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Gut Germinal Center Regeneration and Enhanced Antiviral Immunity by Mesenchymal Stem/Stromal Cells
Weber et al., JCI Insight. 2021.
https://doi.org/10.1172/jci.insight.149033
Researchers investigated the effects of mesenchymal stem/stromal cell (MSC) infusions on gut mucosal recovery, antiviral immunity, and viral suppression in SIV-infected rhesus macaques. MSC treatment heightened virus-specific responses and reduced viral load. Clearance of SIV-positive cells from gut mucosal effector sites was correlated with regeneration of germinal centers, restoration of follicular B cells and T follicular helper cells, and enhanced antigen presentation by viral trapping within the follicular dendritic cell network. These changes were associated with enhanced gene expression for type I/II interferon signaling, B cell proliferation, and interleukin 7. MSC treatment also activated metabolic pathways associated with enhanced immunity and viral reduction. Supported by ORIP (P51OD011107) and NIAID.
In Vitro and In Vivo Functions of SARS-CoV-2 Infection-Enhancing and Neutralizing Antibodies
Li et al., Cell. 2021.
https://doi.org/10.1016/j.cell.2021.06.021
Antibody-dependent enhancement of infection is a concern for clinical use of antibodies. Researchers isolated neutralizing antibodies against the receptor-binding domain (RBD) or N-terminal domain (NTD) of SARS-CoV-2 spike from COVID-19 patients. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific binding modes. RBD and NTD antibodies mediated both neutralization and infection enhancement in vitro. However, infusion of these antibodies into mice or macaques resulted in suppression of virus replication, demonstrating that antibody-enhanced infection in vitro does not necessarily predict enhanced infection in vivo. RBD-neutralizing antibodies having cross-reactivity against coronaviruses were protective against SARS-CoV-2, the most potent of which was DH1047. Supported by ORIP (P40OD012217, U42OD021458, S10OD018164), NIAID, NCI, NIGMS, and NIH Common Fund.
Thioesterase Superfamily Member 1 Undergoes Stimulus-Coupled Conformational Reorganization to Regulate Metabolism in Mice
Li et al., Nature Communications. 2021.
https://doi.org/10.1038/s41467-021-23595-x
Thermogenesis is suppressed in brown adipose tissue by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase. Them1 is highly upregulated by cold ambient temperature, where it reduces fatty acid availability and limits thermogenesis. Investigators show that Them1 regulates metabolism by undergoing conformational changes in response to β-adrenergic stimulation that alter Them1 intracellular distribution. Them1 forms metabolically active puncta near lipid droplets and mitochondria. Upon stimulation, Them1 is phosphorylated at the N-terminus, inhibiting puncta formation and activity, and resulting in a diffuse intracellular localization. Investigators show that Them1 puncta are biomolecular condensates that are inhibited by phosphorylation. Them1 forms intracellular biomolecular condensates that limit fatty acid oxidation and suppress thermogenesis. When energy is demanded, the condensates are disrupted by phosphorylation to allow for maximal thermogenesis. The stimulus-coupled reorganization of Them1 provides fine-tuning of thermogenesis and energy expenditure. Supported by ORIP (S10OD019988) and others.
Loss of Gap Junction Delta-2 (GJD2) Gene Orthologs Leads to Refractive Error in Zebrafish
Quint et al., Communications Biology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34083742/
Myopia is the most common developmental disorder of juvenile eyes. Although little is known about the functional role of GJD2 in refractive error development, the authors find that depletion of gjd2a (Cx35.5) or gjd2b (Cx35.1) orthologs in zebrafish cause changes in eye biometry and refractive status. Their immunohistological and scRNA sequencing studies show that Cx35.5 (gjd2a) is a retinal connexin; its depletion leads to hyperopia and electrophysiological retina changes. They found a lenticular role; lack of Cx35.1 (gjd2b) led to a nuclear cataract that triggered axial elongation. The results provide functional evidence of a link between gjd2 and refractive error. Supported by ORIP (R24OD026591), NIGMS, and NINDS.
Neutralizing Antibody Vaccine for Pandemic and Pre-Emergent Coronaviruses
Saunders et al., Nature. 2021.
https://doi.org/10.1038/s41586-021-03594-0
SARS-CoV-2 is a new member of the betacoronavirus (beta-CoV) genus, which also includes two common mild beta-CoVs and the life-threatening SARS-CoV-1 and MERS-CoV. Vaccines that elicit protective immunity against SARS-CoV-2 and beta-CoVs that circulate in animals could prevent future pandemics. Researchers designed a novel 24-mer SARS-CoV-2 receptor binding domain-sortase A conjugated nanoparticle vaccine (RBD-scNP). Investigators demonstrated that the immunization of macaques with RBD-scNP, and adjuvanted with 3M-052 and alum, elicits cross-neutralizing antibody responses against bat coronaviruses, SARS-CoV, and multiple SARS-CoV-2 variants of concern. This pioneering approach serves as a multimeric protein platform for the further development of generalized anti-beta-CoV vaccines. Supported by ORIP (U42OD021458), NIAID, and NCI.
