Post-exposure intranasal IFNα suppresses replication and neuroinvasion of Venezuelan Equine Encephalitis virus within olfactory sensory neurons
(2024) Journal of Neuroinflammation, 21 (1), art. no. 24, .
Cain, M.D.a b , Klein, N.R.b , Jiang, X.a b , Salimi, H.a b , Wu, Q.a b , Miller, M.J.b , Klimstra, W.B.e , Klein, R.S.a b c d
a Center for Neuroimmunology & Neuroinfectious Diseases, Washington University School of Medicine, St. Louis, MO, United States
b Departments of Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
d Departments of Neurosciences, Washington University School of Medicine, St. Louis, MO, United States
e Department of Immunology and Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States
Abstract
Background: Venezuelan Equine Encephalitis virus (VEEV) may enter the central nervous system (CNS) within olfactory sensory neurons (OSN) that originate in the nasal cavity after intranasal exposure. While it is known that VEEV has evolved several mechanisms to inhibit type I interferon (IFN) signaling within infected cells, whether this inhibits virologic control during neuroinvasion along OSN has not been studied. Methods: We utilized an established murine model of intranasal infection with VEEV and a repository of scRNAseq data from IFN-treated OSN to assess the cellular targets and IFN signaling responses after VEEV exposure. Results: We found that immature OSN, which express higher levels of the VEEV receptor LDLRAD3 than mature OSN, are the first cells infected by VEEV. Despite rapid VEEV neuroinvasion after intranasal exposure, olfactory neuroepithelium (ONE) and olfactory bulb (OB) IFN responses, as assessed by evaluation of expression of interferon signaling genes (ISG), are delayed for up to 48 h during VEEV neuroinvasion, representing a potential therapeutic window. Indeed, a single intranasal dose of recombinant IFNα triggers early ISG expression in both the nasal cavity and OB. When administered at the time of or early after infection, IFNα treatment delayed onset of sequelae associated with encephalitis and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the ONE, which inhibited subsequent invasion into the CNS. Conclusions: Our results demonstrate a critical and promising first evaluation of intranasal IFNα for the treatment of human encephalitic alphavirus exposures. © 2024, The Author(s).
Funding details
Washington University School of Medicine in St. LouisWUSM
Document Type: Article
Publication Stage: Final
Source: Scopus
Associations between COVID-19 and putative markers of neuroinflammation: A diffusion basis spectrum imaging study
(2024) Brain, Behavior, and Immunity – Health, 36, art. no. 100722, .
Zhang, W.a , Gorelik, A.J.b , Wang, Q.a , Norton, S.A.b , Hershey, T.a b c d , Agrawal, A.c , Bijsterbosch, J.D.a , Bogdan, R.b
a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychological & Brain Sciences, Washington University, St. Louis, MO, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
COVID-19 remains a significant international public health concern. Yet, the mechanisms through which symptomatology emerges remain poorly understood. While SARS-CoV-2 infection may induce prolonged inflammation within the central nervous system, the evidence primarily stems from limited small-scale case investigations. To address this gap, our study capitalized on longitudinal UK Biobank neuroimaging data acquired prior to and following COVID-19 testing (N = 416 including n = 224 COVID-19 cases; Mage = 58.6). Putative neuroinflammation was assessed in gray matter structures and white matter tracts using non-invasive Diffusion Basis Spectrum Imaging (DBSI), which estimates inflammation-related cellularity (DBSI-restricted fraction; DBSI-RF) and vasogenic edema (DBSI-hindered fraction; DBSI-HF). We hypothesized that COVID-19 case status would be associated with increases in DBSI markers after accounting for potential confound (age, sex, race, body mass index, smoking frequency, and data acquisition interval) and multiple testing. COVID-19 case status was not significantly associated with DBSI-RF (|β|’s < 0.28, pFDR >0.05), but with greater DBSI-HF in left pre- and post-central gyri and right middle frontal gyrus (β′s > 0.3, all pFDR = 0.03). Intriguingly, the brain areas exhibiting increased putative vasogenic edema had previously been linked to COVID-19-related functional and structural alterations, whereas brain regions displaying subtle differences in cellularity between COVID-19 cases and controls included regions within or functionally connected to the olfactory network, which has been implicated in COVID-19 psychopathology. Nevertheless, our study might not have captured acute and transitory neuroinflammatory effects linked to SARS-CoV-2 infection, possibly due to symptom resolution before the imaging scan. Future research is warranted to explore the potential time- and symptom-dependent neuroinflammatory relationship with COVID-19. © 2024 The Authors
Author Keywords
COVID-19; DBSI; Diffusion basis spectrum imaging; Long COVID; Neuroimaging; Neuroinflammation; UK biobank
Funding details
National Science FoundationNSFDGE-213989
National Institutes of HealthNIHHD070855, NS109487, R01 AG061162, R01 DA054750, R01 DK126826, R21 AA027827, U01 DA055367
National Institute of Mental HealthNIMHR01 MH128286
Washington University in St. LouisWUSTL
McDonnell Center for Systems Neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations
(2024) The Journal of Experimental Medicine, 221 (2), .
