Selected Grantee Publications
Creb5 Establishes the Competence for Prg4 Expression in Articular Cartilage
Zhang et al., Communications Biology. 2021.
https://doi.org/10.1038/s42003-021-01857-0
Cells comprising the superficial zone of articular cartilage express lubricin, encoded by the Prg4 gene, that lubricates joints. Researchers identified Creb5 as a transcription factor that is required for TGF-β and EGFR signaling to induce Prg4 expression. Forced expression of Creb5 in deep-zone chondrocytes of articular cartilage confers competence for TGF-β and EGFR signals to induce Prg4 expression. The researchers showed that Creb5 directly binds to two Prg4 promoter-proximal regulatory elements, which work together with a more distal regulatory element to drive induction of Prg4 by TGF-β. Thus, Creb5 is a critical regulator of Prg4/lubricin expression in the articular cartilage. Supported by ORIP (U42OD11158), NIAMS, and NIDDK.
Natural Killer Cells Activated Through NKG2D Mediate Lung Ischemia-Reperfusion Injury
Calabrese et al., Journal of Clinical Investigation. 2021.
https://www.jci.org/articles/view/137047
Pulmonary ischemia-reperfusion injury (IRI) causes early mortality and has no effective therapies. While natural killer (NK) cells are innate lymphocytes capable of recognizing injured cells, their roles in acute lung injury are incompletely understood. Here, investigators demonstrated that NK cells were increased in frequency and cytotoxicity in 2 different IRI mouse models. They showed that NK cells trafficked to the lung tissue from peripheral reservoirs and were more mature within lung tissue. Acute lung ischemia-reperfusion injury was blunted in a NK cell–deficient mouse strain but restored with adoptive transfer of NK cells. In human lung tissue, NK cells were increased at sites of ischemia-reperfusion injury and activated NK cells were increased in prospectively-collected human bronchoalveolar lavage in subjects with severe IRI. These data support a causal role for recipient peripheral NK cells in pulmonary IRI via NK cell NKG2D receptor ligation. Therapies targeting NK cells may hold promise in acute lung injury. Supported by ORIP (S10OD026940), NHLBI, and NIDDK.
Severely Ill COVID-19 Patients Display Impaired Exhaustion Features in SARS-CoV-2-Reactive CD8+ T Cells
Kusnadi et al., Science Immunology. 2021.
https://immunology.sciencemag.org/content/6/55/eabe4782.long
How CD8+ T cells respond to SARS-CoV-2 infection is not fully known. Investigators reported on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patient cells were segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was “exhausted” or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed less cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival Nuclear Factor κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. Overall, this single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2. Supported by ORIP (S10RR027366 and S10OD025052), NIAID, NHLBI, and NIGMS.
Lung Expression of Human Angiotensin-Converting Enzyme 2 Sensitizes the Mouse to SARS-CoV-2 Infection
Han et al., American Journal of Respiratory Cell and Molecular Biology. 2021.
https://doi.org/10.1165/rcmb.2020-0354OC
A rapidly deployable mouse model that recapitulates a disease caused by a novel pathogen would be a valuable research tool during a pandemic. Researchers were able to produce C57BL/6J mice with lung expression of human angiotensin-converting enzyme 2 (hACE2), the receptor for SARS-CoV-2. They did so by oropharyngeal delivery of a recombinant human adenovirus type 5 expressing hACE2. The transduced mice were then infected with SARS-CoV-2. Thereafter, the mice developed interstitial pneumonia with perivascular inflammation, exhibited higher viral load in lungs compared to controls, and displayed a gene expression phenotype resembling the clinical response in lungs of humans with COVID-19. Supported by ORIP (P51OD011104, R21OD024931), NHLBI, and NIGMS.
Sequence Diversity Analyses of an Improved Rhesus Macaque Genome Enhance its Biomedical Utility
Warren et al., Science. 2020.
https://science.sciencemag.org/content/370/6523/eabc6617
Investigators sequenced and assembled an Indian-origin female rhesus macaque (RM) genome using a multiplatform genomics approach that included long-read sequencing, extensive manual curation, and experimental validation to generate a new comprehensive annotated reference genome. As a result, 99.7% of the gaps in the earlier draft genome are now closed, and more than 99% of the genes are represented. Whole-genome sequencing of 853 RMs of both sexes identified 85.7 million single-nucleotide variants and 10.5 million indel variants, including potentially damaging variants in genes associated with human autism and developmental delay. The improved assembly of segmental duplications, new lineage-specific genes and expanded gene families provide a framework for developing noninvasive NHP models for human disease, as well as studies of genetic variation and phenotypic consequences. Supported by ORIP (P51OD011106, P51OD011107, P51OD011132, P51OD011104, U42OD024282, U42OD010568, R24OD011173, R24OD021324, R24OD010962), NHGRI, NIMH, NHLBI, and NIGMS.
