Selected Grantee Publications
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.
CD8+ T Cells Control SIV Infection Using Both Cytolytic Effects and Non-Cytolytic Suppression of Virus Production
Policicchio et al., Nature Communications. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10589330/
HIV continuously evades and subdues the host immune responses through multiple strategies, and an understanding of these strategies can help inform research efforts. Using a mathematical model, investigators assessed whether CD8+ cells from male rhesus macaques exert a cytolytic response against infected cells prior to viral production. Their goal was to elucidate the possible mode of action of CD8+ cells on simian immunodeficiency virus (SIV)–infected cells. Models that included non‑cytolytic reduction of viral production best explained the viral profiles across all macaques, but some of the best models also included cytolytic mechanisms. These results suggest that viral control is best explained by the combination of cytolytic and non-cytolytic effects. Supported by ORIP (P40OD028116, R01OD011095), NIAID, NIDDK, and NHLBI.
A Germ-Free Humanized Mouse Model Shows the Contribution of Resident Microbiota to Human-Specific Pathogen Infection
Wahl et al., Nature Biotechnology. 2023.
https://www.nature.com/articles/s41587-023-01906-5
Germ-free (GF) mice are of limited value in the study of human-specific pathogens because they do not support their replication. In this report, investigators developed a GF humanized mouse model using the bone marrow–liver–thymus platform to provide a robust and flexible in vivo model that can be used to study the role of resident microbiota in human health and disease. They demonstrated that resident microbiota promote viral acquisition and pathogenesis by using two human-specific pathogens, Epstein–Barr virus and HIV. Supported by ORIP (P40OD010995), FIC, NIAID, NCI, and NIDDK.
Giardia Hinders Growth by Disrupting Nutrient Metabolism Independent of Inflammatory Enteropathy
Giallourou et al., Nature Communications. 2023.
https://www.nature.com/articles/s41467-023-38363-2
Giardia lamblia is one of the most common intestinal pathogens among children in low- and middle-income countries. Investigators performed translational investigations using the Malnutrition and Enteric Diseases (MAL-ED) male and female cohort, as well as mice of both sexes, to identify mechanistic pathways that might explain Giardia-induced effects on early childhood growth. They identified signatures in the urinary metabolome of young children, suggesting that host growth restriction during infection is mediated by dysregulated amino acid metabolism. Supported by ORIP (P40OD010995), NIAID, and NIDDK.
Prolonged Experimental CD4+ T-Cell Depletion Does Not Cause Disease Progression In SIV-Infected African Green Monkeys
Le Hingrat et al., Nature Communications. 2023.
https://www.nature.com/articles/s41467-023-36379-2
Chronically simian immunodeficiency virus (SIV)–infected African green monkeys (AGMs) partially recover mucosal CD4+ T cells, maintain gut integrity, and do not progress to AIDS. Investigators assessed the impact of prolonged, antibody-mediated CD4+ T cell depletion on gut integrity and natural history of SIV infection in AGMs. All circulating CD4+ T cells and more than 90% of mucosal CD4+ T cells were depleted. Plasma viral loads and cell-associated viral RNA in tissues were lower in CD4+-cell-depleted animals. CD4+-cell-depleted AGMs maintained gut integrity, controlled immune activation, and did not progress to AIDS. Therefore, CD4+ T cell depletion is not a determinant of SIV-related gut dysfunction when gastrointestinal tract epithelial damage and inflammation are absent, suggesting that disease progression and resistance to AIDS are independent of CD4+ T cell restoration in SIV-infected AGMs. Supported by ORIP (P40OD028116), NIAID, NIDDK, and NHLBI.
Reduced Alcohol Preference and Intake after Fecal Transplant in Patients with Alcohol Use Disorder Is Transmissible to Germ-Free Mice
Wolstenholme et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-34054-6
Alcohol use disorder is a major cause of reduced life expectancy worldwide, and this misuse has increased exponentially during the COVID-19 pandemic. Fecal microbiota transplant has been shown previously to reduce alcohol craving in humans with cirrhosis. Here, the investigators report that the reduction in craving and alcohol preference is transmissible to male germ-free mice only when live bacteria—and not germ-free supernatants—are used for colonization. This differential colonization was associated with alterations in the gut immune–inflammatory response through short-chain fatty acids. Supported by ORIP (P40OD010995), NIAAA, NIDDK, and NIMH.
Targeted Suppression of Human IBD-Associated Gut Microbiota Commensals by Phage Consortia for Treatment of Intestinal Inflammation
Federici et al., Cell. 2022.
https://www.doi.org/10.1016/j.cell.2022.07.003
Human gut commensals increasingly are suggested to affect noncommunicable diseases, such as inflammatory bowel disease (IBD), yet their targeted suppression remains an unmet challenge. In this report, investigators identified a clade of Klebsiella pneumoniae (Kp) strains—featuring a unique antibiotic resistance and mobilome signature—that is associated strongly with disease exacerbation and severity. Transfer of clinical IBD-associated Kp strains into colitis-prone, germ-free, and colonized mice of both sexes enhances intestinal inflammation. An orally administered combination phage therapy targeting sensitive and resistant IBD-associated Kp clade members enables effective Kp suppression, suggesting the feasibility of avoiding antibiotic resistance while effectively inhibiting noncommunicable disease–contributing pathobionts. Supported by ORIP (P40OD010995) and NIDDK.
Deep Learning Is Widely Applicable to Phenotyping Embryonic Development and Disease
Naert et al., Development. 2021.
https://pubmed.ncbi.nlm.nih.gov/34739029/
Genome editing simplifies the generation of new animal models for congenital disorders. The authors illustrate how deep learning (U-Net) automates segmentation tasks in various imaging modalities. They demonstrate this approach in embryos with polycystic kidneys (pkd1 and pkd2) and craniofacial dysmorphia (six1). They provide a library of pre-trained networks and detailed instructions for applying deep learning to datasets and demonstrate the versatility, precision, and scalability of deep neural network phenotyping on embryonic disease models. Supported by ORIP (P40OD010997, R24OD030008), NICHD, NIDDK, and NIMH.
Lipocalin-2 Is an Anorexigenic Signal in Primates
Petropoulou et al., eLife. 2020.
https://doi.org/10.7554/eLife.58949
The hormone lipocalin-2 (LCN2) suppresses food intake in mice. Researchers demonstrated that LCN2 increases after a meal and reduces hunger in people with normal weight or overweight, but not in obese individuals. The researchers also showed that LCN2 crosses the blood-brain barrier and binds to the hypothalamus in vervet monkeys. LCN2 was found to bind to the hypothalamus in human, baboon, and rhesus macaque brain sections. When injected into vervets, LCN2 suppressed food intake and lowered body weight without toxic effects in short-term experiments. These findings lay the groundwork to investigate whether LCN2 might be a useful treatment for obesity. Supported by ORIP (P40OD010965), NCATS, NIDDK, NIA, and NHLBI.