Selected Grantee Publications
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- S10 [SIG, BIG, HEI]
Effect of Metabolic Status on Response to SIV Infection and Antiretroviral Therapy in Nonhuman Primates
Webb et al., JCI Insight. 2024.
https://pubmed.ncbi.nlm.nih.gov/39115937
This study examines how metabolic health influences the efficacy of antiretroviral therapy (ART). Using lean and obese male rhesus macaques, researchers explored the progression of simian immunodeficiency virus (SIV) infection. Obese macaques with metabolic dysfunction experienced more rapid disease progression and had a diminished response to ART than lean macaques. This study suggests metabolic health plays a significant role in HIV progression and treatment outcomes, highlighting the importance of managing metabolic conditions in people with HIV. Supported by ORIP (P51OD011092, S10OD025002), NIAID, and NIDDK.
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.
Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression
Hasselluhn et al., Cancer Discovery. 2024.
https://pubmed.ncbi.nlm.nih.gov/37966260/
This study presents a key mechanism that prevents pancreatic ductal adenocarcinoma (PDAC) from undergoing neoangiogenesis, which affects its development, pathophysiology, metabolism, and treatment response. Using human and murine PDAC explants, which effectively retain the complex cellular interactions of native tumor tissues, and single-cell regulatory network analysis, the study identified a cascade of three paracrine pathways bridging between multiple cell types and acting sequentially, Hedgehog to WNT to VEGF, as a key suppressor of angiogenesis in KRAS-mutant PDAC cells. This study provides an experimental paradigm for dissecting higher-order cellular interactions in tissues and has implications for PDAC treatment strategies. Supported by ORIP (S10OD012351, S10OD021764), NCI, and NIDDK.
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.
Enhanced IL-17 Producing and Maintained Cytolytic Effector Functions of Gut Mucosal CD161+ CD8+ T Cells in SIV-Infected Rhesus Macaques
Thirugnanam et al., Viruses. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10535321/
HIV infection is associated with the depletion of CD161-expressing CD4+ Th17 cells, but the effects on other IL-17–producing T cell subsets are not understood fully. Researchers characterized the functions of non-invariant CD161-expressing CD8+ T cell subpopulations in peripheral blood and mucosal tissues of rhesus macaques (sex not specified) during chronic simian immunodeficiency virus (SIV) infection. They demonstrated that cell frequencies and function were unaffected by infection, but enhanced IL-17 production capacity and sustained Th1-type and cytolytic functions were observed. This work suggests that CD161-expressing CD8+ T cells might have important functions in gut mucosal immunity during chronic HIV infection. Supported by ORIP (P51OD011104, S10OD026800), NIAID, NIDDK, and NIMH.
CD8+ T Cells Promote HIV Latency by Remodeling CD4+ T Cell Metabolism to Enhance Their Survival, Quiescence, and Stemness
Mutascio et al., Immunity. 2023.
https://www.doi.org/10.1016/j.immuni.2023.03.010
An HIV reservoir persists following antiretroviral therapy, representing the main barrier to an HIV cure. Using a validated in vitro model, investigators explored the mechanism by which CD8+ T cells promote HIV latency and inhibit latency reversal in HIV-infected CD4+ T cells. They reported that CD8+ T cells favor the establishment of HIV latency by modulating metabolic, stemness, and survival pathways that correlate with the downregulation of HIV expression and promote HIV latency. In future studies, comparative analyses may provide insight into common molecular mechanisms in the silencing of HIV expression by CD8+ T cells and macrophages, which can be applied to new intervention strategies that target the HIV reservoir. Supported by ORIP (P51OD011132, S10OD026799), NIAID, NIDDK, NIDA, NHLBI, and NINDS.
Hematopoietic Stem Cells Preferentially Traffic Misfolded Proteins to Aggresomes and Depend on Aggrephagy to Maintain Protein Homeostasis
Chua et al., Cell Stem Cell. 2023.
https://pubmed.ncbi.nlm.nih.gov/36948186/
Investigators studied the mechanism of hematopoietic stem cells (HSCs) being dependent on managing proteostasis. Their findings demonstrated that HSCs preferentially depend on aggrephagy, a form of autophagy, to maintain proteostasis. When aggrephagy is disabled, HSCs compensate by increasing proteasome activity, but proteostasis is ultimately disrupted as protein aggregates accumulate and HSC function is impaired. The investigators also showed that Bag3 deficiency blunts aggresome formation in HSCs, resulting in protein aggregate accumulation, myeloid-biased differentiation, and diminished self-renewal activity, thus demonstrating Bag3 as a regulator of HSC proteostasis. HSC aging is associated with loss of aggresomes and reduced autophagic flux. Protein degradation pathways are thus configured in young-adult HSCs to preserve proteostasis and fitness but become dysregulated during aging. Supported by ORIP (S10OD032316, S10OD021831), NCI, and NIDDK.
Elevated Transferrin Receptor Impairs T Cell Metabolism and Function in Systemic Lupus Erythematosus
Voss et al., Science Immunol. 2023.
https://www.science.org/doi/10.1126/sciimmunol.abq0178
Systemic lupus erythematosus (SLE) is an autoimmune disease in which dysfunctional T cells exhibit abnormalities in metabolism. Investigators performed a CRISPR screen to examine mechanisms associated with the role of excess iron in dysfunctional T cells. The transferrin receptor (CD71) was identified as differentially critical for Type 1 T helper cells and inhibitory for induced regulatory T cells. Activated T cells induced CD71 and iron uptake, which was exaggerated in SLE-prone T cells. Disease severity correlated with CD71 expression in cells from male and female patients with SLE, and blocking CD71 in vitro enhanced interleukin 10 secretion. These findings suggest that T cell iron uptake via CD71 contributes to T cell dysfunction and can be targeted to limit SLE-associated pathology. Supported by ORIP (S10OD030264), NIAID, NCI, and NIDDK.
Gut Microbiome Dysbiosis in Antibiotic-Treated COVID-19 Patients Is Associated with Microbial Translocation and Bacteremia
Bernard-Raichon et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-33395-6
The investigators demonstrated that SARS-CoV-2 infection induced gut microbiome dysbiosis in male mice. Samples collected from human COVID-19 patients of both sexes also revealed substantial gut microbiome dysbiosis. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicated that bacteria might translocate from the gut into the systemic circulation of COVID-19 patients. These results were consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19. Supported by ORIP (S10OD021747), NCI, NHLBI, NIAID, and NIDDK.
Distinct Metabolic States Guide Maturation of Inflammatory and Tolerogenic Dendritic Cells
Adamik et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32849-1
The investigators mapped single-cell metabolic states and immune profiles of inflammatory and tolerogenic monocytic dendritic cells using recently developed multiparametric approaches. Activation scores revealed simultaneous engagement of multiple metabolic pathways in distinct monocytic dendritic cell differentiation stages (e.g., rapid reprogramming of glycolytic monocytes and transient co-activation of mitochondrial pathways followed by maturation of dendritic cells). This data set provides insights into metabolic pathways that affect the immune profiles of human dendritic cells. Supported by ORIP (S10OD026940) and NIDDK.