The Immune Landscape in Tuberculosis Reveals Populations Linked to Disease and Latency
Esaulova et al., Cell Host Microbe. 2020.
https://pubmed.ncbi.nlm.nih.gov/33340449/
Mycobacterium tuberculosis infection of adult rhesus macaques (RMs), predominantly males (81%), recapitulates both latent (LTBI) and active pulmonary TB (PTB) observed in humans. The immune characterization in lungs of RMs with PTB exhibited an influx of plasmacytoid dendritic cells, an interferon-responsive macrophage population, and activated T cell responses. In contrast, a CD27+ natural killer (NK) cell subset accumulated in the lungs of RMs with LTBI. This NK cell population was also detected in the circulation of humans with LTBI. This characterization of lung immune cells enhances our understanding of TB immunopathogenesis and provides potential targets for therapies and vaccines for TB control. Supported by ORIP (P51OD011104 and P51OD011133), NHLBI, and NIAID.
Imbalance of Regulatory and Cytotoxic SARS-CoV-2-Reactive CD4+ T Cells in COVID-19
Meckiff et al., Cell. 2020.
https://pubmed.ncbi.nlm.nih.gov/33096020/
It is not clear why COVID-19 is deadly in some people and mild in others. To understand the underlying mechanism, investigators studied the contribution of CD4+ T cells in immune responses to SARS-CoV-2 infection. They analyzed single-cell transcriptomic data of >100,000 viral antigen-reactive CD4+ T cells from 40 COVID-19 patients. In hospitalized patients compared to non-hospitalized patients, they found increased proportions of cytotoxic follicular helper cells (TFH) and cytotoxic T helper (TH) cells responding to SARS-CoV-2 and reduced proportion of SARS-CoV-2-reactive regulatory T cells (TREG). Importantly, in hospitalized COVID-19 patients, a strong cytotoxic TFH response was observed early in the illness, which correlated negatively with antibody levels to SARS-CoV-2 spike protein. Polyfunctional TH1 and TH17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4+ T cells compared to influenza-reactive CD4+ T cells. Together, these analyses provided insights into the gene expression patterns of SARS-CoV-2-reactive CD4+ T cells in distinct disease severities. Supported by ORIP (S10RR027366, S10OD025052), NIAID, NHLBI, and NIGMS.
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.
Estrogen Acts Through Estrogen Receptor 2b to Regulate Hepatobiliary Fate During Vertebrate Development
Chaturantabut et al., Hepatology. 2020.
https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.31184
During liver development, bipotent progenitor cells differentiate into hepatocytes and biliary epithelial cells to ensure a functional liver. The developmental cues controlling the differentiation of committed progenitors into these cell types are not completely understood. These authors report an essential role for estrogenic regulation in vertebrate liver development to affect hepatobiliary fate decisions. The studies identify17β-estradiol (E2), nuclear estrogen receptor 2b (esr2b), and downstream bone morphogenetic protein (BMP) activity as important regulators of hepatobiliary fate decisions during vertebrate liver development. These results have significant implications for liver development in infants exposed to abnormal estrogen levels or estrogenic compounds during pregnancy. Supported by ORIP (R24OD017870) and NIDDK.
Fructose Stimulated De Novo Lipogenesis Is Promoted by Inflammation
Jelena et al., Nature Metabolism. 2020.
https://pubmed.ncbi.nlm.nih.gov/32839596
Non-alcoholic fatty liver disease (NAFD) affects 30% of adult Americans. While NAFD starts as simple steatosis with little liver damage, its severe manifestation as non-alcoholic steatohepatitis (NASH) is a leading cause of liver failure, cirrhosis, and cancer. Fructose consumption is proposed to increase the risk of hepatosteatosis and NASH. Excessive intake of fructose causes barrier deterioration and low-grade endotoxemia. Using a mouse model, the study examined the mechanism of how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis. The results demonstrated that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signaling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to fatty acid in both mouse and human hepatocytes. The finding may be of relevance to several common liver diseases and metabolic disorders. Supported by ORIP (S10OD020025), NCI, NIEHS, NIDDK, NIAID, and NIAAA.