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- Reinert, Line S, et al.
(author)
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Brain immune cells undergo cGAS-STING-dependent apoptosis during herpes simplex virus type 1 infection.
- 2020
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In: The Journal of clinical investigation. - 1558-8238. ; 131:1
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Journal article (peer-reviewed)abstract
- Protection of the brain from viral infections involves the type I interferon (IFN-I) system, defects in which renders humans susceptible to herpes simplex encephalitis (HSE). However, excessive cerebral IFN-I levels leads to pathologies, suggesting the need for tight regulation of responses. Based on data from mouse models, human HSE cases, and primary cell culture systems, we here show that microglia and other immune cells undergo apoptosis in the HSV-1-infected brain through a mechanism dependent on the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) pathway, but independent of IFN-I. HSV-1 infection of microglia induced cGAS-dependent apoptosis at high viral doses, while lower viral doses led to IFN-I responses. Importantly, inhibition of caspase activity prevented microglial cell death and augmented IFN-I responses. Accordingly, HSV-1-infected organotypic brain slices, or mice treated with caspase inhibitor, exhibited lower viral load and improved outcome of infection. Collectively, we identify an activation-induced apoptosis program in brain immune cells which down-modulates local immune responses.
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- Ren, Fanghui, et al.
(author)
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ER stress induces caspase-2-tBID-GSDMEdependent cell death in neurons lytically infected with herpes simplex virus type 2
- 2023
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In: EMBO JOURNAL. - 0261-4189 .- 1460-2075. ; 42:19
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Journal article (peer-reviewed)abstract
- Neurotropic viruses, including herpes simplex virus (HSV) types 1 and 2, have the capacity to infect neurons and can cause severe diseases. This is associated with neuronal cell death, which may contribute to morbidity or even mortality if the infection is not controlled. However, the mechanistic details of HSV-induced neuronal cell death remain enigmatic. Here, we report that lytic HSV-2 infection of human neuron-like SH-SY5Y cells and primary human and murine brain cells leads to cell death mediated by gasdermin E (GSDME). HSV-2-induced GSDME-mediated cell death occurs downstream of replication-induced endoplasmic reticulum stress driven by inositol-requiring kinase 1 alpha (IRE1 alpha), leading to activation of caspase-2, cleavage of the pro-apoptotic protein BH3interacting domain death agonist (BID), and mitochondriadependent activation of caspase-3. Finally, necrotic neurons released alarmins, which activated inflammatory responses in human iPSC-derived microglia. In conclusion, lytic HSV infection in neurons activates an ER stress-driven pathway to execute GSDMEmediated cell death and promote inflammation.
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- Heinz, J. L., et al.
(author)
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Whole exome sequencing of patients with varicella-zoster virus and herpes simplex virus induced acute retinal necrosis reveals rare disease-associated genetic variants
- 2023
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In: Frontiers in Molecular Neuroscience. - 1662-5099. ; 16
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Journal article (peer-reviewed)abstract
- Purpose: Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are neurotropic human alphaherpesviruses endemic worldwide. Upon primary infection, both viruses establish lifelong latency in neurons and reactivate intermittently to cause a variety of mild to severe diseases. Acute retinal necrosis (ARN) is a rare, sight-threatening eye disease induced by ocular VZV or HSV infection. The virus and host factors involved in ARN pathogenesis remain incompletely described. We hypothesize an underlying genetic defect in at least part of ARN cases.Methods: We collected blood from 17 patients with HSV-or VZV-induced ARN, isolated DNA and performed Whole Exome Sequencing by Illumina followed by analysis in Varseq with criteria of CADD score > 15 and frequency in GnomAD < 0.1% combined with biological filters. Gene modifications relative to healthy control genomes were filtered according to high quality and read-depth, low frequency, high deleteriousness predictions and biological relevance.Results: We identified a total of 50 potentially disease-causing genetic variants, including missense, frameshift and splice site variants and on in-frame deletion in 16 of the 17 patients. The vast majority of these genes are involved in innate immunity, followed by adaptive immunity, autophagy, and apoptosis; in several instances variants within a given gene or pathway was identified in several patients.Discussion: We propose that the identified variants may contribute to insufficient viral control and increased necrosis ocular disease presentation in the patients and serve as a knowledge base and starting point for the development of improved diagnostic, prophylactic, and therapeutic applications.
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- Vandecrux, Baptiste, et al.
(author)
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The firn meltwater Retention Model Intercomparison Project (RetMIP) : evaluation of nine firn models at four weather station sites on the Greenland ice sheet
- 2020
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In: The Cryosphere. - : Copernicus GmbH. - 1994-0416 .- 1994-0424. ; 14:11, s. 3785-3810
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Journal article (peer-reviewed)abstract
- Perennial snow, or firn, covers 80 % of the Greenland ice sheet and has the capacity to retain surface meltwater, influencing the ice sheet mass balance and contribution to sea-level rise. Multilayer firn models are traditionally used to simulate firn processes and estimate meltwater retention. We present, intercompare and evaluate outputs from nine firn models at four sites that represent the ice sheet's dry snow, percolation, ice slab and firn aquifer areas. The models are forced by mass and energy fluxes derived from automatic weather stations and compared to firn density, temperature and meltwater percolation depth observations. Models agree relatively well at the dry-snow site while elsewhere their meltwater infiltration schemes lead to marked differences in simulated firn characteristics. Models accounting for deep meltwater percolation overestimate percolation depth and firn temperature at the percolation and ice slab sites but accurately simulate recharge of the firn aquifer. Models using Darcy's law and bucket schemes compare favorably to observed firn temperature and meltwater percolation depth at the percolation site, but only the Darcy models accurately simulate firn temperature and percolation at the ice slab site. Despite good performance at certain locations, no single model currently simulates meltwater infiltration adequately at all sites. The model spread in estimated meltwater retention and runoff increases with increasing meltwater input. The highest runoff was calculated at the KAN_U site in 2012, when average total runoff across models (+/- 2 sigma) was 353 +/- 610 mm w. e. (water equivalent), about 27 +/- 48 % of the surface meltwater input. We identify potential causes for the model spread and the mismatch with observations and provide recommendations for future model development and firn investigation.
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