Selected Grantee Publications
RNA Landscapes of Brain and Brain-Derived Extracellular Vesicles in Simian Immunodeficiency Virus Infection and Central Nervous System Pathology
Huang et al., The Journal of Infectious Diseases. 2024.
https://pubmed.ncbi.nlm.nih.gov/38079216/
Brain tissue–derived extracellular vesicles (bdEVs) act locally in the central nervous system (CNS) and may indicate molecular mechanisms in HIV CNS pathology. Using brain homogenate (BH) and bdEVs from male pigtailed macaques, researchers identified dysregulated RNAs in acute and chronic infection. Most dysregulated messenger RNAs (mRNAs) in bdEVs reflected dysregulation in source BH, and these mRNAs are disproportionately involved in inflammation and immune responses. Additionally, several circular RNAs were differentially abundant in source tissue and might be responsible for specific differences in small RNA levels in bdEVs during simian immunodeficiency virus (SIV) infection. This RNA profiling shows potential regulatory networks in SIV infection and SIV-related CNS pathology. Supported by ORIP (U42OD013117), NCI, NIAID, NIDA, NIMH, and NINDS.
Time of Sample Collection Is Critical for the Replicability of Microbiome Analyses
Allaband et al., Nature Metabolism. 2024.
https://pubmed.ncbi.nlm.nih.gov/38951660/
Lack of replicability remains a challenge in microbiome studies. As the microbiome field moves from descriptive and associative research to mechanistic and interventional studies, being able to account for all confounding variables in the experimental design will be critical. Researchers conducted a retrospective analysis of 16S amplicon sequencing studies in male mice. They report that sample collection time affects the conclusions drawn from microbiome studies. The lack of consistency in the time of sample collection could help explain poor cross-study replicability in microbiome research. The effect of diurnal rhythms on the outcomes and study designs of other fields is unknown but is likely significant. Supported by ORIP (T32OD017863), NCATS, NCI, NHLBI, NIAAA, NIAID, NIBIB, NIDDK, and NIGMS.
Integrin αvβ3 Upregulation in Response to Nutrient Stress Promotes Lung Cancer Cell Metabolic Plasticity
Nam, Cancer Research. 2024.
https://pubmed.ncbi.nlm.nih.gov/38588407/
Tumor-initiating cells can survive in harsh environments via stress tolerance and metabolic flexibility; studies on this topic can yield new targets for cancer therapy. Using cultured cells and live human surgical biopsies of non-small cell lung cancer, researchers demonstrated that nutrient stress drives a metabolic reprogramming cascade that allows tumor cells to thrive despite a nutrient-limiting environment. This cascade results from upregulation of integrin αvβ3, a cancer stem cell marker. In mice, pharmacological or genetic targeting prevented lung cancer cells from evading the effects of nutrient stress, thus blocking tumor initiation. This work suggests that this molecular pathway leads to cancer stem cell reprogramming and could be linked to metabolic flexibility and tumor initiation. Supported by ORIP (K01OD030513), NCI, NIGMS, and NINDS.
Transcriptome- and Proteome-Wide Effects of a Circular RNA Encompassing Four Early Exons of the Spinal Muscular Atrophy Genes
Luo, Scientific Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/38714739/
Spinal muscular atrophy (SMA) is a leading genetic cause of mortality in infants and often results from a deficiency of deletions of or mutations in the SMN1 gene. In this study, researchers report the transcriptome- and proteome-wide effects of overexpression of C2A‑2B3-4, a circular RNA produced by SMN1 and SMN2, in cells. They report that C2A-2B-3-4 is associated with expression of genes associated with chromatin remodeling, transcription, spliceosome function, ribosome biogenesis, lipid metabolism, cytoskeletal formation, cell proliferation, and neuromuscular junction formation. More work is needed to investigate the role of these genes in processes associated with SMA and other pathological conditions, including cancer and male infertility. Supported by ORIP (T35OD027967) and NINDS.
Potent HPIV3-Neutralizing IGHV5-51 Antibodies Identified from Multiple Individuals Show L Chain and CDRH3 Promiscuity
Abu-Shmais et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38488511/
Human parainfluenza virus 3 fusion glycoprotein (HPIV3 F), responsible for facilitating viral entry into host cells, is a major target of neutralizing antibodies that inhibit infection. More work is needed to understand these dynamics. Researchers characterized the genetic signatures, epitope specificity, neutralization potential, and publicness of HPIV3-specific antibodies identified across multiple individuals. From this work, they identified 12 potently neutralizing antibodies targeting three nonoverlapping epitopes on HPIV3 F. Six of the antibodies used immunoglobulin heavy variable gene, IGHV 5-51. These antibodies used different L chain variable genes (VL) and diverse H chain CDR 3 (CDRH3) sequences. These findings help elucidate the genetic and functional characteristics of HPIV3-neutralizing antibodies and indicate the existence of a reproducible H chain variable–dependent antibody response associated with VL and CDRH3 promiscuity. Supported by ORIP (K01OD036063), NCATS, NCI, NEI, NIAID, and NIDDK.
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.
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.
Cdk8/CDK19 Promotes Mitochondrial Fission Through Drp1 Phosphorylation and Can Phenotypically Suppress Pink1 Deficiency in Drosophila
Liao et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-47623-8
Pink1 is a mitochondrial kinase implicated in Parkinson’s disease and is conserved among humans, rodents, and flies. In this study, researchers found that Cdk8 in Drosophila (i.e., the orthologue of vertebrate CDK8 and CDK19) promotes the phosphorylation of Drp1 (i.e., a protein required for mitochondrial fission) at the same residue as Pink1. Cdk8 is expressed in both the cytoplasm and nucleus, and neuronal loss of Cdk8 reduces fly life span and causes bang sensitivity and elongated mitochondria in both muscles and neurons. Overexpression of Cdk8 suppresses elevated levels of reactive oxygen species, mitochondrial dysmorphology, and behavioral defects in flies with low levels of Pink1. These findings suggest that Cdk8 regulates Drp1-mediated mitochondrial fission in a similar manner as Pink1 and may contribute to the development of Parkinson’s disease. Supported by ORIP (R24OD022005, R24OD031447, P40OD018537, P40OD010949), NICHD, and NINDS.
SHIV-C109p5 NHP Induces Rapid Disease Progression in Elderly Macaques with Extensive GI Viral Replication
Bose et al., Journal of Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38299866/
Researchers are interested in developing animal models infected with simian–human immunodeficiency virus (SHIV) to better understand prevention of HIV acquisition. Researchers generated pathogenic SHIV clade C transmitted/founder stock by in vivo passage using geriatric rhesus macaques of both sexes. They reported that the infection resulted in high sustained viral loads and induced rapid pathology and wasting, necessitating euthanasia between 3 and 12 weeks post-infection. The extensive viral replication in gut and lymphoid tissues indicated a fit viral stock. This work provides a new nonhuman primate model for HIV pathogenicity and cure studies. Supported by ORIP (R24OD010947) 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.