Selected Grantee Publications
- 560 results found
Innate Lymphoid Cells and Interferons Limit Neurologic and Articular Complications of Brucellosis
Moley et al., American Journal of Pathology. 2023.
https://www.sciencedirect.com/science/article/pii/S0002944023001980?via%3Dihub=
Brucellosis is a globally significant zoonotic disease. The current study investigated the role of innate lymphoid cells (ILCs) in the pathogenesis of focal brucellosis caused by Brucella melitensis. Following pulmonary infection with B. melitensis, mice lacking adaptive immune cells and ILCs developed arthritis, neurologic complications, and meningitis. Transcriptional analysis of Brucella-infected brains revealed marked upregulation of genes associated with inflammation and interferon responses. Collectively, these findings indicate that ILCs and interferons play an important role in prevention of focal complications during Brucella infection and that mice with deficiencies in ILCs or interferons can be used to study pathogenesis of neurobrucellosis. Supported by ORIP (T32OD011126) and NIAID.
Infection of the Maternal–Fetal Interface and Vertical Transmission Following Low-Dose Inoculation of Pregnant Rhesus Macaques (Macaca mulatta) with an African-Lineage Zika Virus
Koenig et al., PLOS ONE. 2023.
https://doi.org/10.1371/journal.pone.0284964
Researchers examined transmission of Zika virus to nonhuman primate fetuses during pregnancy. Even with a low dosage of inoculation of the dams, the investigators found that the Zika virus infected fetuses, despite the presence of a “placental fortress,” which normally protects fetuses during gestation. This transmission illustrates the high level of infectivity threat that Zika poses, which may increase if mosquitoes expand their global habitats. Understanding how Zika breaches the placental barrier will help researchers develop strategies to prevent fetal infection during pregnancy and thereby prevent adverse outcomes, such as brain malformation defects. Supported by ORIP (P51OD011106, S10OD023526), NIAID, NCI, and NIGMS.
Antibody-Dependent Cellular Cytotoxicity, Infected Cell Binding and Neutralization by Antibodies to the SIV Envelope Glycoprotein
Grunst et al., PLOS Pathogens. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10256149/
Antibodies that bind to the envelope glycoprotein (Env) on the surface of virus-infected cells can recruit cells from the immune system to kill infected cells by antibody-dependent cellular cytotoxicity (ADCC). Researchers characterized ADCC, Env binding, and neutralization in rhesus macaque antibodies that were specific for diverse epitopes of the simian immunodeficiency virus (SIV) envelope glycoprotein. They found that most antibodies that inhibit SIV infectivity also bind to Env on infected cells and mediate ADCC, but this trend was not observed in select instances. Based on these findings, the authors suggest that some antibody–Env interactions can uncouple antiviral activities. Supported by ORIP (P51OD011106) and NIAID.
Efficient Ex Vivo Expansion of Conserved Element Vaccine-Specific CD8+ T Cells from SHIV-Infected, ART-Suppressed Nonhuman Primates
Dross et al., Frontiers in Immunology. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10189133/
HIV-specific T cells are necessary for control of HIV-1 replication but are largely insufficient for viral clearance. Using male rhesus macaques, investigators sought to increase the frequency of specific T cell responses in vivo using an ex vivo cell manufacturing approach. The resulting products contained high frequencies of specific, polyfunctional T cells, but no significant differences in T cell persistence were observed, nor was acquisition of simian–human immunodeficiency virus (SHIV). This work underscores this animal model as an important approach to optimize the manufacturing of antigen-specific immune effectors that can prevent virus acquisition and control viral rebound after discontinuing antiretroviral therapy (ART). Supported by ORIP (P51OD010425, U42OD011123), NIAID, and NCI.
Complement Contributes to Antibody-Mediated Protection Against Repeated SHIV Challenge
Goldberg et al., PNAS. 2023.
