Selected Grantee Publications
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- 357 results found
- Immunology
- Neurological
Effect of Passive Administration of Monoclonal Antibodies Recognizing Simian Immunodeficiency Virus (SIV) V2 in CH59-Like Coil/Helical or β-Sheet Conformations on Time of SIVmac251 Acquisition
Stamos et al., Journal of Virology. 2023.
https://journals.asm.org/doi/10.1128/jvi.01864-22
Research suggests that the SIV variable region 2 (V2) is a region of virus vulnerability, likely because of its exposure on the apex of virions and on the surfaces of SIV-infected cells. Researchers examined the effects of two monoclonal antibodies, NCI05 and NCI09, on the acquisition of SIV using rhesus macaques (sex not specified). They found that NCI05, but not NCI09, delays SIV acquisition, highlighting the complexity of antibody responses to V2. Both antibodies were unable to decrease the risk of viral acquisition. This study demonstrates that such antibodies as NCI05 alone are insufficient to protect against SIV acquisition. Supported by ORIP (S10OD027000), NIAID, and NCI.
In Vivo MRI Is Sensitive to Remyelination in a Nonhuman Primate Model of Multiple Sclerosis
Donadieu et al., eLife. 2023.
https://pubmed.ncbi.nlm.nih.gov/37083540/
Experimental autoimmune encephalomyelitis (EAE) in the common marmoset is a model for studying inflammatory demyelination in multiple sclerosis (MS). Researchers investigated the feasibility and sensitivity of magnetic resonance imaging (MRI) in characterizing remyelination, a crucial step to recover from MS. Investigators demonstrated that multisequence 7T MRI could detect spontaneous remyelination in marmoset EAE at high statistical sensitivity and specificity in vivo. This study suggests that in vivo MRI can be used for preclinical testing of therapeutic remyelinating agents for MS. Supported by ORIP (R21OD030163) and NINDS.
An E1–E2 Fusion Protein Primes Antiviral Immune Signaling in Bacteria
Ledvina et al., Nature. 2023.
https://www.nature.com/articles/s41586-022-05647-4
Investigators show that the cGAS/DncV–like nucleotidyltransferase (CD‑NTase)–associated protein 2 (Cap2) primes bacterial CD-NTases for activation through a ubiquitin transferase–like mechanism. A cryo-electron microscopy structure of the Cap2-CD-NTase complex reveals Cap2 as an all-in-one ubiquitin transferase–like protein, with distinct domains resembling eukaryotic E1 and E2 proteins. The structure captures a reactive-intermediate state with the CD-NTase C terminus positioned in the Cap2 E1 active site and conjugated to AMP. Cap2 conjugates the CD-NTase C terminus to a target molecule that primes the CD-NTase for increased cGAMP production. The investigators further demonstrate bacteria control immune signaling using an ancient, minimized ubiquitin transferase–like system and provide insight into the evolution of the E1 and E2 machinery across domains of life. Supported by ORIP (S10OD023498, S10OD021527, S10OD025267) and NIGMS.
Cerebrospinal Fluid Protein Markers Indicate Neuro-Damage in SARS-CoV-2-Infected Nonhuman Primates
Maity et al., Molecular & Cellular Proteomics. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981268/
In this study, researchers examined the proteins expressed in cerebrospinal fluid (CSF) in nonhuman primates (NHPs) to better understand how COVID-19 infection can result in brain pathology, a common outcome. The study found that even in NHPs with minimal or mild COVID‑19, CSF proteins were significantly dysregulated compared with uninfected NHPs. Furthermore, the most affected proteins were enriched in the same brain regions that show lesions after COVID-19 infection, including the cerebral cortex, basal ganglia, and brain stem. Collectively, these regions have wide-ranging control over such crucial functions as cognition, motor control, and breathing, showing how even mild COVID-19 infection can result in significant neurological impairment. Supported by ORIP (P51OD011104, S10OD032453), NIGMS, NCI, and NICHD.
Hematopoietic Stem Cells Preferentially Traffic Misfolded Proteins to Aggresomes and Depend on Aggrephagy to Maintain Protein Homeostasis
Chua et al., Cell Stem Cell. 2023.
https://pubmed.ncbi.nlm.nih.gov/36948186/
Investigators studied the mechanism of hematopoietic stem cells (HSCs) being dependent on managing proteostasis. Their findings demonstrated that HSCs preferentially depend on aggrephagy, a form of autophagy, to maintain proteostasis. When aggrephagy is disabled, HSCs compensate by increasing proteasome activity, but proteostasis is ultimately disrupted as protein aggregates accumulate and HSC function is impaired. The investigators also showed that Bag3 deficiency blunts aggresome formation in HSCs, resulting in protein aggregate accumulation, myeloid-biased differentiation, and diminished self-renewal activity, thus demonstrating Bag3 as a regulator of HSC proteostasis. HSC aging is associated with loss of aggresomes and reduced autophagic flux. Protein degradation pathways are thus configured in young-adult HSCs to preserve proteostasis and fitness but become dysregulated during aging. Supported by ORIP (S10OD032316, S10OD021831), NCI, and NIDDK.
