Selected Grantee Publications
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- 11 results found
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- Infectious Diseases
- Vaccines/Therapeutics
Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy
Racine et al., Journal of Immunology. 2024.
Myocarditis has emerged as a relatively rare but often lethal autoimmune complication of checkpoint inhibitor (ICI) cancer therapy, and significant mortality is associated with this phenomenon. Investigators developed a new mouse model system that spontaneously develops myocarditis. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, the treatment accelerates skeletal muscle myositis. The team performed characterization of cardiac and skeletal muscle T cells using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies. Supported by ORIP (U54OD020351, U54OD030187), NCI, NIA, NIDDK, and NIGMS.
Deep Analysis of CD4 T Cells in the Rhesus CNS During SIV Infection
Elizaldi et al., PLOS Pathogens. 2023.
https://pubmed.ncbi.nlm.nih.gov/38060615/
Systemic HIV infection results in chronic inflammation that causes lasting damage to the central nervous system (CNS), despite long-term antiretroviral therapy (ART). Researchers studied neurocognitive outcomes in male and female rhesus macaques infected with simian immunodeficiency virus (SIV) using an ART regimen simulating suboptimal adherence; one group received no ART, and the other received ART with periodic interruptions. Using single-cell transcriptomic profiling, the researchers also identified molecular programs induced in the brain upon infection. They found that acute infection led to marked imbalance in the CNS CD4/CD8 T‑cell ratio, which persisted into the chronic phase. The studies provide insight into the role of CD4 T cells in the CNS during HIV infection. Supported by ORIP (P51OD011107, K01OD023034), NIA, NIAID, and NCI.
IL-21-IgFc Immunotherapy Alters Transcriptional Landscape of Lymph Node Cells Leading to Enhanced Flu Vaccine Response in Aging and SIV Infection
Pallikkuth et al., Aging Cell. 2023.
https://pubmed.ncbi.nlm.nih.gov/37712598/
Aging is associated with increased risk of seasonal flu disease burden and serious flu-related complications, particularly for people with HIV. In this study, investigators aimed to elucidate the immunomodulation following flu vaccination in aging male and female rhesus macaques infected with simian immunodeficiency virus (SIV). Their results suggest that IL-21 treatment at the time of flu vaccination modulates the inductive lymph node germinal center activity to reverse SIV-associated immune dysfunction. The authors identified IL-21 as a potential candidate molecule for immunotherapy to enhance flu vaccine responses in affected populations. Further studies could examine the overall benefit of IL-21 immunotherapy on mucosal lung immunity and protection against infection. Supported by ORIP (R24OD010947), NIA, and NIAID.
p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy
Faget et al., Cancer Discovery. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238649/
This study emphasizes the importance of the metastatic tumor microenvironment in metastatic breast cancer growth and the identification of effective antimetastatic therapies. Using a stromal labeling approach and single-cell RNA sequencing, the authors showed that a combination of p38MAPK inhibition (p38i) and anti-OX40 synergistically reduced metastatic tumor growth and increased overall survival. Further engagement of cytotoxic T cells cured all metastatic disease in mice and produced durable immunologic memory. The Cancer Genome Atlas data analysis revealed that patients with p38i metastatic stromal signature and a high tumor mutational burden (TMB) had increased overall survival. These findings suggest that patients with high TMB would benefit the most from the p38i plus anti-OX40 approach. Supported by ORIP (S10OD028483), NIA, NCI, and NIGMS.
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.
SARS-CoV-2 Infects Neurons and Induces Neuroinflammation in a Non-Human Primate Model of COVID-19
Beckman et al., Cell Reports. 2022.
https://www.doi.org/10.1016/j.celrep.2022.111573
SARS-CoV-2 causes brain fog and other neurological complications in some patients. It has been unclear whether SARS-CoV-2 infects the brain directly or whether central nervous system sequelae result from systemic inflammatory responses triggered in the periphery. Using a rhesus macaque model, researchers detected SARS-CoV-2 in the olfactory cortex and interconnected regions 7 days after infection, demonstrating that the virus enters the brain through the olfactory nerve. Neuroinflammation and neuronal damage were more severe in elderly monkeys with type 2 diabetes. The researchers found that in aged monkeys, SARS-CoV-2 traveled farther along nerve pathways to regions associated with Alzheimer's disease. Supported by ORIP (P51OD011107) and NIA.
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.
Advancing Human Disease Research with Fish Evolutionary Mutant Models
Beck et al., Trends in Genetics. 2021.
https://pubmed.ncbi.nlm.nih.gov/34334238/
Model organism research is essential to understand disease mechanisms. However, laboratory-induced genetic models can lack genetic variation and often fail to mimic disease severity. Evolutionary mutant models (EMMs) are species with evolved phenotypes that mimic human disease. They have improved our understanding of cancer, diabetes, and aging. Fish are the most diverse group of vertebrates, exhibiting a kaleidoscope of specialized phenotypes, many that would be pathogenic in humans but are adaptive in the species' specialized habitat. Evolved compensations can suggest avenues for novel disease therapies. This review summarizes current research using fish EMMs to advance our understanding of human disease. Supported by ORIP (R01OD011116), NIA, NIDA, and NIGMS.
Innate Immunity Stimulation via CpG Oligodeoxynucleotides Ameliorates Alzheimer’s Disease Pathology in Aged Squirrel Monkeys
Patel et al., Brain: A Journal of Neurology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34128045/
Alzheimer's disease is the only illness among the top 10 causes of death for which there is no disease-modifying therapy. The authors have shown in transgenic Alzheimer's disease mouse models that harnessing innate immunity via TLR9 agonist CpG oligodeoxynucleotides (ODNs) modulates age-related defects associated with immune cells and safely reduces amyloid plaques, oligomeric amyloid-β, tau pathology, and cerebral amyloid angiopathy (CAA). They used a nonhuman primate model for sporadic Alzheimer's disease pathology that develops extensive CAA-elderly squirrel monkeys. They demonstrate that long-term use of Class B CpG ODN 2006 induces a favorable degree of innate immunity stimulation. CpG ODN 2006 has been well established in numerous human trials for a variety of diseases. This evidence together with their earlier research validates the beneficial therapeutic outcomes and safety of this innovative immunomodulatory approach. Supported by ORIP (P40OD010938), NINDS, NIA, and NCI.
A Novel Tau-Based Rhesus Monkey Model of Alzheimer’s Pathogenesis
Beckman et al., Alzheimer’s & Dementia. 2021.
https://pubmed.ncbi.nlm.nih.gov/33734581/
Alzheimer’s disease (AD) is becoming more prevalent as the population ages, but there are no effective treatments for this devastating condition. Researchers developed a rhesus monkey model of AD by targeting the entorhinal cortex with an adeno-associated virus expressing mutant tau protein. Within 3 months they observed evidence of misfolded tau propagation, similar to what is hypothesized for AD patients. Treated monkeys developed robust alterations in AD core biomarkers in cerebrospinal fluid and blood. These results highlight the initial stages of tau seeding and propagation in rhesus macaques, a potentially powerful translational model with which to test new AD therapies. Supported by ORIP (P51OD011107) and NIA.