tetano
Editor, Senior Moderator
J Exp Med. 2019 Jun 19. pii: jem.20181621. doi: 10.1084/jem.20181621. [Epub ahead of print]
[h=1]Severe influenza pneumonitis in children with inherited TLR3 deficiency.[/h] Lim HK[SUP]#[/SUP][SUP]1,[/SUP][SUP]2,[/SUP][SUP]3[/SUP], Huang SXL[SUP]#[/SUP][SUP]4,[/SUP][SUP]5,[/SUP][SUP]6[/SUP], Chen J[SUP]#[/SUP][SUP]1,[/SUP][SUP]7[/SUP], Kerner G[SUP]#[/SUP][SUP]2,[/SUP][SUP]3[/SUP], Gilliaux O[SUP]8,[/SUP][SUP]9[/SUP], Bastard P[SUP]2,[/SUP][SUP]3[/SUP], Dobbs K[SUP]10[/SUP], Hernandez N[SUP]1[/SUP], Goudin N[SUP]11[/SUP], Hasek ML[SUP]1[/SUP], Garc?a Reino EJ[SUP]1[/SUP], Lafaille FG[SUP]1[/SUP], Lorenzo L[SUP]2,[/SUP][SUP]3[/SUP], Luthra P[SUP]12,[/SUP][SUP]13[/SUP], Kochetkov T[SUP]1[/SUP], Bigio B[SUP]1[/SUP], Boucherit S[SUP]2,[/SUP][SUP]3[/SUP], Rozenberg F[SUP]14[/SUP], Vedrinne C[SUP]15[/SUP], Keller MD[SUP]16[/SUP], Itan Y[SUP]1,[/SUP][SUP]17,[/SUP][SUP]18[/SUP], Garc?a-Sastre A[SUP]12,[/SUP][SUP]13[/SUP], Celard M[SUP]19[/SUP], Orange JS[SUP]20[/SUP], Ciancanelli MJ[SUP]#[/SUP][SUP]1[/SUP], Meyts I[SUP]#[/SUP][SUP]21,[/SUP][SUP]22,[/SUP][SUP]23[/SUP], Zhang Q[SUP]#[/SUP][SUP]1[/SUP], Abel L[SUP]#[/SUP][SUP]1,[/SUP][SUP]2,[/SUP][SUP]3[/SUP], Notarangelo LD[SUP]#[/SUP][SUP]10[/SUP], Snoeck HW[SUP]#[/SUP][SUP]4,[/SUP][SUP]5[/SUP], Casanova JL[SUP]#[/SUP][SUP]1,[/SUP][SUP]2,[/SUP][SUP]3,[/SUP][SUP]24,[/SUP][SUP]25[/SUP], Zhang SY[SUP]#[/SUP][SUP]26,[/SUP][SUP]2,[/SUP][SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
? 2019 Lim et al.
PMID: 31217193 DOI: 10.1084/jem.20181621
[h=1]Severe influenza pneumonitis in children with inherited TLR3 deficiency.[/h] Lim HK[SUP]#[/SUP][SUP]1,[/SUP][SUP]2,[/SUP][SUP]3[/SUP], Huang SXL[SUP]#[/SUP][SUP]4,[/SUP][SUP]5,[/SUP][SUP]6[/SUP], Chen J[SUP]#[/SUP][SUP]1,[/SUP][SUP]7[/SUP], Kerner G[SUP]#[/SUP][SUP]2,[/SUP][SUP]3[/SUP], Gilliaux O[SUP]8,[/SUP][SUP]9[/SUP], Bastard P[SUP]2,[/SUP][SUP]3[/SUP], Dobbs K[SUP]10[/SUP], Hernandez N[SUP]1[/SUP], Goudin N[SUP]11[/SUP], Hasek ML[SUP]1[/SUP], Garc?a Reino EJ[SUP]1[/SUP], Lafaille FG[SUP]1[/SUP], Lorenzo L[SUP]2,[/SUP][SUP]3[/SUP], Luthra P[SUP]12,[/SUP][SUP]13[/SUP], Kochetkov T[SUP]1[/SUP], Bigio B[SUP]1[/SUP], Boucherit S[SUP]2,[/SUP][SUP]3[/SUP], Rozenberg F[SUP]14[/SUP], Vedrinne C[SUP]15[/SUP], Keller MD[SUP]16[/SUP], Itan Y[SUP]1,[/SUP][SUP]17,[/SUP][SUP]18[/SUP], Garc?a-Sastre A[SUP]12,[/SUP][SUP]13[/SUP], Celard M[SUP]19[/SUP], Orange JS[SUP]20[/SUP], Ciancanelli MJ[SUP]#[/SUP][SUP]1[/SUP], Meyts I[SUP]#[/SUP][SUP]21,[/SUP][SUP]22,[/SUP][SUP]23[/SUP], Zhang Q[SUP]#[/SUP][SUP]1[/SUP], Abel L[SUP]#[/SUP][SUP]1,[/SUP][SUP]2,[/SUP][SUP]3[/SUP], Notarangelo LD[SUP]#[/SUP][SUP]10[/SUP], Snoeck HW[SUP]#[/SUP][SUP]4,[/SUP][SUP]5[/SUP], Casanova JL[SUP]#[/SUP][SUP]1,[/SUP][SUP]2,[/SUP][SUP]3,[/SUP][SUP]24,[/SUP][SUP]25[/SUP], Zhang SY[SUP]#[/SUP][SUP]26,[/SUP][SUP]2,[/SUP][SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
? 2019 Lim et al.
PMID: 31217193 DOI: 10.1084/jem.20181621