Selected Grantee Publications
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- Aquatic Vertebrate Models
- Nonhuman Primate Models
Metabolomics Analysis of Follicular Fluid Coupled With Oocyte Aspiration Reveals Importance of Glucocorticoids in Primate Periovulatory Follicle Competency
Ravisankar et al., Scientific Reports. 2021.
https://www.nature.com/articles/s41598-021-85704-6
Assisted reproductive therapy in primates requires ovarian stimulation protocols, which result in multiple heterogeneous oocytes with variable capacity for fertilization, cleavage, and blastocyst formation. Recovered oocytes from rhesus macaque follicles (n=74 follicles) were fertilized in vitro and classified as failed to cleave, cleaved but arrested, or able to form blastocysts. Metabolomics analysis of the follicular fluid identified 60 metabolites that were different among embryo classifications; key was an increase in the intrafollicular ratio of cortisol to cortisone in the blastocyst group, which was associated with translocation of the glucocorticoid receptor, NR3C1. The data suggest a role for NR3C1 in the regulation of follicular processes, such as expansion of cumulus granulosa cells, via paracrine signaling. Supported by ORIP (P51OD011092) and NICHD.
A Novel Tau-Based Rhesus Monkey Model of Alzheimer’s Pathogenesis
Beckman et al., Alzheimer’s & Dementia. 2021.
https://pubmed.ncbi.nlm.nih.gov/33734581/
Alzheimer’s disease (AD) is becoming more prevalent as the population ages, but there are no effective treatments for this devastating condition. Researchers developed a rhesus monkey model of AD by targeting the entorhinal cortex with an adeno-associated virus expressing mutant tau protein. Within 3 months they observed evidence of misfolded tau propagation, similar to what is hypothesized for AD patients. Treated monkeys developed robust alterations in AD core biomarkers in cerebrospinal fluid and blood. These results highlight the initial stages of tau seeding and propagation in rhesus macaques, a potentially powerful translational model with which to test new AD therapies. Supported by ORIP (P51OD011107) and NIA.
Virus Control in Vaccinated Rhesus Macaques Is Associated with Neutralizing and Capturing Antibodies Against the SHIV Challenge Virus but Not with V1V2 Vaccine–Induced Anti-V2 Antibodies Alone
Hessell et al., Journal of Immunology. 2021.
https://doi.org/10.4049/jimmunol.2001010
In the RV144 human immunodeficiency virus (HIV) vaccine trial, the only immune response associated with reduced infection was a high level of antibodies (Abs) targeting the second variable (V2) loop of the HIV envelope protein (Env). The mechanism underlying this suggested contribution of V2 Abs to protection remains unknown. Researchers tested the role of vaccine-induced anti-V2 Abs in rhesus macaques. Three vaccines strategies were designed to induce only V1V2 Abs before simian-human immunodeficiency virus (SHIV) challenge. Vaccine-induced V2 Abs did not independently control SHIV infection. However, neutralizing and virus capture anti-Env Abs were found to correlate with SHIV control. Supported by ORIP (P51OD011092) and NIAID.
Persistence of Viral RNA in Lymph Nodes in ART-suppressed SIV/SHIV-Infected Rhesus Macaques
Cadena et al., Nature Communications. 2021.
https://doi.org/10.1038/s41467-021-21724-0
The long-lived viral reservoir is a key obstacle to curing HIV/AIDS, yet the features of that reservoir during antiretroviral therapy (ART) remain poorly understood. Researchers undertook a comprehensive analysis of the SIV/SHIV reservoir in multiple lymphoid and non-lymphoid tissues from SIV/SHIV-infected rhesus macaques suppressed with ART for one year. Their findings support a model in which the tissue viral reservoir is rapidly and broadly seeded early during acute infection. Viral RNA persists lymphoid tissues despite a long period of suppressive ART. Therefore, viral latency does not appear to be universally transcriptionally silent; the reservoir may include a spectrum of latency depths. Supported by ORIP (R01OD024917) and NIAID.
A Chromosome-Level Genome of Astyanax mexicanus Surface Fish for Comparing Population-Specific Genetic Differences Contributing to Trait Evolution
Warren et al., Nature Communications. 2021.
https://pubmed.ncbi.nlm.nih.gov/33664263/
Identifying the genetic factors that underlie complex traits is central to understanding the mechanistic underpinnings of evolution. Cave-dwelling Astyanax mexicanus populations are well adapted to subterranean life and many populations appear to have evolved troglomorphic (morphological adaptation of an animal to living in the constant darkness of caves) traits independently, while the surface-dwelling populations can be used as a proxy for the ancestral form. Warren et al. present a high-resolution, chromosome-level surface fish genome, enabling the first genome-wide comparison between surface fish and cavefish populations. Using this resource, they performed quantitative trait locus (QTL) mapping analyses and found new candidate genes for eye loss (dusp26). They also generated the first genome-wide evaluation of deletion variability across cavefish populations to gain insight into this potential source of cave adaptation. The surface fish genome reference now provides a more complete resource for comparative, functional and genetic studies of drastic trait differences within a species. Supported by ORIP (R24OD011198), NIA, NICHD, NIGMS, amd NIDCR.
