Selected Grantee Publications
SIV-Specific Antibodies Protect Against Inflammasome-Driven Encephalitis in Untreated Macaques
Castell et al., Cell Reports. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11552693
Viral infections are the most common infectious cause of encephalitis, and simian immunodeficiency virus (SIV)–infected macaques are a well-established model for HIV. Researchers investigated the protective effects of SIV-specific antibodies against inflammation-driven encephalitis in using untreated, SIV-infected, male and female pigtail and rhesus macaques. Findings indicate that these antibodies reduce neuroinflammation and encephalitis, highlighting the importance of antibodies in controlling neuroimmune responses, especially in the absence of antiretroviral therapy. This study provides insight into immune-modulatory approaches to combating inflammation-driven encephalopathies. Supported by ORIP (U42OD013117, T32OD011089), NIDA, NHLBI, NIAID, NINDS, and NIMH.
Transcriptomic Analysis of Skeletal Muscle Regeneration Across Mouse Lifespan Identifies Altered Stem Cell States
Walter et al., Nature Aging. 2024.
https://pubmed.ncbi.nlm.nih.gov/39578558
Age-related skeletal muscle regeneration dysfunction is poorly understood. Using single-cell transcriptomics and high-resolution spatial transcriptomics, researchers evaluated factors contributing to age-related decline in skeletal muscle regeneration after injury in young, old, and geriatric male and female mice (5, 20, and 26 months old). Eight immune cell types were identified and associated with age-related dynamics and distinct muscle stem cell states specific to old and geriatric tissue. The findings emphasize the role of extrinsic and intrinsic factors, including cellular senescence, in disrupting muscle repair. This study provides a spatial and molecular framework for understanding regenerative decline and cellular heterogeneity in aging skeletal muscle. Supported by ORIP (F30OD032097), NIA, NIAID, NIAMS, NICHD, and NIDA.
Engineered Deletions of HIV Replicate Conditionally to Reduce Disease in Nonhuman Primates
Pitchai et al., Science. 2024.
https://pubmed.ncbi.nlm.nih.gov/39116226/
Current antiretroviral therapy (ART) for HIV is limited by the necessity for continuous administration. Discontinuation of ART leads to viral rebound. A therapeutic interfering particle (TIP) was developed as a novel single-administration HIV therapy using defective interfering particles. TIP treatment in two humanized mouse models demonstrated a significant reduction in HIV viral load. TIP intervention was completed 24 hours prior to a highly pathogenic simian immunodeficiency virus (SIV) challenge in a nonhuman primate (NHP) rhesus macaque infant model. Compared to untreated SIV infection, NHPs that received TIP treatment displayed no visible signs of SIV-induced AIDS and exhibited improved seroconversion and a significant survival advantage to the 30-week clinical endpoint. Peripheral blood mononuclear cells isolated from HIV-infected patients showed that TIP treatment reduced HIV outgrowth. This study demonstrates the potential use of a single-administration TIP for HIV treatment. Supported by ORIP (P51OD011092, U42OD010426), NCI, NIAID, and NIDA.
Spatiotemporal Image Reconstruction to Enable High-Frame-Rate Dynamic Photoacoustic Tomography With Rotating-Gantry Volumetric Imagers
Cam et al., Journal of Biomedical Optics . 2024.
https://pubmed.ncbi.nlm.nih.gov/38249994
Dynamic photoacoustic computed tomography (PACT) is a valuable imaging technique for monitoring physiological processes. However, the current imaging techniques are often limited to two-dimensional spatial imaging. While PACT imagers capable of taking three-dimensional spatial images are commercially available, these systems have substantial limitations. Typically, the data are acquired sequentially rather than simultaneously at all views. The objects being imaged are dynamic and can vary during this process; as such, image reconstruction is inherently difficult, and the result is often incomplete. Cam et al. propose an image reconstruction method that can address these challenges and enable volumetric dynamic PACT imaging using existing preclinical imagers, which has the potential to significantly advance preclinical research and facilitate the monitoring of critical physiological biomarkers. Supported by ORIP (R44OD023029) and NIBIB.
The Effect of Common Paralytic Agents Used for Fluorescence Imaging on Redox Tone and ATP Levels in Caenorhabditis elegans
Morton et al., PLOS One. 2024.
https://pubmed.ncbi.nlm.nih.gov/38669260
Caenorhabditis elegans is a highly valuable model organism in biological research. However, these worms must be paralyzed for most imaging applications, and the effect that common chemical anesthetics may have on the parameters measured—especially biochemical measurements such as cellular energetics and redox tone—is poorly understood. In this study, the authors used two reporters—QUEEN-2m for relative ATP levels and reduction-oxidation–sensitive green fluorescent protein for redox tone—to assess the impact of commonly used chemical paralytics. The results show that all chemical anesthetics at doses required for full paralysis alter redox tone and/or ATP levels, and anesthetic use alters the detected outcome of rotenone exposure on relative ATP levels and redox tone. Therefore, it is important to tailor the use of anesthetics to different endpoints and experimental questions and to develop less disruptive paralytic methods for optimal imaging of dynamic in vivo reporters. Supported by ORIP (P40OD010440, R44OD024963) and NIEHS.
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.
Synthetic Protein Circuits for Programmable Control of Mammalian Cell Death
Xia et al., Cell. 2024.
https://pubmed.ncbi.nlm.nih.gov/38657604/
Natural cell-death pathways have been shown to eliminate harmful cells and shape immunity. Researchers used synthetic protein-level cell-death circuits, collectively termed “synpoptosis” circuits, to proteolytically regulate engineered executioner proteins and mammalian cell death. They show that the circuits direct cell death modes, respond to combinations of protease inputs, and selectively eliminate target cells. This work provides a foundation for programmable control of mammalian cell death. Future studies could focus on programmable control of cell death in various contexts, including cancer, senescence, fibrosis, autoimmunity, and infection. Supported by ORIP (F30OD036190) and NIBIB.
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.