The first clinical efficacy trials of a broadly neutralizing antibody (bNAb) resulted in less benefit than expected and suggested that improvements are needed to prevent HIV infection. Using rhesus macaques of both sexes, investigators sought to further investigate the contribution of antibody-mediated activation of complement to the protective potency of an HIV bNAb in passive transfer and simian–human immunodeficiency virus (SHIV) challenge experiments. They observed that fewer bNAbs were required to protect animals from plasma viremia when complement activity was enhanced, suggesting that complement-mediated effector functions contribute to in vivo antiviral activity and might contribute to further improvements in the efficacy of antibody-mediated prevention strategies. Supported by ORIP (P51OD011092, U42OD023038) and NIAID.
Using Mass Spectrometry Imaging to Map Fluxes Quantitatively in the Tumor Ecosystem
Schwaiger-Haber et al., Nature Communications. 2023.
https://pubmed.ncbi.nlm.nih.gov/37208361/
Mass spectrometry imaging (MSI) can be used to identify metabolic patterns within different microenvironments of tumors but has not been fully integrated into metabolomics workflows. Investigators developed an integrated approach by combining MSI, stable isotope labeling, and a spatial variant of Isotopologue Spectral Analysis to study metabolic pathways across the brains of mice harboring GL261 glioma, a mouse model for glioblastoma. This study reveals the importance of multiple anabolic pathways, including fatty acid elongation flux, in glioma. Supported by ORIP (R24OD024624).
Therapeutic Blocking of VEGF Binding to Neuropilin-2 Diminishes PD-L1 Expression to Activate Antitumor Immunity in Prostate Cancer
Wang et al., Science Translational Medicine. 2023.
Prostate cancers often escape immune detection and destruction. Investigators report that neuropilin-2 (NRP2), which functions as a vascular endothelial growth factor (VEGF) receptor on tumor cells, is an attractive target to activate antitumor immunity in prostate cancer. They found that NRP2 depletion increased T cell activation in vitro. Additionally, inhibition of the binding of VEGF to NRP2 using a mouse-specific anti-NRP2 monoclonal antibody resulted in necrosis and tumor regression. These findings provide justification for the initiation of clinical trials using this function-blocking antibody in treatment of prostate cancer, especially for patients with aggressive disease. Supported by ORIP (R24OD026440) and NCI.
Giardia Hinders Growth by Disrupting Nutrient Metabolism Independent of Inflammatory Enteropathy
Giallourou et al., Nature Communications. 2023.
https://www.nature.com/articles/s41467-023-38363-2
Giardia lamblia is one of the most common intestinal pathogens among children in low- and middle-income countries. Investigators performed translational investigations using the Malnutrition and Enteric Diseases (MAL-ED) male and female cohort, as well as mice of both sexes, to identify mechanistic pathways that might explain Giardia-induced effects on early childhood growth. They identified signatures in the urinary metabolome of young children, suggesting that host growth restriction during infection is mediated by dysregulated amino acid metabolism. Supported by ORIP (P40OD010995), NIAID, and NIDDK.
Cell-Type Memory in a Single-Cell Eukaryote Requires the Continuous Presence of a Specific Transcription Regulator
Lee et al., PNAS. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10214202/
Investigators studied the fundamental question and underlying mechanism of how a eukaryotic cell type can be stably maintained through many rounds of DNA replication and cell division in a fungal species where two different cell types (i.e., white and opaque) arise from the same genome. Investigators found that destruction of Wor1, the primary transcription activator of the opaque state, led opaque cells to irreversibly lose their memory and switch to the white-cell state within about 1 hour. This study demonstrates that the continuous presence of Wor1 is needed to maintain the opaque cell state. Data also suggested that a threshold concentration of Wor1 is needed to maintain the opaque state, indicating the importance of the transcription factor in maintaining cell-type memory. Supported by ORIP (S10OD028511), NIAID, and NIGMS.
Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography
Coughlan et al., JAMA Neurology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37010830/
To understand the predominance (70%) of women among individuals with Alzheimer’s disease, the investigators studied regional tau and β-amyloid (Aβ) in relation to age at menopause and hormone therapy (HT) in postmenopausal women and age-matched men using positron emission tomography. The study demonstrated that females exhibited higher tau deposition compared with age-matched males, particularly in the setting of elevated Aβ; earlier age at menopause and late initiation of HT were associated with increased tau vulnerability. This study suggests female individuals with these conditions may be at higher risk of pathological burden. Supported by ORIP (S10OD025245), NIA, and NICHD.