TLR3 immunity to infection in mice and humans

Zhang, Shen-Ying; Herman, Melina; Ciancanelli, Michael J.; Diego, Rebeca Pérez de; Sancho‐Shimizu, Vanessa; Abel, Laurent; Casanova, Jean‐Laurent

doi:10.1016/j.coi.2012.11.001

Cited by 150 publications

(144 citation statements)

References 170 publications

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“…Late relapses of HSE are particularly rare and their underlying mechanism remains unclear. 30 The 3 patients with TLR3 deficiency reported in this study, like one of the 3 previously reported TLR3-deficient patients, 6 had recurrent HSE, with intervals of about 2 to 26 years between HSE episodes (table 1). Late relapses of HSE have occurred in 4 of the 6 (67%) TLR3-deficient patients identified to date.…”

Section: 26mentioning

confidence: 97%

“…The clinical penetrance of TLR3 deficiencies as well as that of other human TLR3 pathway deficiencies (UNC-93B, TRIF, TBK1) is incomplete for HSE. 6 Diverse factors may be causative of the incomplete penetrance of human TLR3 pathway deficiencies, including environmental factors, pathogen-related (viral infection load and virus strain) or pathogen-unrelated (another infection) factors, or host factors, including genetic (modifiers) or epigenetic (age at infection) factors. In any event, our finding that a small albeit sizeable fraction of children with HSE (5%) carry morbid mutations in TLR3 suggests that this is a core morbid gene, defining a core morbid pathway.…”

Section: 26mentioning

confidence: 99%

“…4,5 The pathogenesis of HSE had long remained unclear. Our recent studies have demonstrated that HSE may result from singlegene inborn errors of TLR3-mediated immunity in some children, 6 with homozygous or …”

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confidence: 99%

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TLR3 deficiency in herpes simplex encephalitis

Lim¹,

Seppänen²,

Hautala³

et al. 2014

Neurology

137

120

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Objective: To determine the proportion of children with herpes simplex encephalitis (HSE) displaying TLR3 deficiency, the extent of TLR3 allelic heterogeneity, and the specific clinical features of TLR3 deficiency. Methods:We determined the sequence of all exons of TLR3 in 110 of the 120 patients with HSE enrolled in our study who do not carry any of the previously described HSE-predisposing mutations of TLR3 pathway genes (TLR3, UNC93B1, TRIF, TRAF3, and TBK1). All the new mutant TLR3 alleles detected were characterized experimentally in-depth to establish the causal relationship between the genotype and phenotype.Results: In addition to the 3 previously reported TLR3-deficient patients from the same cohort, 6 other children or young adults with HSE carry 1 of 5 unique or extremely rare (minor allele frequency ,0.001) missense TLR3 alleles. Two alleles (M374T, D592N) heterozygous in 3 patients are not deleterious in vitro. The other 3 are deleterious via different mechanisms: G743D1R811I and L360P heterozygous in 2 patients are loss-of-function due to low levels of expression and lack of cleavage, respectively, and R867Q homozygous in 1 patient is hypomorphic. The 3 patients' fibroblasts display impaired TLR3 responses and enhanced herpes simplex virus 1 susceptibility. Overall, TLR3 deficiency is therefore found in 6 (5%) of the 120 patients studied. There is high allelic heterogeneity, with 3 forms of autosomal dominant partial defect by negative dominance or haploinsufficiency, and 2 forms of autosomal recessive defect with complete or partial deficiency. Finally, 4 (66%) of the 6 TLR3-deficient patients had at least 1 late relapse of HSE, whereas relapse occurred in only 12 (10%) of the total cohort of 120 patients.Conclusions: Childhood-onset HSE is due to TLR3 deficiency in a traceable fraction of patients, in particular the ones with HSE recurrence. Mutations in TLR3 and TLR3 pathway genes should be searched and experimentally studied in children with HSE, and patients with proven TLR3 deficiency should be followed carefully. TLR3 is one of the most highly conserved TLRs in humans that have evolved under the strongest purifying selection.1 TLR3 recognizes double-stranded RNA (dsRNA), a by-product produced during the viral replication of most viruses, including herpes simplex virus 1 (HSV-1).2 The most common known clinical consequence of human TLR3 deficiency is childhood herpes simplex encephalitis (HSE). Childhood HSE is a rare life-threatening complication of primary infection with HSV-1, a common neurotropic dsDNA virus that is innocuous in most children.3 HSE is the most common form of sporadic viral encephalitis in Western countries. 4,5 The pathogenesis of HSE had long remained unclear. Our recent studies have demonstrated that HSE may result from singlegene inborn errors of TLR3-mediated immunity in some children, 6 with homozygous or