New SHIVs and Improved Design Strategy for Modeling HIV-1 Transmission, Immunopathogenesis, Prevention, and Cure
Li et al., Journal of Virology. 2021.
https://doi.org/10.1128/JVI.00071-21
Researchers knew that substitution of HIV-1 Env residue 375-serine by aromatic residues enhances binding to rhesus CD4 enabling primary HIV-1 Envs to support replication as simian-human immunodeficiency virus (SHIV) chimeras in rhesus monkeys. The investigators constructed SHIVs containing 10 primary Envs corresponding to HIV-1 subtypes A, B, C, AE, and AG. Only one with histidine at Env375 replicated efficiently in rhesus cells. Replacement of wild-type Env375 residues by tryptophan, tyrosine, phenylalanine, or histidine in the other 9 SHIVs led to efficient replication. These new SHIVs transmit via mucosal routes like HIV-1 and have use for vaccine testing in nonhuman primates. Supported by ORIP (U42OD021458, P40OD012217), NIAID, and NCI.
Autologous Transplant Therapy Alleviates Motor and Depressive Behaviors in Parkinsonian Monkeys
Tao et al., Nature Medicine. 2021.
https://www.nature.com/articles/s41591-021-01257-1
Generation of induced pluripotent stem cells (iPSCs) enables standardized of dopamine (DA) neurons for autologous transplantation therapy to improve motor functions in Parkinson disease (PD). Adult male rhesus PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs of PD over a 2-year period without immunosuppressive therapy. Mathematical modeling showed correlations between surviving DA neurons with PET signal intensity and behavior recovery regardless of autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number. The results demonstrate favorable efficacy of the autologous transplant approach to treat PD. Supported by ORIP (P51OD011106) NINDS, and NICHD.
Polyfunctional Tier 2–Neutralizing Antibodies Cloned Following HIV-1 Env Macaque Immunization Mirror Native Antibodies in a Human Donor
Spencer et al., Journal of Immunology. 2021.
https://doi.org/10.4049/jimmunol.2001082
HIV vaccine efforts are limited by viral strain diversity and the shielding of neutralization epitopes on the viral envelope, yet isolation of broadly neutralizing antibodies from infected individuals suggests the potential for eliciting protective antibodies through vaccination. Researchers cloned 58 monoclonal antibodies (mAbs) from a rhesus monkey immunized with envelope glycoprotein immunogens from an HIV-1 clade C–infected volunteer. Twenty mAbs exhibited some neutralizing activity. Cloned mAbs targeting the V3 region and CD4 binding site were capable of tier 2 (i.e., moderate) neutralization. This study demonstrates partial recapitulation of the human donor’s humoral immune response through nonhuman primate vaccination. Supported by ORIP (P51OD011092) and NIAID.
Larval Zebrafish Use Olfactory Detection of Sodium and Chloride to Avoid Salt Water
Herrera et al., Current Biology. 2021.
https://pubmed.ncbi.nlm.nih.gov/33338431/
Zebrafish are freshwater fish unable to tolerate high-salt environments and would benefit from neural mechanisms that enable the navigation of salt gradients to avoid high salinity. Yet zebrafish lack epithelial sodium channels, the primary conduit land animals use to taste sodium. This suggests fish may possess novel, undescribed mechanisms for salt detection. In the present study, the authors show that zebrafish indeed respond to small temporal increases in salt by reorienting more frequently. In summary, this study establishes that zebrafish larvae can navigate and thus detect salinity gradients and that this is achieved through previously undescribed sensory mechanisms for salt detection. Supported by ORIP (R43OD024879, R44OD024879) and NINDS.
Acoustofluidic Rotational Tweezing Enables High-Speed Contactless Morphological Phenotyping of Zebrafish Larvae
Chen et al., Nature Communications. 2021.
https://pubmed.ncbi.nlm.nih.gov/33602914/
These authors demonstrate an acoustofluidic rotational tweezing platform that enables contactless, high-speed, 3D multispectral imaging and digital reconstruction of zebrafish larvae for quantitative phenotypic analysis. The acoustic-induced polarized vortex streaming achieves contactless and rapid (~1 s/rotation) rotation of zebrafish larvae enabling multispectral imaging of the zebrafish body and internal organs. They developed a 3D reconstruction pipeline that yields accurate 3D models based on the multi-view images for quantitative evaluation. With its contactless nature and advantages in speed and automation, the acoustofluidic rotational tweezing system has the potential to be a valuable asset for developmental biology and pre-clinical drug development in pharmacology. Supported by ORIP (R43OD024963), NCI, and NIGMS.