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Severe influenza pneumonitis in children with inherited TLR3 deficiency.

ABSTRACT: 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-? and -?, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients' iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-?2b or IFN-?1 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.

SUBMITTER: Lim HK

PROVIDER: S-EPMC6719423 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Severe influenza pneumonitis in children with inherited TLR3 deficiency.

Lim Hye Kyung HK Huang Sarah X L SXL Chen Jie J Chen Jie J Kerner Gaspard G Gilliaux Olivier O Bastard Paul P Dobbs Kerry K Hernandez Nicholas N Goudin Nicolas N Hasek Mary L ML García Reino Eduardo Javier EJ Lafaille Fabien G FG Lorenzo Lazaro L Luthra Priya P Kochetkov Tatiana T Bigio Benedetta B Boucherit Soraya S Rozenberg Flore F Vedrinne Catherine C Keller Michael D MD Itan Yuval Y García-Sastre Adolfo A Celard Marie M Orange Jordan S JS Ciancanelli Michael J MJ Meyts Isabelle I Zhang Qian Q Abel Laurent L Notarangelo Luigi D LD Snoeck Hans-Willem HW Casanova Jean-Laurent JL Zhang Shen-Ying SY

The Journal of experimental medicine 20190619 9

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 <i>TLR3</i> 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 cort ...[more]

PMID: 31217193

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Project description:Pandemic A/H1N1/2009 influenza causes severe lower respiratory complications in rare cases. The association between host immune responses and clinical outcome in severe cases is unknown.We utilized gene expression, cytokine profiles and generation of antibody responses following hospitalization in 19 critically ill patients with primary pandemic A/H1N1/2009 influenza pneumonia for identifying host immune responses associated with clinical outcome. Ingenuity pathway analysis 8.5 (IPA) (Ingenuity Systems, Redwood City, CA) was used to select, annotate and visualize genes by function and pathway (gene ontology). IPA analysis identified those canonical pathways differentially expressed (P < 0.05) between comparison groups. Hierarchical clustering of those genes differentially expressed between groups by IPA analysis was performed using BRB-Array Tools v.3.8.1.The majority of patients were characterized by the presence of comorbidities and the absence of immunosuppressive conditions. pH1N1 specific antibody production was observed around day 9 from disease onset and defined an early period of innate immune response and a late period of adaptive immune response to the virus. The most severe patients (n = 12) showed persistence of viral secretion. Seven of the most severe patients died. During the late phase, the most severe patient group had impaired expression of a number of genes participating in adaptive immune responses when compared to less severe patients. These genes were involved in antigen presentation, B-cell development, T-helper cell differentiation, CD28, granzyme B signaling, apoptosis and protein ubiquitination. Patients with the poorest outcomes were characterized by proinflammatory hypercytokinemia, along with elevated levels of immunosuppressory cytokines (interleukin (IL)-10 and IL-1ra) in serum.Our findings suggest an impaired development of adaptive immunity in the most severe cases of pandemic influenza, leading to an unremitting cycle of viral replication and innate cytokine-chemokine release. Interruption of this deleterious cycle may improve disease outcome.

Dataset Information

Severe influenza pneumonitis in children with inherited TLR3 deficiency.

Publications

Severe influenza pneumonitis in children with inherited TLR3 deficiency.

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