Cadiz, M.P.a b , Gibson, K.A.a , Todd, K.T.a , Nascari, D.G.a c d , Massa, N.a b , Lilley, M.T.b , Olney, K.C.a , Al-Amin, M.M.e , Jiang, H.f , Holtzman, D.M.f , Fryer, J.D.a b c d
a Department of Neuroscience, Mayo Clinic, Scottsdale, AZ, United States
b Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Scottsdale, AZ, United States
c Biochemistry and Molecular Biology Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Scottsdale, AZ, United States
d MD/PhD Training Program, Mayo Clinic, Scottsdale, AZ, United States
e Department of Medical and Molecular Genetics, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States
f Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Aducanumab, an anti-amyloid immunotherapy for Alzheimer’s disease, efficiently reduces Aβ, though its plaque clearance mechanisms, long-term effects, and effects of discontinuation are not fully understood. We assessed the effect of aducanumab treatment and withdrawal on Aβ, neuritic dystrophy, astrocytes, and microglia in the APP/PS1 amyloid mouse model. We found that reductions in amyloid and neuritic dystrophy during acute treatment were accompanied by microglial and astrocytic activation, and microglial recruitment to plaques and adoption of an aducanumab-specific pro-phagocytic and pro-degradation transcriptomic signature, indicating a role for microglia in aducanumab-mediated Aβ clearance. Reductions in Aβ and dystrophy were sustained 15 but not 30 wk after discontinuation, and reaccumulation of plaques coincided with loss of the microglial aducanumab signature and failure of microglia to reactivate. This suggests that despite the initial benefit from treatment, microglia are unable to respond later to restrain plaque reaccumulation, making further studies on the effect of amyloid-directed immunotherapy withdrawal crucial for assessing long-term safety and efficacy. © 2024 Cadiz et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread
(2024) Cell, 187 (2), pp. 428-445.e20.
Chen, Y.a b , Song, S.a , Parhizkar, S.a c d , Lord, J.a , Zhu, Y.a , Strickland, M.R.a , Wang, C.a , Park, J.a , Tabor, G.T.a , Jiang, H.a c d , Li, K.a , Davis, A.A.a c , Yuede, C.M.a c d e f , Colonna, M.b c , Ulrich, J.D.a c d , Holtzman, D.M.a c d
a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
d Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
A recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer’s Disease (AD) caused by a PSEN1-E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear. We generated a humanized APOE3ch knock-in mouse and crossed it to an amyloid-β (Aβ) plaque-depositing model. We injected AD-tau brain extract to investigate tau seeding and spreading in the presence or absence of amyloid. Similar to the case report, APOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque-associated tau pathology. Additionally, we observed decreased amyloid response and enhanced microglial response around plaques. We also demonstrate increased myeloid cell phagocytosis and degradation of tau aggregates linked to weaker APOE3ch binding to heparin sulfate proteoglycans. APOE3ch influences the microglial response to Aβ plaques, which suppresses Aβ-induced tau seeding and spreading. The results reveal new possibilities to target Aβ-induced tauopathy. © 2023 Elsevier Inc.
Funding details
National Institutes of HealthNIHRF1AG047644, RF1NS090934
Alzheimer’s AssociationAAAARF-21-850865
JPB FoundationJPBF
Cure Alzheimer’s FundCAF
University of WashingtonUW
Center for Cellular Imaging, Washington UniversityWUCCI
Document Type: Article
Publication Stage: Final
Source: Scopus
Transcription factor interactions explain the context-dependent activity of CRX binding sites
(2024) PLoS Computational Biology, 20 (1), art. no. e1011802, .
Loell, K.J.a b , Friedman, R.Z.a b , Myers, C.A.c , Corbo, J.C.c , Cohen, B.A.a b , White, M.A.a b
a Department of Genetics, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
b The Edison Family Center for Genome Sciences & Systems Biology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
c Department of Pathology and Immunology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
The effects of transcription factor binding sites (TFBSs) on the activity of a cis-regulatory element (CRE) depend on the local sequence context. In rod photoreceptors, binding sites for the transcription factor (TF) Cone-rod homeobox (CRX) occur in both enhancers and silencers, but the sequence context that determines whether CRX binding sites contribute to activation or repression of transcription is not understood. To investigate the context-dependent activity of CRX sites, we fit neural network-based models to the activities of synthetic CREs composed of photoreceptor TFBSs. The models revealed that CRX binding sites consistently make positive, independent contributions to CRE activity, while negative homotypic interactions between sites cause CREs composed of multiple CRX sites to function as silencers. The effects of negative homotypic interactions can be overcome by the presence of other TFBSs that either interact cooperatively with CRX sites or make independent positive contributions to activity. The context-dependent activity of CRX sites is thus determined by the balance between positive heterotypic interactions, independent contributions of TFBSs, and negative homotypic interactions. Our findings explain observed patterns of activity among genomic CRX-bound enhancers and silencers, and suggest that enhancers may require diverse TFBSs to overcome negative homotypic interactions between TFBSs. © 2024 Loell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Document Type: Article
Publication Stage: Final
Source: Scopus
Estrogen-induced glial IL-1β mediates extrinsic retinal ganglion cell vulnerability in murine Nf1 optic glioma
(2024) Annals of Clinical and Translational Neurology, .
Tang, Y.a b , Chatterjee, J.a , Wagoner, N.a , Bozeman, S.a , Gutmann, D.H.a
a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Ophthalmology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Optic pathway gliomas (OPGs) arising in children with neurofibromatosis type 1 (NF1) can cause retinal ganglion cell (RGC) dysfunction and vision loss, which occurs more frequently in girls. While our previous studies demonstrated that estrogen was partly responsible for this sexually dimorphic visual impairment, herein we elucidate the underlying mechanism. In contrast to their male counterparts, female Nf1OPG mice have increased expression of glial interleukin-1β (IL-1β), which is neurotoxic to RGCs in vitro. Importantly, both IL-1β neutralization and leuprolide-mediated estrogen suppression decrease IL-1β expression and ameliorate RGC dysfunction, providing preclinical proof-of-concept evidence supporting novel neuroprotective strategies for NF1-OPG-induced vision loss. © 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
National Eye InstituteNEIP30EY002687
National Institute of Neurological Disorders and StrokeNINDSR25‐NS090978
Document Type: Article
Publication Stage: Article in Press
Source: Scopus