Selected Grantee Publications
Diverse Targets of SMN2-Directed Splicing-Modulating Small Molecule Therapeutics for Spinal Muscular Atrophy
Ottesen et al., Nucleic Acids Research. 2023.
https://academic.oup.com/nar/article/51/12/5948/7110763?login=true
Spinal muscular atrophy (SMA) results from deletions or mutations of the SMN1 gene. SMN2 is a nearly identical copy of SMN1 but cannot compensate for its loss. Manipulation of splicing to restore SMN2 exon 7 inclusion provides a promising therapeutic avenue for SMA, and two small-molecule agents—risdiplam and branaplam—restore body-wide inclusion of the SMN2 exon 7 upon oral administration. In this study, researchers demonstrate the advantages of combined treatments with low doses of risdiplam and branaplam. These findings can be applied to develop the next generation of small‑molecule therapeutics, with a focus on better efficacies and fewer off-target effects. Supported by ORIP (T35OD027967) and NINDS.
SALL1 Enforces Microglia-Specific DNA Binding and Function of SMADs to Establish Microglia Identity
Fixsen et al., Nature Immunology. 2023.
https://doi.org/10.1038/s41590-023-01528-8
Microglia function is thought to play a role in neurodevelopmental, psychiatric, and neurodegenerative diseases. Using knockout mice, investigators explored functional interactions between spalt-like transcription factor 1 (SALL1) and SMAD4, which demonstrated that interactions are mediated by a conserved microglia-specific SALL1 super-enhancer and result in direct activation of regulatory elements. The concerted interactions induce a microglia lineage determining program of gene expression. These findings indicate that expression of SALL1 and associated genes could contribute to phenotypes of aging and neurodegenerative diseases. Supported by ORIP (S10OD026929), NIA, NIMH, and NINDS.
A Comprehensive Drosophila Resource to Identify Key Functional Interactions Between SARS-CoV-2 Factors and Host Proteins
Guichard et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480566/
To address how interactions between SARS-CoV-2 factors and host proteins affect COVID-19 symptoms, including long COVID, and facilitate developing effective therapies against SARS-CoV-2 infections, researchers reported the generation of a comprehensive set of resources, mainly genetic stocks and a human cDNA library, for studying viral–host interactions in Drosophila. Researchers further demonstrated the utility of these resources and showed that the interaction between NSP8, a SARS-CoV-2 factor, and ATE1 arginyltransferase, a host factor, causes actin arginylation and cytoskeleton disorganization, which may be relevant to several pathogenesis processes (e.g., coagulation, cardiac inflammation, fibrosis, neural damage). Supported by ORIP (R24OD028242, R24OD022005, R24OD031447), NIAID, NICHD, NIGMS, and NINDS.
Osteopontin Is an Integral Mediator of Cardiac Interstitial Fibrosis in Models of Human Immunodeficiency Virus Infection
Robinson et al., The Journal of Infectious Diseases. 2023.
https://www.doi.org/10.1093/infdis/jiad149
HIV infection is associated with increased risk of cardiovascular disease. Plasma osteopontin (Opn) is correlated with cardiac pathology, but more work is needed to understand the underlying mechanisms driving cardiac fibrosis. Researchers explored this topic using mouse embryonic fibroblasts, male macaques, and humanized mice of both sexes. They reported the accumulation of Opn in the heart with simian immunodeficiency virus infection. Systemic inhibition of Opn can prevent HIV-associated interstitial fibrosis in the left ventricle. These findings suggest that Opn could be a potential target for adjunctive therapies to reduce cardiac fibrosis in people with HIV. Supported by ORIP (P51OD011104), NIAID, NHLBI, NIMH, and NINDS.
GluN2B Inhibition Confers Resilience against Long-Term Cocaine-Induced Neurocognitive Sequelae
Li et al., Neuropsychopharmacology. 2023.
https://www.nature.com/articles/s41386-022-01437-8
Cocaine self-administration can disrupt the capacity of humans and rodents to flexibly modify familiar behavioral routines, but effects on mechanistic factors—particularly those driving long-term behavioral changes—have not been characterized fully. Researchers used mice to examine the flexibility of decision-making behavior with oral cocaine self-administration. They found that GluN2B inhibition prevented cocaine-induced dysregulation of neuronal structure and function in the orbitofrontal cortex (OFC), preserving mature, mushroom-shaped dendritic spine densities on deep-layer pyramidal neurons. These findings suggest that cocaine potentiates GluN2B-dependent signaling, which triggers a series of durable adaptations that result in the dysregulation of post-synaptic neuronal structure in the OFC, ultimately weakening the capacity for flexible choice. Supported by ORIP (P51OD011132) and NINDS.
