COVID-19 research

Gene: TLR3

Green List (high evidence)

I forgot to add severe influenza pneumonia in the associated phenotype in the previous comment

Created: 24 Apr 2020, 4:06 p.m. | Last Modified: 24 Apr 2020, 4:06 p.m.

Panel Version: 0.160

These studies demonstrate the deleterious effect of some TLR3 mutations and predisposition to Herpes simplex encephalitis in 4 separate studies on unrelated patients from different countries. TLR3 mutations in 3 children were associated with severe influenza pneumonitis. Finally, 2 other studies evaluate the protective effect of a common polymorphism of TLR3 against HIV infection in repetitively exposed individuals. Accordingly, we might find protective or deleterious effects in COVID19 patients due to different mutations of TLR3.

TLR3 is a receptor for dsRNA (intermediate in the replication of many viruses including HSV) which induces IFN response to prevent the cytopathic effects of different viruses. A heterozygous dominant-negative mutation of TLR3 was discovered in 2 unrelated children with HSE. TLR3 mutant fibroblasts from the 2 patients were infected by HSV-1 and vesicular stomatitis virus(VSV).IFNB and IFNL production were impaired in those cells, viral replication was higher and cell survival was lower in the 2 patients' cells when compared with the controls. Blood leukocyte response normally with to poly (I:C) which explains why the disease is not disseminated and also explains the redundant role of TLR3 in blood cells(13).
Similar findings were reported in a polish child in 2011, however, the patient here was compound heterozygous for a missense mutation leading to autosomal recessive inheritance of TLR3 deficiency(14).
Treatment with IFN alpha and beta canceled the effect of the dominant-negative mutation increasing the causality relationship between TLR3 mutants and viral immune response(13).
Relatives of the 2 patients with the same mutation did not show decreased interferon response nor they showed HSE as a complication of HSV which means that this mutation does not have full penetrance(13).

In another study, 110 patients with HSE were sequenced (exons of TLR3) to establish a new association of TLR3 mutations and HSE. The study reported 5 novel variants other than those previously described in the literature. 2 of them were not pathogenically demonstrated by in vitro studies while 3 of them were pathogenic with similar findings to those described above. Additionally, they found 3 patients with the same mutations previously described in the literature so the total of patients with deleterious TLR3 mutations would be 6 out of 110. 4 of those 6 patients(66%) with TLR6 mutations had a relapse In contrast to 12 out of 120(total cohort) (10%)(15).

In a recent study done on 16 patients with adult-onset HSE using whole-exome sequencing(WES), 1 patient was discovered to have TLR3 deficiency, while 8 other patients had mutations in other genes in the TLR3 pathway(2 patients with a mutation in IRF3, 2 patients with mutations in STAT1, 2 patients with mutations in TRIF, 1 patient with a mutation in TYK2,1 patients with a mutation in MAVS, and finally 1 patient with a mutation in TBK1)(16)

A common polymorphism in TLR3(rs3775291) was linked to increased resistance to HIV1 infection by the genotyping study of Spanish and Italian cohorts with a P value of .023 and .029 respectively. The study compared HIV exposed seronegative cohort(IV drug abuse and sexually active ) with controls. Repetitive HIV exposure in the cohort was evidenced by HCV seropositivity. In vitro infection of PBMCs with HIV showed increased resistance in cells carrying the allele and also TLR3 stimulation by TLR3 agonists showed an increased level of expression of CD69, IL-6, and CCL3(17).

A similar study was conducted on the Caucasian population showing the protective effect of the allele against HIV infection(18).

Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-β and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients’ iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I, and/or III IFN–mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature(PMID: 31217193
)




13.Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317(5844):1522–1527. doi:10.1126/science.1139522

14.Guo Y, Audry M, Ciancanelli M, et al. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med. 2011;208(10):2083–2098. doi:10.1084/jem.20101568

15.Lim HK, Seppänen M, Hautala T, et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology. 2014;83(21):1888–1897. doi:10.1212/WNL.0000000000000999

16.Mørk N, Kofod-Olsen E, Sørensen KB, et al. Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. Genes Immun. 2015;16(8):552–566. doi:10.1038/gene.2015.46

17.Sironi M, Biasin M, Cagliani R, et al. A common polymorphism in TLR3 confers natural resistance to HIV-1 infection. J Immunol. 2012;188(2):818–823. doi:10.4049/jimmunol.1102179

18.Huik K, Avi R, Pauskar M, et al. Association between TLR3 rs3775291 and resistance to HIV among highly exposed Caucasian intravenous drug users. Infect Genet Evol. 2013;20:78–82. doi:10.1016/j.meegid.2013.08.008

19.Lim HK, Huang SXL, Chen J, et al. Severe influenza pneumonitis in children with inherited TLR3 deficiency. J Exp Med. 2019;216(9):2038–2056. doi:10.1084/jem.20181621

Created: 24 Apr 2020, 4:04 p.m. | Last Modified: 24 Apr 2020, 4:05 p.m.

Panel Version: 0.160

Mode of inheritance
Other

Phenotypes
Herpes simplex encephalitis predisposition , severe influenza Pneumonia ,HIV resistance to infection

Green List (high evidence)

agree with green gene

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

YES- this is covered on our targeted exome

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

Comment on mode of pathogenicity: Only missense variants reported to date

Created: 19 Jun 2018, 11:45 a.m.

Comment on publications: Added publication listing variants

Created: 19 Jun 2018, 11:36 a.m.

Comment on list classification: There are plausible disease-causing mutations identified in more than 3 families. All variants reported to date are missense.

Created: 19 Jun 2018, 11:32 a.m.

Changed penetrance to 'incomplete'

Created: 19 Jun 2018, 11:30 a.m.

Added 'missense' tag as all variants reported so far in exons are missense.

Created: 19 Jun 2018, 10:55 a.m.

In OMIM TLR3 is associated with {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 2} and {HIV1 infection, resistance to}. 10 independent cases of missense variants in TLR3 in patients with herpes simplex encephalitis are reported by Zhang et al. (2007) (PMID: 17872438), Guo et al. (2011) (PMID: 21911422), Lim et al. (2014) (PMID: 25339207) and Mork et al. (2015) (26513235). Patients show a mixture of 1 heterozygous mutation, compound heterozygous mutations and homozygous mutation. Some family members of the two patients reported by Zhang et al. (2007) were also heterozygous for the mutation found, were HSV-1 seropositive but had not suffered from HSE suggesting that the mutation confers an autosomal dominant predisposition to the disease with incomplete penetrance. Lim et al (2014) also report dominant negative and haploinsufficiency effects. A review of literature finds a report by Sironi et al (2017) (PMID: 28368532) which describe a HSE patient with a previously reported variant (p.Leu297Val) and another with an intronic variant c.−8 + 6T > C, rs765240183), located 6 nucleotides downstream from the donor splice site of the first noncoding exon. All variants reported so far in exons are missense. Not in Gene2Phenotype. This gene should be rated green as there plausible disease-causing mutations identified in 3 or more families.

Created: 18 Jun 2018, 1:49 p.m.

Green List (high evidence)

Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): TLR3 .PanelApp HGNC gene symbol check: TLR3 . IUIS Disease: TLR3 deficiency . IUIS Inheritance: AD or AR .T cells: N/A, .B cells: N/A, .IUIS Other affected cells: Central nervous system (CNS) resident cells and fibroblasts. IUIS Associated features: Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here). IUIS Major category: Defects in Intrinsic and Innate Immunity. IUIS Subcategory: Herpes Simplex Encephalitis (HSE)

Created: 2 Jul 2018, 10:35 a.m.

This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s)
GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.

Created: 19 Apr 2018, 12:30 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: TLR3, PanelApp HGNC gene symbol check: TLR3, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Defects in innate immunity / Herpetic encephalitis / Herpetic encephalitis (HSE)

Created: 17 Apr 2018, 12:29 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: TLR3, GRID_Gene_Symbol: TLR3, GRID_Transcript_ENS_Community submitted: ENST00000296795, GRID_Transcript_RefSeq: NM_003265.2, GRID_Transcript_ENS_used_on_Production: ENST00000296795

Created: 17 Apr 2018, 12:12 p.m.