genomics/fulltext/S2666-979X(24)00069-7
Rattus norvegicus has been used in many fields of study related to human disease; its genome was sequenced shortly after the genomes of Homo sapiens and Mus musculus. Investigators report extensive analyses of the improvements in mRatBN7.2, compared with the previous version. They conducted a broad analysis of a whole-genome sequencing data set of 163 samples from 120 inbred rat strains and substrains. Several additional resources have been created. This new assembly and its associated resources create a more solid platform for research on the many dimensions of physiology, behavior, and pathobiology of rats and can provide more reliable and meaningful translation of findings to human populations. Supported by ORIP (R24OD024617), NHGRI, NHLBI, and NIDA.
Surgical Protocol for Partial Heart Transplantation in Growing Piglets
Medina, World Journal for Pediatric and Congenital Heart Surgery. 2024.
https://pubmed.ncbi.nlm.nih.gov/38780414/
Researchers are interested in using partial heart transplantation (i.e., only the part of the heart containing the necessary heart valve is transplanted) to deliver growing heart valve implants. This novel technique allows partial heart transplants to grow, similar to the valves in heart transplants. More work is needed, however, to understand the underlying biological mechanisms of this approach and achieve progress in clinical care. In the present study, the authors present a surgical protocol for partial heart transplantation in growing piglets. This model will enable other researchers to seek fundamental knowledge about the nature of partial heart transplants. Supported by ORIP (U42OD011140) and NHLBI.
Ultrasoft Platelet-Like Particles Stop Bleeding in Rodent and Porcine Models of Trauma
Nellenbach et al., Science Translational Medicine. 2024.
https://www.science.org/doi/10.1126/scitranslmed.adi4490
Platelet transfusions are the current standard of care to control bleeding in patients following acute trauma, but their use is limited by short shelf life and limited supply. Immunogenicity and contamination risks also are a concern. Using ultrasoft and highly deformable nanogels coupled to fibrin-specific antibody fragments, researchers developed synthetic platelet-like particles (PLPs) as an alternative for immediate treatment of uncontrolled bleeding. They report that PLPs reduced bleeding and facilitated healing of injured tissue in mice, rat, and swine models (sex not specified) for traumatic injury. These findings can inform further translational studies of synthetic PLPs for the treatment of uncontrolled bleeding in a trauma setting. Supported by ORIP (T32OD011130) and NHLBI.
Obesity Causes Mitochondrial Fragmentation and Dysfunction in White Adipocytes Due to RalA Activation
Xia et al., Nature Metabolism. 2024.
https://pubmed.ncbi.nlm.nih.gov/38286821/
This study presents a molecular mechanism for mitochondrial dysfunction as a characteristic trait of obesity. Chronic activation of the small GTPase RalA in inguinal white adipocytes (iWAT), in male mice fed a high-fat diet (HFD) represses energy expenditure by shifting mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction. Targeted deletion of RalA in iWAT attenuated HFD-induced obesity due to increased energy expenditure and mitochondrial oxidative phosphorylation. Mechanistically, RalA dephosphorylates inhibitory Serine637 on fission protein Drp1, leading to excessive fission in adipocytes and mitochondrial fragmentation. Expression of a human homolog of Drp1—DNM1L—in adipose tissue is positively correlated with obesity and insulin resistance. These findings open avenues to investigate RalA-Drp1 axis in energy homeostasis. Supported by ORIP (S10OD023527), NCI, NHLBI, and NIDDK.
Macrophages Derived From Human Induced Pluripotent Stem Cells (iPSCs) Serve As a High-Fidelity Cellular Model for Investigating HIV-1, Dengue, and Influenza viruses
Yang et al., Journal of Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38323811/
Macrophages can be weaponized by viruses to host viral reproduction and support long-term persistence. The most common way of studying these cells is by isolating their precursors from donor blood and differentiating the isolated cells into macrophages. This method is costly and technically challenging, and it produces varying results. In this study, researchers confirmed that macrophages derived from iPSC cell lines—a model that is inexpensive, consistent, and modifiable by genome editing—are a suitable model for experiments involving HIV and other viruses. Macrophages derived from iPSCs are as susceptible to infection as macrophages derived from blood, with similar infection kinetics and phenotypes. This new model offers researchers an unlimited source of cells for studying viral biology. Supported by ORIP (R01OD034046, S10OD021601), NIAID, NIDA, NIGMS, and NHLBI.
De Novo Variants in FRYL Are Associated With Developmental Delay, Intellectual Disability, and Dysmorphic Features
Pan et al., The American Journal of Human Genetics. 2024.
https://www.cell.com/ajhg/fulltext/S0002-9297(24)00039-9
FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans, and its functions in mammals are largely unknown. Investigators report 13 individuals who have de novo heterozygous variants in FRYL and one individual with a heterozygous FRYL variant that is not confirmed to be de novo. The individuals present with developmental delay; intellectual disability; dysmorphic features; and other congenital anomalies in cardiovascular, skeletal, gastrointestinal, renal, and urogenital systems. Using fruit flies, investigators provide evidence that haploinsufficiency in FRYL likely underlies a disorder in humans with developmental and neurological symptoms. Supported by ORIP (U54OD030165), NHLBI, NICHD, and NCATS.
Newly Identified Roles for PIEZO1 Mechanosensor in Controlling Normal Megakaryocyte Development and in Primary Myelofibrosis
Abbonante et al., American Journal of Hematology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38165047/
Mechanisms through which mature megakaryocytes (Mks) and their progenitors sense the bone marrow extracellular matrix to promote lineage differentiation are only partially understood. The authors report that PIEZO1, a mechanosensitive cation channel, is expressed in mouse and human Mks, and activation of PIEZO1 increased the number of immature Mks in mice. Piezo1/2 knockout mice show an increase in Mk size and platelet count, both at basal state and upon marrow regeneration. Together, these data suggest that PIEZO1 places a brake on Mk maturation and platelet formation in physiology, and its upregulation might contribute to aggravating disease. Supported by ORIP (K01OD025290), NHGRI, NHLBI, and NCATS.
Stable HIV Decoy Receptor Expression After In Vivo HSC Transduction in Mice and NHPs: Safety and Efficacy in Protection From SHIV
Li, Molecular Therapy. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10124088/
Autologous hematopoietic stem cell (HSC) gene therapy offers a promising HIV treatment strategy, but cost, complexity, and toxicity remain significant challenges. Using female mice and female nonhuman primates (NHPs) (i.e., rhesus macaques), researchers developed an approach based on the stable expression of eCD4-Ig, a secreted decoy protein for HIV and simian–human immunodeficiency virus (SHIV) receptors. Their goals were to (1) assess the kinetics and serum level of eCD4-Ig, (2) evaluate the safety of HSC transduction with helper-dependent adenovirus–eCD4-Ig, and (3) test whether eCD4-Ig expression has a protective effect against viral challenge. They found that stable expression of the decoy receptor was achieved at therapeutically relevant levels. These data will guide future in vivo studies. Supported by ORIP (P51OD010425) and NHLBI.
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.