Sequential Intrahost Evolution and Onward Transmission of SARS-CoV-2 Variants
Gonzalez-Reiche et al., Nature Communications. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10239218/
Most patients with COVID-19 clear the virus upon resolution of acute infection, but a subset of immunocompromised individuals develop persistent SARS-CoV-2 infections. In this study, investigators describe sequential persistent SARS-CoV-2 infections in three individuals that led to the emergence, forward transmission, and continued evolution of the Omicron BA.1 variant Omicron BA.1.23. The study demonstrated that in the presence of suboptimal immune responses, persistent viral replication is an important driver of SARS-CoV-2 diversification. This and other studies also highlight that strategies to prevent virus persistence and shedding and more effective therapies are needed to limit the spread of newly emerging, neutralization-resistant variants in vulnerable patients. Supported by ORIP (S10OD026880, S10OD030463), NIAID, and NCATS.
The Drosophila Chemokine-Like Orion Bridges Phosphatidylserine and Draper in Phagocytosis of Neurons
Ji et al., PNAS. 2023.
https://pubmed.ncbi.nlm.nih.gov/37276397/
Degenerating neurons can be cleared by phagocytosis triggered by “eat-me” signal phosphatidylserine (PS) and mediated by the engulfment receptor Draper (Drpr), yet the process is poorly understood. Investigators used several Drosophila models to study dendrite degeneration and demonstrated that the fly chemokine-like protein Orion binds to PS and mediates interactions between PS and Drpr to enable phagocytosis. This study identifies a link between immunomodulatory proteins and phagocytosis of neurons and reveals conserved mechanisms of clearing degenerating neurons. Supported by ORIP (R24OD031953, R21OD023824, S10OD018516) and NINDS.
Lymph-Node-Based CD3+ CD20+ Cells Emerge From Membrane Exchange Between T Follicular Helper Cells and B Cells and Increase Their Frequency Following Simian Immunodeficiency Virus Infection
Samer et al., Journal of Virology. 2023.
https://www.doi.org/10.1128/jvi.01760-22
CD4+ T follicular helper cells are known to persist during antiretroviral therapy (ART) and have been identified as key targets for viral replication and persistence. Researchers identified a lymphocyte population that expresses CD3 (i.e., T cell lineage marker) and CD20 (i.e., B cell lineage marker) on the cellular surface in lymphoid tissues from rhesus macaques of both sexes and humans of male and female sexes. In macaques, the cells increased following simian immunodeficiency virus infection, were reduced with ART, and increased in frequency after ART interruption. These cells represent a potential area for future therapeutic strategies. Supported by ORIP (P51OD011132, U42OD011023), NIAID, NCI, NIDDK, NIDA, NHLBI, and NINDS.
Effects of Acute Femoral Head Ischemia on the Growth Plate and Metaphysis in a Piglet Model of Legg-Calvé-Perthes Disease
Armstrong et al., Osteoarthritis and Cartilage. 2023.
https://pubmed.ncbi.nlm.nih.gov/36696941/
Legg-Calvé-Perthes disease (LCPD) can lead to permanent deformity of the femoral head and premature osteoarthritis, but the underlying cause remains unknown. More work is needed to determine optimal treatment methods for LCPD. Using a piglet model for LCPD, researchers assessed the effects of acute femoral head ischemia on the proximal femoral growth plate and metaphysis. They reported that alterations to the growth plate zones and metaphysis occurred by 2 days post-ischemia and persisted at 7 days post-ischemia. These findings suggest that growth disruption may occur sooner after the onset of ischemia than researchers had hypothesized previously. Supported by ORIP (T32OD010993, K01OD021293), NIAMS, and NCATS.
CD8+ T Cells Promote HIV Latency by Remodeling CD4+ T Cell Metabolism to Enhance Their Survival, Quiescence, and Stemness
Mutascio et al., Immunity. 2023.
https://www.doi.org/10.1016/j.immuni.2023.03.010
An HIV reservoir persists following antiretroviral therapy, representing the main barrier to an HIV cure. Using a validated in vitro model, investigators explored the mechanism by which CD8+ T cells promote HIV latency and inhibit latency reversal in HIV-infected CD4+ T cells. They reported that CD8+ T cells favor the establishment of HIV latency by modulating metabolic, stemness, and survival pathways that correlate with the downregulation of HIV expression and promote HIV latency. In future studies, comparative analyses may provide insight into common molecular mechanisms in the silencing of HIV expression by CD8+ T cells and macrophages, which can be applied to new intervention strategies that target the HIV reservoir. Supported by ORIP (P51OD011132, S10OD026799), NIAID, NIDDK, NIDA, NHLBI, and NINDS.