Selected Grantee Publications
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- 123 results found
- Neurological
- Women's Health
A Potent Myeloid Response Is Rapidly Activated in the Lungs of Premature Rhesus Macaques Exposed to Intra-Uterine Inflammation
Jackson et al., Mucosal Immunology. 2022.
https://www.doi.org/10.1038/s41385-022-00495-x
Up to 40% of preterm births are associated with histological chorioamnionitis (HCA), which can lead to neonatal mortality, sepsis, respiratory disease, and neurodevelopmental problem. Researchers used rhesus macaques to comprehensively describe HCA-induced fetal mucosal immune responses and delineate the individual roles of IL-1β and TNFα in HCA-induced fetal pathology. Their data indicate that the fetal innate immune system can mount a rapid, multifaceted pulmonary immune response to in utero exposure to inflammation. Taken together, this work provides mechanistic insights into the association between HCA and the postnatal lung morbidities of the premature infant and highlights the therapeutic potential of inflammatory blockade in the fetus. Supported by ORIP (P51OD011107), NIEHS, NIDDK, NHLBI, and NICHD.
Antibody-Peptide Epitope Conjugates for Personalized Cancer Therapy
Zhang et al., Cancer Research. 2022.
https://pubmed.ncbi.nlm.nih.gov/34965933/
Antibody-peptide epitope conjugates (APEC) are a new class of modified antibody-drug conjugates that redirect T cell viral immunity against tumor cells. Investigators developed an experimental pipeline to create patient-specific APECs and identified new preclinical therapies for ovarian carcinoma. Based on functional assessment of viral peptide antigen responses to common viruses like cytomegalovirus in ovarian cancer patients, a library of 192 APECs with distinct protease cleavage sequences was created using the anti-epithelial cell adhesion molecule (EpCAM) antibody. The streamlined and systemic approach includes assessing APEC function in vivo using a new zebrafish xenograft platform that facilitates high-resolution single-cell imaging to assess therapy responses and then validating top candidates using traditional mouse xenograft studies and primary patient samples. This study develops a high-throughput preclinical platform to identify patient-specific antibody-peptide epitope conjugates that target cancer cells and demonstrates the potential of this immunotherapy approach for treating ovarian carcinoma. Supported by ORIP (R24OD016761).
Functional and Ultrastructural Analysis of Reafferent Mechanosensation in Larval Zebrafish
Odstrcil et al., Current Biology. 2022.
https://www.sciencedirect.com/science/article/pii/S096098222101530X
All animals need to differentiate between exafferent stimuli (caused by the environment) and reafferent stimuli (caused by their own movement). Researchers characterized how hair cells in zebrafish larvae discriminate between reafferent and exafferent signals. Dye labeling of the lateral line nerve and functional imaging was combined with ultra-structural electron microscopy circuit reconstruction to show that cholinergic signals originating from the hindbrain transmit efference copies, and dopaminergic signals from the hypothalamus may affect threshold modulation. Findings suggest that this circuit is the core implementation of mechanosensory reafferent suppression in these young animals. Supported by ORIP (R43OD024879, R44OD024879) and NINDS.
Neuroinflammatory Profiling in SIV-Infected Chinese-Origin Rhesus Macaques on Antiretroviral Therapy
Solis-Leal et al., Viruses. 2022.
https://www.doi.org/10.3390/v14010139
The central nervous system (CNS) HIV reservoir contributes to residual neuroimmune activation, which can lead to HIV-associated neurocognitive disorder. Researchers characterized the expression of signaling molecules associated with inflammation in plasma, cerebrospinal fluid, and basal ganglia of Chinese-origin rhesus macaques (sex not specified) with simian immunodeficiency virus (SIV). They reported a correlation between levels of CCL2 in plasma and cerebrospinal fluid, suggesting that researchers could infer the degree of CNS inflammation by testing CCL2 levels in peripheral blood. Overall, these findings provide insight into neuroinflammation and signaling associated with HIV persistence in the CNS. Supported by ORIP (P51OD011104, P51OD011133), NIMH, and NINDS.
Complement Blockade in Recipients Prevents Delayed Graft Function and Delays Antibody-mediated Rejection in a Nonhuman Primate Model of Kidney Transplantation
Eerhart et al., Transplantation. 2022.
Investigators evaluated the efficacy of a high-dose recombinant human C1 esterase inhibitor (rhC1INH) in preventing delayed graft function (DGF) in a rhesus macaque (RM) model for kidney transplantation after brain death and prolonged cold ischemia. The majority (4 of 5) of vehicle-treated recipients developed DGF, whereas DGF was observed in only 1 of 8 rhC1INH-treated recipients. RMs treated with rhC1INH also had faster creatine recovery, superior urinary output, and reduced biomarkers of allograft injury for the first week. The results suggest high-dose C1INH treatment in transplant recipients is an effective strategy to reduce kidney injury and inflammation, prevent DGF, delay antibody-mediated rejection development, and improve transplant outcomes. Supported by ORIP (P51OD011106), NIAID, and NIDDK.
