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Fc-Mediated Pan-Sarbecovirus Protection After Alphavirus Vector Vaccination
Adams et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37000623/
Group 2B β-coronaviruses (i.e., sarbecoviruses) have resulted in regional and global epidemics. Here, the authors evaluate the mechanisms of cross-sarbecovirus protective immunity using a panel of alphavirus-vectored vaccines covering bat to human strains. They reported that vaccination does not prevent virus replication, but it protects against lethal heterologous disease outcomes in SARS-CoV-2 and clade 2 bat sarbecovirus challenge models. Full-length spike vaccines elicited the broadest pan-sarbecovirus protection. Additionally, antibody-mediated cross-protection was lost in absence of FcR function, supporting a model for non-neutralizing, protective antibodies. Taken together, these findings highlight the value of universal sarbecovirus vaccine designs that couple FcR-mediated cross-protection with potent cross-neutralizing antibody responses. Supported by ORIP (K01OD026529), NIAID, and NCI.
Spike and Nsp6 Are Key Determinants of SARS-CoV-2 Omicron BA.1 Attenuation
Chen et al., Nature. 2023.
https://pubmed.ncbi.nlm.nih.gov/36630998/
The ability of the SARS-CoV-2 virus to mutate and create variants of concern demands new vaccines to control the COVID-19 pandemic. The SARS-CoV-2 Omicron variant was shown to be more immune evasive and less virulent than current major variants. The spike (S) protein in this variant carries many mutations that drive these phenotypes. Researchers generated a chimeric recombinant SARS-CoV-2 virus encoding the S gene of Omicron (BA.1 lineage) in an ancestral SARS-CoV-2 isolate and compared it with the naturally circulating Omicron variant. The Omicron S-bearing virus escaped vaccine-induced humoral immunity, owing to mutations in the receptor-binding motif. The recombinant virus replicated efficiently in distal lung cell lines and in K18-hACE2 mice. Moreover, mutations induced in non-structural protein 6 (nsp6) in addition to the S protein were sufficient to restate the attenuated phenotype of Omicron. These findings indicate that the pathogenicity of Omicron is determined by mutations both inside and outside of the S gene. Supported by ORIP (S10OD026983, S10OD030269).
Characterizing a Photoacoustic and Fluorescence Imaging Platform for Preclinical Murine Longitudinal Studies
Thompson et al., Journal of Biomedical Optics . 2023.
https://pubmed.ncbi.nlm.nih.gov/36895414/
Preclinical studies using animal models require medical imaging technology with sufficient resolution and sensitivity for anatomical, functional, and molecular assessments. Photoacoustic (PA) tomography provides high resolution and specificity, and fluorescence (FL) molecular tomography provides high sensitivity; the combination of these imaging modalities capitalizes on their strengths and mitigates disadvantages. In this publication, the authors describe TriTom, a preclinical imaging system that integrates PA and FL. They characterized the PA spatial resolution, PA sensitivity, PA spectral accuracy, optical spatial resolution, and FL sensitivity of the platform and demonstrated anatomical imaging in mice. This report demonstrates TriTom’s suitability for biomedical imaging applications. Supported by ORIP (R43OD023029) and NCI.
In-Depth Virological and Immunological Characterization of HIV-1 Cure after CCR5A32/A32 Allogeneic Hematopoietic Stem Cell Transplantation
Jensen et al., Nature Medicine. 2023.
https://pubmed.ncbi.nlm.nih.gov/36807684/
Evidence suggests that CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) can cure HIV-1, but the immunological and virological correlates are unknown. Investigators performed a longitudinal virological and immunological analysis of the peripheral blood and tissue compartments of a 53-year-old male patient more than 9 years after CCR5Δ32/Δ32 allogeneic HSCT and 48 months after analytical treatment interruption. Sporadic traces of HIV-1 DNA were detected in peripheral T cell subsets and tissue-derived samples, but repeated ex vivo quantitative and in vivo outgrowth assays in humanized mice of both sexes did not reveal replication-competent virus. This case provides new insights that could guide future cure strategies. Supported by ORIP (P51OD011092) and NIAID.
