Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis

Lafaille, Fabien G.; Harschnitz, Oliver; Lee, Yoon Seung; Zhang, Peng; Hasek, Mary; Kerner, Gaspard; Itan, Yuval; Ewaleifoh, Osefame; Rapaport, Franck; Carlile, Thomas M.; Carter-Timofte, Madalina E.; Paquet, Dominik; Dobbs, Kerry; Zimmer, Bastian; Gao, Daxing; Rojas-Durán, María F.; Kwart, Dylan; Rattina, Vimel; Ciancanelli, Michael J.; McAlpine, Jessica L.; Lorenzo, Lazaro; Boucherit, Soraya; Rozenberg, Flore; Halwani, Rabih; Henry, B.; Amenzoui, N.; Alsum, Zobaida; Marquès, Laura; Church, Joseph A.; Al‐Muhsen, Saleh; Tardieu, Marc; Bousfiha, Ahmed Aziz; Paludan, Søren R.; Mogensen, Trine H.; Quintana-Murci, Lluı́s; Tessier‐Lavigne, Marc; Smith, Greg; Notarangelo, Luigi D.; Studer, Lorenz; Gilbert, Wendy V.; Abel, Laurent; Casanova, Jean‐Laurent; Zhang, Shen-Ying

doi:10.1038/s41591-019-0672-3

Cited by 95 publications

(84 citation statements)

References 66 publications

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“…IFN-β affected the phosphorylation levels of STAT1 [242], MAPK1/2 [207] and JAK1 [242] and total STAT1 protein levels [244] in primary rodent neuronal cultures. In addition, unlike normal neuronal cells, the exposure of STAT1-mutated neurons to IFN-β did not render them resistant to HSV-1 infection [247], which indicates that this IFN indeed affects neuronal STAT1 signaling. Still, the low expression of STAT1 in neurons [244] might explain why IFN-β does not have such profound effects on neurons compared to microglia and astrocytes.…”

Section: Neuronsmentioning

confidence: 95%

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Kleijn

Martens

2020

IJMS

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Multiple sclerosis (MS) is characterized by peripheral and central inflammatory features, as well as demyelination and neurodegeneration. The available Food and Drug Administration (FDA)-approved drugs for MS have been designed to suppress the peripheral immune system. In addition, however, the effects of these drugs may be partially attributed to their influence on glial cells and neurons of the central nervous system (CNS). We here describe the molecular effects of the traditional and more recent FDA-approved MS drugs Fingolimod, Dimethyl Fumarate, Glatiramer Acetate, Interferon-β, Teriflunomide, Laquinimod, Natalizumab, Alemtuzumab and Ocrelizumab on microglia, astrocytes, neurons and oligodendrocytes. Furthermore, we point to a possible common molecular effect of these drugs, namely a key role for NFκB signaling, causing a switch from pro-inflammatory microglia and astrocytes to anti-inflammatory phenotypes of these CNS cell types that recently emerged as central players in MS pathogenesis. This notion argues for the need to further explore the molecular mechanisms underlying MS drug action.

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Section: Neuronsmentioning

confidence: 95%

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Kleijn

Martens

2020

IJMS

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“…With the exception of the identification of the causal virus, the pathogenesis of HSE remained unexplained until 2006-2007, when inborn errors of UNC-93B-dependent TLR3 immunity were found to underlie the development of isolated forebrain HSE in some children (9,10). Other autosomal recessive (AR) or dominant (AD) inborn errors have since been reported to underlie forebrain HSE through an impairment of the TLR3 responsive pathway (9,(11)(12)(13)(14)(15) or snoRNA31 function (16). Moreover, an AR partial DBR1 deficiency has been shown to impair RNA lariat metabolism and to underlie brainstem viral encephalitis, including brainstem HSE (17).…”

Section: Introductionmentioning

confidence: 99%

Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency

Bastard¹,

Manry²,

Chen³

et al. 2021

Journal of Clinical Investigation

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Inborn errors of TLR3-dependent IFN-a/b-and-l-mediated immunity in the central nervous system (CNS) can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-a/b and-l are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3'UTR of the last exon of IFNAR1, who died from HSE at the age of two years. An older cousin died following vaccination against measles, mumps and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other, less severe viral illnesses. The encoded IFNAR1 protein is expressed on the cell surface but is truncated and cannot interact with the tyrosine kinase TYK2. The patient's fibroblasts and EBV-B cells did not respond to IFN-a2b or IFN-b, in terms of STAT1, STAT2 and STAT3 phosphorylation, or the genome-wide induction of IFN-stimulated genes. The patient's fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-a2b or IFN-b. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This viral disease occurred in natural conditions, unlike those previously reported in other patients with IFNAR1 or IFNAR2 deficiency. This experiment of Nature indicates that IFN-a/b are essential for anti-HSV-1 immunity in the CNS.

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“…Therefore, in addition to the acute symptoms of viral encephalitis, such as altered mental status, fever, seizures, and neurologic deficits, the long-term neurological sequela for survivors are often highly disabling (1). To prevent brain damage in response to infections, the brain abundantly uses cell-preserving and cell autonomous mechanisms to control virus infections (10)(11)(12)(13), and the more disruptive antiviral activities must be tightly controlled.…”

Section: Introductionmentioning

confidence: 99%

Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production

Reinert¹,

Rashidi²,

Tran³

et al. 2021

Journal of Clinical Investigation

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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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Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis

Cited by 95 publications

References 66 publications

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency

Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production

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