AAV Capsid Variants with Brain-Wide Transgene Expression and Decreased Liver Targeting After Intravenous Delivery in Mouse and Marmoset
Goertsen et al., Nature Neuroscience. 2021.
https://www.nature.com/articles/s41593-021-00969-4
Genetic intervention is increasingly being explored as a therapeutic option for debilitating disorders of the central nervous system (CNS). This project focused on organ-specific targeting of adeno-associated virus (AAV) capsids after intravenous delivery. These results constitute an important step forward toward achieving the goal of engineered AAV vectors that can be used to broadly deliver gene therapies to the CNS in humans. Supported by ORIP (U24OD026638), NIMH, and NINDS.
Precise Visuomotor Transformations Underlying Collective Behavior in Larval Zebrafish
Harpaz et al., Nature Communications. 2021.
https://www.nature.com/articles/s41467-021-26748-0
Sensory signals from neighbors, analyzed in the visuomotor stream of animals, is poorly understood. The authors studied aggregation behavior in larval zebrafish and found that over development larvae transition from over dispersed groups to tight shoals. Young larvae turn away from virtual neighbors by integrating and averaging retina-wide visual occupancy within each eye, and by using a winner-take-all strategy for binocular integration. Observed algorithms accurately predict group structure over development. These findings allow testable predictions regarding the neuronal circuits underlying collective behavior in zebrafish. Supported by ORIP (R43OD024879, R44OD024879) and NINDS.
Monoclonal Antibodies Protect Aged Rhesus Macaques From SARS-CoV-2-Induced Immune Activation and Neuroinflammation
Verma et al., Cell Reports. 2021.
https://www.sciencedirect.com/science/article/pii/S2211124721014157?via%3Dihub%C2%A0=
In aged diabetic female rhesus macaques, prophylactic administration of neutralizing monoclonal antibodies (mAbs) effectively limits SARS-CoV-2 replication in both the upper and lower respiratory tract, and decreases immune activation, including reducing interferon-induced chemokines and limiting effector CD4 T cell influx into the cerebrospinal fluid. These protective mechanisms took place in the areas of the body targeted by the virus and may prevent adverse inflammatory consequences of SARS-CoV-2 infection in high-risk populations. Supported by ORIP (P51OD011107), NIAID, and NIA.
Deciphering the Role of Mucosal Immune Responses and the Cervicovaginal Microbiome in Resistance to HIV Infection in HIV-Exposed Seronegative Women
Ponnan et al., Microbiology Spectrum. 2021.
https://journals.asm.org/doi/10.1128/Spectrum.00470-21
Identifying correlates of protection in HIV-exposed seronegative (HESN) individuals requires identification of HIV-specific local immune responses. Researchers performed a comprehensive investigation of the vaginal mucosa and cervicovaginal microbiome in HESN women. They found elevated antiviral cytokines, soluble immunoglobulins, activated NK cells, CXCR5+ CD8+ T cells, and T follicular helper cells in HESN women compared to HIV-unexposed healthy women. They also found greater bacterial diversity and increased abundance of Gardnerella species in the mucosa of HESN women. These findings suggest that the genital tract of HESN women contains innate immune factors, antiviral mediators, and T cell subsets that protect against HIV. Supported by ORIP (P51OD011132) and NIAID.
Selective G Protein Signaling Driven by Substance P–Neurokinin Receptor Dynamics
Harris et al., Nature Chemical Biology. 2021.
https://www.nature.com/articles/s41589-021-00890-8
Investigators determined the cryogenic-electron microscopy structures of active neurokinin-1 receptor (NK1R) bound to neuropeptide substance P (SP) or the G protein q (Gq)-biased peptide SP6–11. Peptide interactions deep within NK1R are critical for receptor activation. Conversely, interactions between SP and NK1R extracellular loops are required for potent Gs-signaling but not Gq-signaling. Molecular dynamics simulations showed that these superficial contacts restrict SP flexibility. SP6–11, which lacks these interactions, is dynamic while bound to NK1R. Structural dynamics of NK1R agonists therefore depend on interactions with the receptor extracellular loops and regulate G protein signaling selectivity. This data unveils the molecular mechanism of how two stimuli (SP and Neurokinin A) yield distinct G protein signaling at the same G protein-coupled receptor. Supported by ORIP (S10OD021741, S10OD020054) and others.