Structural Insights Into the Broad Protection Against H1 Influenza Viruses by a Computationally Optimized Hemagglutinin Vaccine
Dzimianski et al., Communications Biology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37185989/
Influenza is an ongoing public health concern, and computationally optimized broadly reactive antigen (COBRA) hemagglutinin proteins represent a potential strategy for formulating broadly effective influenza vaccines. Researchers determined the crystal structure of COBRA P1, as well as its binding to 1F8, a broadly neutralizing antibody. This work provides valuable insights into the underlying molecular basis for the broad effectiveness of P1, and these insights can be applied to future vaccine designs. Supported by ORIP (K01OD026569), NIAID, and NIGMS.
Infant Rhesus Macaques Immunized Against SARS-CoV-2 Are Protected Against Heterologous Virus Challenge 1 Year Later
Milligan et al., Science Translational Medicine. 2023.
https://doi.org/10.1126/scitranslmed.add6383
The Moderna and Pfizer–BioNTech mRNA vaccines received emergency use authorization for infants 6 months and older in June 2022, but questions remain regarding the durability of vaccine efficacy against emerging variants in this age group. Using a two-dose vaccine regimen consisting of stabilized prefusion Washington-strain spike protein encoded by mRNA and encapsulated in lipid nanoparticles, the investigators immunized 2-month-old rhesus macaques of both sexes. They found that the immune responses persisted and protected from severe disease after heterologous challenge with the Delta variant 1 year later. The decay kinetics of vaccine-induced neutralizing antibody responses in the infant monkeys are comparable to those observed in adult humans and nonhuman primates. Supported by ORIP (P51OD011107), NIAID, and NCI.
Late Gene Expression–Deficient Cytomegalovirus Vectors Elicit Conventional T Cells That Do Not Protect Against SIV
Hansen et al., Journal of Clinical Investigation Insight. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070102/
Cytomegalovirus (CMV)–based vaccines aim to exploit unique immunological adaptations, including host manipulation and immune evasion strategies. Translating CMV-based vaccines from rhesus macaques to humans requires translating the immune factors responsible for efficacy, as well as vaccine vectors that are sufficiently safe for widespread use. Researchers examined the impact of a stringent attenuation strategy on vector-induced immune protection against simian immunodeficiency virus (SIV) in rhesus macaques of both sexes. They reported that elicited CD8+ T cells exclusively failed to protect against SIV challenge. These data suggest that late viral gene expression and/or residual in vivo spreading are required to induce protective CD8+ T cell responses. Supported by ORIP (P51OD011092, P51OD011107, S10OD016261), NCI, NIAID, and NCATS.
Mechanism of STMN2 Cryptic Splice-Polyadenylation and its Correction for TDP-43 Proteinopathies
Baughn et al., Science. 2023.
Loss of the RNA-binding protein TDP-43 from the nuclei of affected neurons is a hallmark of neurodegeneration in TDP-43 proteinopathies (e.g., amyotrophic lateral sclerosis, frontotemporal dementia). Loss of functional TDP-43 is accompanied by misprocessing of the stathmin-2 (STMN2) RNA precursor. Investigators determined the elements through which TDP‑43 regulates STMN2 pre‑mRNA processing and identified steric binding antisense oligonucleotides that are capable of restoring normal STMN2 protein and RNA levels. This approach is potentially applicable for human therapy. Supported by ORIP (U42OD010921), NIA, NCI, NIGMS, and NINDS.
Chronic Immune Activation and Gut Barrier Dysfunction Is Associated with Neuroinflammation in ART-Suppressed SIV+ Rhesus Macaques
Byrnes et al., PLOS Pathogens. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10085024/
About 40% of people with HIV develop neurocognitive disorders, potentially resulting from persistent infection in the brain and neuroinflammation. Investigators characterized the central nervous system reservoir and immune environment of simian immunodeficiency virus (SIV)–infected rhesus macaques of both sexes during acute, chronic, or antiretroviral therapy (ART)–suppressed infection. They reported that neuroinflammation and blood–brain barrier dysfunction correlated with viremia and immune activation in the gut. Their findings suggest that gastrointestinal tract damage can contribute to neuroimmune activation and inflammation, even in the absence of SIV or HIV infection. This work also has implications for other neurological disorders where chronic inflammation is associated with pathogenesis. Supported by ORIP (P51OD011132, P51OD011092, U42OD011023, R24OD010445), NIAID, NCI, and NIMH.