A Class of Anti-Inflammatory Lipids Decrease with Aging in the Central Nervous System
Tan et al., Nature Chemical Biology. 2023.
https://doi.org/10.1038/s41589-022-01165-6
Impaired lipid metabolism in the brain has been implicated in neurological disorders of aging, yet analyses of lipid pathway changes with age have been lacking. The researchers examined the brain lipidome of mice of both sexes across the lifespan using untargeted lipidomics. They found that 3-sulfogalactosyl diacylglycerols (SGDGs) are structural components of myelin and decline with age in the central nervous system. The researchers discovered that SGDGs also are present in male human and rhesus macaque brains, demonstrating their evolutionary conservation in mammals. The investigators showed that SGDGs possess anti-inflammatory activity, suggesting a potential role for this lipid class in age-related neurodegenerative diseases. Supported by ORIP (P51OD011092), NIA, NCI, NIDDK, and NINDS.
PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS
Hung et al., Cell . 2023.
https://doi.org/10.1016/j.cell.2023.01.005
Investigators showed that pharmacological suppression of PIKFYVE activity reduces pathology and extends survival of animal models and patient-derived motor neurons representing diverse forms of amyotrophic lateral sclerosis (ALS). Upon PIKFYVE inhibition, exocytosis is activated to transport aggregation-prone proteins out of the cells, a process that does not require stimulating macroautophagy or the ubiquitin-proteosome system. These findings suggest therapeutic potential to manage multiple forms of ALS. Supported by ORIP (S10OD021553) and NINDS.
Production and Characterization of Monoclonal Antibodies to Xenopus Proteins
Horr et al., Development. 2023.
https://pubmed.ncbi.nlm.nih.gov/36789951/
Monoclonal antibodies are powerful and versatile tools that enable the study of proteins in diverse contexts. They are often utilized to assist with identification of subcellular localization and characterization of the function of target proteins of interest. However, because there can be considerable sequence diversity between orthologous proteins in Xenopus and mammals, antibodies produced against mouse or human proteins often do not recognize Xenopus counterparts. To address this issue, the authors refined existing mouse monoclonal antibody production protocols to generate antibodies against Xenopus proteins of interest. Here, they describe several approaches for the generation of useful mouse anti-Xenopus antibodies to multiple Xenopus proteins and their validation in various experimental approaches. Supported by ORIP (R24OD021485, S10OD010645) and NIDCR.
Chronic TREM2 Activation Exacerbates Aβ-Associated Tau Seeding and Spreading
Jain et al., Journal of Experimental Medicine. 2023.
Using a mouse model for amyloidosis in which Alzheimer’s Disease (AD)–associated tau is injected into the brain to induce amyloid β (Aβ)–dependent tau seeding/spreading, investigators found that chronic administration of an activating triggering receptor expressed on myeloid cells 2 (TREM2) antibody increases microglial activation of dystrophic neurites surrounding Aβ plaques (NP) but increases NP-tau pathology and neuritic dystrophy without altering Aβ plaque burden. These data suggest that sustained microglial activation through TREM2 that does not result in strong myeloid removal might exacerbate Aβ-induced tau pathology, which could have important clinical implications. Supported by ORIP (S10OD021629) and NIA.
TMEM161B Modulates Radial Glial Scaffolding in Neocortical Development
Wang et al., PNAS. 2023.
https://www.pnas.org/doi/10.1073/pnas.2209983120
Neocortical folding (i.e., gyrification) is a fundamental evolutionary mechanism allowing the expansion of cortical surface area and increased cognitive function. This study identifies TMEM161B in gyral spacing in humans, likely affecting radial glial cell polarity through effects on the actin cytoskeleton. Patients carrying TMEM161B mutations exhibit striking neocortical polymicrogyria and intellectual disability. TMEM161B knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. The data implicating TMEM161B in murine holoprosencephaly may suggest shared mechanisms between the formation of the brain midline and cortical gyrification. Supported by ORIP (U54OD030187), NINDS, and NHGRI.
Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection
Abeynaike et al., Viruses. 2023.
https://www.mdpi.com/1999-4915/15/2/365
A major obstacle to human natural killer (NK) cell reconstitution is the lack of human interleukin‑15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Researchers show that immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical cord blood–derived hematopoietic stem cells (HSCs). These mice demonstrate robust and long-term reconstitution with human immune cells but do not develop graft-versus-host disease, allowing long-term studies of human NK cells. The HSC-engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses. This work provides a robust novel model to study NK cell responses to HIV-1. Supported by ORIP (R24OD026440), NIAID, NCI, and NIDDK.