Single-Cell Protein Activity Analysis Identifies Recurrence-Associated Renal Tumor Macrophages
Obradovic et al., Cell. 2021.
https://doi.org/10.1016/j.cell.2021.04.038
Post-surgery course of clear cell renal carcinoma (ccRCC) is mixed because of the heterogeneity of the disease. Using high-performance computing cluster and storage systems, investigators established an inclusive ccRCC tumor microenvironment (TME) map by using single-cell RNA sequencing data of subpopulations of tumor and tumor-adjacent tissues. Analysis of the data identified key TME subpopulations as well as their master regulators and candidate cell-cell interactions, revealing clinically relevant cell populations. Specifically, the study uncovered a tumor-specific macrophage subpopulation, validated by spatially resolved, quantitative multispectral immunofluorescence. In a large clinical validation cohort, markers of this subpopulation were significantly enriched in tumors from patients who recurred following surgery. Supported by ORIP (S10OD012351, S10OD021764) and others.
Algorithms Underlying Flexible Phototaxis in Larval Zebrafish
Chen et al., Journal of Experimental Biology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34027982/
Given that physiological and environmental variables undergo constant fluctuations over time, how do biological control systems maintain control over these values? The authors demonstrate that larval zebrafish use phototaxis to maintain environmental luminance at a set point, that the value of this set point fluctuates on a time scale of seconds when environmental luminance changes, and it is determined by calculating the mean input across both sides of the visual field. Feedback from the surroundings drives allostatic changes to the luminance set point. The authors describe a novel behavioral algorithm with which larval zebrafish exert control over a sensory variable. Supported by ORIP (R43OD024879, R44OD024879) and NINDS.
Nonhuman Primate Models for SARS-CoV-2 Research: Cryopreservation as a Means to Maintain Critical Models and Enhance the Genetic Diversity of Colonies
Arnegard and Hild et al., Lab Animal. 2021.
https://doi.org/10.1038/s41684-021-00792-1
This commentary, written by ORIP staff, addresses the need for improved cryopreservation methods and resources for nonhuman primate (NHP) gametes and embryos to safeguard newly developed NHP models and enhance the genetic diversity of NHP colonies without reliance on animal importations. Cryopreservation also plays critical roles in medical approaches to preserve the fertility of patients who must undergo potentially gonadotoxic treatments, as well as nascent genome editing efforts to develop new NHP models for human diseases. Given these diverse benefits to research progress, ORIP continues to fund the development of cryopreservation tools and approaches for NHPs and other animal models.
Cryopreservation and Preparation of Thawed Spermatozoa from Rhesus Macaques (Macaca mulatta) for In Vitro Fertilization
De Carvalho et al., Journal of the American Association for Laboratory Animal Science. 2021.
https://www.ingentaconnect.com/content/aalas/jaalas/pre-prints/content-jaalas-20-000028
Optimizing procedures for cryopreservation and subsequent thawing for rhesus macaques is required to prevent cryodamage that negatively impacts artificial insemination and in vitro fertilization rates. Investigators systematically assessed two cryopreservation methods and four recovery methods in three interdependent experiments. Results demonstrated that slow-freezing, coupled with density gradient centrifugation provided the highest efficacy in functional sperm for in vitro use. Additional studies are required to further optimize sperm cryopreservation in rhesus macaques. Supported by ORIP (P51OD011092).
Combining In Vivo Corneal Confocal Microscopy With Deep Learning-Based Analysis Reveals Sensory Nerve Fiber Loss in Acute Simian Immunodeficiency Virus Infection
McCarron et al., Cornea. 2021.
https://doi.org/10.1097/ICO.0000000000002661
Researchers characterized corneal subbasal nerve plexus features of normal and simian immunodeficiency virus (SIV)-infected pigtail and rhesus macaques using in vivo confocal microscopy and a deep learning approach for automated assessments. Corneal nerve fiber length and fractal dimension measurements did not differ between species, but pigtail macaques had significantly higher baseline corneal nerve fiber tortuosity than rhesus macaques. Acute SIV infection induced decreased corneal nerve fiber length and fractal dimension in the pigtail macaque model for HIV. Adapting deep learning analyses to clinical corneal nerve assessments will improve monitoring of small sensory nerve fiber damage in numerous clinical contexts, including HIV. Supported by ORIP (U42OD013117) and NINDS.