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Section: 26mentioning

confidence: 97%

Section: 26mentioning

confidence: 99%

See 1 more Smart Citation

TLR3 deficiency in herpes simplex encephalitis

Lim¹,

Seppänen²,

Hautala³

et al. 2014

Neurology

137

120

View full text Add to dashboard Cite

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“…TLR2/6 and TLR4 responses have not been assessed in MyD88-and IRAK-4-deficient fibroblasts, in which TLR3 responses to poly(I:C) are intact and mediated by the TRIF-dependent pathway (67)(68)(69). In addition, CD62L shedding and proinflammatory cytokine production in response to IL-1R agonists (IL-1β) or any of the TLR agonists tested, other than poly(I:C), that signal via receptors other than TLR3 in most human leukocyte subsets (69) (TLR1/2, TLR2/6, TLR5, TLR7, TLR8, TLR9, and partially TLR4) were abolished in all IRAK-4-and MyD88-deficient leukocyte subsets tested ex vivo (granulocytes, monocytes, plasmacytoid and myeloid dendritic cells, NK, T, and B cells) or generated in vitro (monocyte-derived dendritic cells) (52,55).…”

Section: Significancementioning

confidence: 99%

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

Mina

Borghesi

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1. Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4-or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient's fibroblasts, which responded very poorly to all TLR2/6 (PAM 2 CSK 4 , LTA, FSL-1), TLR1/2 (PAM 3 CSK 4 ), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1β. By contrast, the patient's peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1β. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.IRAK-1 | IRAK-4 | Toll-like receptor | interleukin-1 receptor | primary immunodeficiency

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“…We assessed the usefulness of the HGC, by applying a hypothesis-driven approach to generate a Toll-like receptor 3 (TLR3)-specific connectome. Inborn errors of TLR3 immunity have been shown to underlie the pathogenesis of herpes simplex virus 1 (HSV-1) encephalitis (HSE) in a small fraction of affected children (10)(11)(12)(13). No genetic etiology has yet been identified for most children with HSE and the TLR3 connectome may facilitate the selection of candidate variants in these patients (3,14).…”

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confidence: 99%

The human gene connectome as a map of short cuts for morbid allele discovery

Itan

Zhang

Vogt

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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High-throughput genomic data reveal thousands of gene variants per patient, and it is often difficult to determine which of these variants underlies disease in a given individual. However, at the population level, there may be some degree of phenotypic homogeneity, with alterations of specific physiological pathways underlying the pathogenesis of a particular disease. We describe here the human gene connectome (HGC) as a unique approach for human Mendelian genetic research, facilitating the interpretation of abundant genetic data from patients with the same disease, and guiding subsequent experimental investigations. We first defined the set of the shortest plausible biological distances, routes, and degrees of separation between all pairs of human genes by applying a shortest distance algorithm to the full human gene network. We then designed a hypothesis-driven application of the HGC, in which we generated a Toll-like receptor 3-specific connectome useful for the genetic dissection of inborn errors of Toll-like receptor 3 immunity. In addition, we developed a functional genomic alignment approach from the HGC. In functional genomic alignment, the genes are clustered according to biological distance (rather than the traditional molecular evolutionary genetic distance), as estimated from the HGC. Finally, we compared the HGC with three state-of-the-art methods: String, FunCoup, and HumanNet. We demonstrated that the existing methods are more suitable for polygenic studies, whereas HGC approaches are more suitable for monogenic studies. The HGC and functional genomic alignment data and computer programs are freely available to noncommercial users from http://lab.rockefeller.edu/casanova/HGC and should facilitate the genome-wide selection of disease-causing candidate alleles for experimental validation.

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TLR3 immunity to infection in mice and humans

Cited by 150 publications

References 170 publications

TLR3 deficiency in herpes simplex encephalitis

TLR3 deficiency in herpes simplex encephalitis

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

The human gene connectome as a map of short cuts for morbid allele discovery

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