TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons

Gao, Daxing; Ciancanelli, Michael J.; Zhang, Peng; Harschnitz, Oliver; Bondet, Vincent; Hasek, Mary; Chen, Jie; Mu, Xin; Itan, Yuval; Cobat, Aurélie; Sancho‐Shimizu, Vanessa; Bigio, Benedetta; Lorenzo, Lazaro; Ciceri, Gabriele; McAlpine, Jessica L.; Anguiano, Esperanza; Jouanguy, Emmanuelle; Chaussabel, Damien; Meyts, Isabelle; Diamond, Michael S.; Abel, Laurent; Hur, Sun; Smith, Greg; Notarangelo, Luigi D.; Duffy, Darragh; Studer, Lorenz; Casanova, Jean‐Laurent; Zhang, Shen-Ying

doi:10.1172/jci134529

Cited by 69 publications

(65 citation statements)

References 100 publications

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“…Inherited IFNAR1 deficiency underlies critical COVID-19 probably due to its broad cellular impact (5,6,8). By contrast, inborn errors of the TLR3 pathway underlie critical influenza or COVID-19 pneumonia by impairing the production of type I IFNs by cells other than pDCs, such as pulmonary epithelial cells (5)(6)(7)(8)65).…”

Section: Discussionmentioning

confidence: 99%

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X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Asano¹,

Boisson²,

Onodi³

et al. 2021

Sci. Immunol.

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285

266

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Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10 −5 ). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10 −4 . We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7. The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.

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Section: Discussionmentioning

confidence: 99%

“…64 Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. 65 Department of Molecular Biology and Genetics, Bilkent University, Bilkent -Ankara, Turkey. 66 Laboratory of Immunogenetics of Human Diseases, Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain.…”

mentioning

confidence: 99%

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Asano¹,

Boisson²,

Onodi³

et al. 2021

Sci. Immunol.

Self Cite

285

266

View full text Add to dashboard Cite

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“…Furthermore, TLR2, TLR4, TLR7, TLR8 and TLR9 take part in the initiation of the immune response against neurotropic viruses [ 85 , 86 , 89 , 201 , 282 ]. CNS resident cell subsets including neurons, astrocytes and microglia express distinct patterns of TLRs, whereas the overall expression levels vary between the different cell subsets [ 70 , 108 , 111 , 112 , 113 , 114 , 115 , 118 , 120 , 121 , 122 , 123 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 137 ]. Thanks to the increasing number of studies about the exploitation of TLR-mediated sensing and TLR signaling, important knowledge is being collected about the potential of preventive and therapeutic interventions against neurotropic infections [ 70 , 158 , 199 , 215 , 283 , 284 ].…”

Section: Discussionmentioning

confidence: 99%

“…Virtually all TLRs known in the murine and human system are expressed in neurons. However, the expression of TLR5 in neurons from mice and TLR9 and TLR10 in neurons from humans are controversially discussed [ 70 , 111 , 113 , 114 , 118 , 122 , 123 , 125 , 126 , 127 , 128 , 129 , 130 , 137 ].…”

Section: Figurementioning

confidence: 99%

Toll-like Receptors in Viral Encephalitis

Gern

Mulenge

Pavlou

et al. 2021

Viruses

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Viral encephalitis is a rare but serious syndrome. In addition to DNA-encoded herpes viruses, such as herpes simplex virus and varicella zoster virus, RNA-encoded viruses from the families of Flaviviridae, Rhabdoviridae and Paramyxoviridae are important neurotropic viruses. Whereas in the periphery, the role of Toll-like receptors (TLR) during immune stimulation is well understood, TLR functions within the CNS are less clear. On one hand, TLRs can affect the physiology of neurons during neuronal progenitor cell differentiation and neurite outgrowth, whereas under conditions of infection, the complex interplay between TLR stimulated neurons, astrocytes and microglia is just on the verge of being understood. In this review, we summarize the current knowledge about which TLRs are expressed by cell subsets of the CNS. Furthermore, we specifically highlight functional implications of TLR stimulation in neurons, astrocytes and microglia. After briefly illuminating some examples of viral evasion strategies from TLR signaling, we report on the current knowledge of primary immunodeficiencies in TLR signaling and their consequences for viral encephalitis. Finally, we provide an outlook with examples of TLR agonist mediated intervention strategies and potentiation of vaccine responses against neurotropic virus infections.

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“…TLR3 receptor recognizes double-stranded RNA (dsRNA), which is a typical intermediate product of viral replication. TLR3 activation triggers antiviral responses such as interferon production, NK cell activation, and inflammation [18][19][20]. The heterozygous novel TLR3 p.L742F variant was observed in two of the seven unrelated NE encephalitis patients (29%, p = 0.0195) [8].…”

Section: Puuv Encephalitismentioning

confidence: 97%

Central Nervous System and Ocular Manifestations in Puumala Hantavirus Infection

Hautala

Partanen

Kubin

et al. 2021

Viruses

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Puumala hantavirus (PUUV), carried and spread by the bank vole (Myodes glareolus), causes a mild form of hemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE). Acute high fever, acute kidney injury (AKI), thrombocytopenia, and hematuria are typical features of this syndrome. In addition, headache, blurred vision, insomnia, vertigo, and nausea are commonly associated with the disease. This review explores the mechanisms and presentations of ocular and central nervous system involvement in acute NE.

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TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons

Cited by 69 publications

References 100 publications

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Toll-like Receptors in Viral Encephalitis

Central Nervous System and Ocular Manifestations in Puumala Hantavirus Infection

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