Selected Grantee Publications
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- 351 results found
- Immunology
- Vaccines/Therapeutics
Effect of Viral Strain and Host Age on Clinical Disease and Viral Replication in Immunocompetent Mouse Models of Chikungunya Encephalomyelitis
Anderson et al., Viruses. 2023.
https://pubmed.ncbi.nlm.nih.gov/37243143/
Chikungunya virus (CHIKV) is associated with neurologic complications, but studies in the central nervous system are challenging to perform in humans. Using a mouse model of both sexes, researchers established the relative severity of neurological disease across multiple stages of neurodevelopment in three strains of CHIKV. The disease was found to be strain dependent, with differences in severity of neurological disease, viral titers in the brain and spinal cord, and proinflammatory gene expression and CD4+ T cell infiltration in the brain. This work provides a mouse model for future studies of CHIKV pathogenesis and the host immune response. Supported by ORIP (K01OD026529), NIAID, and NCI.
Cannabinoid Enhancement of lncRNA MMP25-AS1/MMP25 Interaction Reduces Neutrophil Infiltration and Intestinal Epithelial Injury in HIV/SIV Infection
Premadasa et al., Journal of Clinical Investigation Insight. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10132162/
Gastrointestinal CD4+ T cell depletion during acute simian immunodeficiency virus (SIV) and HIV infection causes significant structural and functional damage, disrupting intestinal immune homeostasis and leading to intestinal epithelial barrier dysfunction. Oral phytocannabinoids are safe and well tolerated in people with HIV, but more information is needed regarding the effects of long-term tetrahydrocannabinol (THC) use on the intestinal epithelial compartment. Investigators profiled gene expression in the colonic epithelium of SIV-infected rhesus macaques of both sexes that were administered THC. They reported that low-dose THC can reduce neutrophil infiltration and intestinal epithelial injury, potentially by downregulating MMP25 expression through modulation of a long noncoding RNA, MMP25-AS1. Supported by ORIP (P51OD011104, P51OD011103), NIAID, and NIDA.
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.
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.
Effect of the Snake Venom Component Crotamine on Lymphatic Endothelial Cell Responses and Lymph Transport
Si et al., Microcirculation. 2023.
https://onlinelibrary.wiley.com/doi/10.1111/micc.12775
The pathology of snake envenomation is closely tied to the severity of edema in the tissue surrounding the area of the bite. This study focused on one of the most abundant venom components in North American viper venom, crotamine, and the effects it has on the cells and function of the lymphatic system. The authors found that genes that encode targets of crotamine are highly present in lymphatic tissues and cells and that there is a differential distribution of those genes that correlates with phasic contractile activity. They found that crotamine potentiates calcium flux in human dermal lymphatic endothelial cells in response to stimulation with histamine and shear stress—but not alone—and that it alters the production of nitric oxide in response to shear, as well as changes the level of F-actin polymerization of those same cells. Crotamine alters lymphatic transport of large molecular weight tracers to local lymph nodes and is deposited within the node, mostly in the immediate subcapsular region. Results suggest that snake venom components may have an impact on the function of the lymphatic system and provide new targets for improved therapeutics to treat snakebites. Supported by ORIP (P40OD010960).
Pembrolizumab and Cabozantinib in Recurrent Metastatic Head and Neck Squamous Cell Carcinoma: A Phase 2 Trial
Saba et al., Nature Medicine. 2023.
https://www.doi.org/10.1038/s41591-023-02275-x
A multicenter clinical trial was conducted in 33 evaluable (36 enrolled) patients with recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC) on a regimen combining cabozantinib, a tyrosine kinase inhibitor, with the standard of care of anti–programmed cell death protein 1 agent pembrolizumab. Results showed that 17 patients (52%) exhibited partial response and 13 (39%) exhibited stable disease, with an overall clinical benefit rate of 91%. Median progression-free survival (PFS) was 14.6 months, and the 1-year PFS was 54%. The pembrolizumab and cabozantinib regimen was well tolerated in patients with RMHNSCC. The promising clinical benefit warrants further investigation. Supported by ORIP (S10OD021644), NCI, and NIDCR.
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.
Longitudinal Characterization of Circulating Extracellular Vesicles and Small RNA During Simian Immunodeficiency Virus Infection and Antiretroviral Therapy
Huang et al., AIDS. 2023.
https://www.doi.org/10.1097/QAD.0000000000003487
Antiretroviral therapy is effective for controlling HIV infection but does not fully prevent early aging disorders or serious non-AIDS events among people with HIV. Using pigtail and rhesus macaques (sex not specified), researchers profiled extracellular vesicle small RNAs during different phases of simian immunodeficiency virus infection to explore the potential relationship between extracellular vesicle–associated small RNAs and the infection process. They reported that average particle counts correlated with infection, but the trend could not be explained fully by virions. These findings raise new questions about the distribution of extracellular vesicle RNAs in HIV latent infection. Supported by ORIP (U42OD013117), NIDA, NIMH, NIAID, NCI, and NINDS.