Severe #influenza #pneumonitis in #children with inherited #TLR3 #deficiency (J Exp Med., abstract)

[Source: Journal of Experimental Medicine, full page: (LINK). Abstract, edited.]

Severe influenza pneumonitis in children with inherited TLR3 deficiency

Hye Kyung Lim, Sarah X.L. Huang,  Jie Chen,  Gaspard Kerner, Olivier Gilliaux, Paul Bastard, Kerry Dobbs, Nicholas Hernandez, Nicolas Goudin, Mary L. Hasek, Eduardo Javier García Reino, Fabien G. Lafaille, Lazaro Lorenzo, Priya Luthra, Tatiana Kochetkov, Benedetta Bigio, Soraya Boucherit, Flore Rozenberg, Catherine Vedrinne, Michael D. Keller, Yuval Itan, Adolfo García-Sastre, Marie Celard, Jordan S. Orange, Michael J. Ciancanelli, Isabelle Meyts, Qian Zhang, Laurent Abel, Luigi D. Notarangelo, Hans-Willem Snoeck, Jean-Laurent Casanova, Shen-Ying Zhang

DOI: 10.1084/jem.20181621 | Published June 19, 2019



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.

Submitted: 22 August 2018 – Revision received 10 April 2019 – Accepted: 9 May 2019

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Keywords: Influenza A; Pneumonitis; ARDS; Genetics.


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Giuseppe Michieli

I am an Italian blogger, active since 2005 with main focus on emerging infectious diseases such as avian influenza, SARS, antibiotics resistance, and many other global Health issues. Other fields of interest are: climate change, global warming, geological and biological sciences. My activity consists mainly in collection and analysis of news, public services updates, confronting sources and making decision about what are the 'signals' of an impending crisis (an outbreak, for example). When a signal is detected, I follow traces during the entire course of an event. I started in 2005 my blog ''A TIME'S MEMORY'', now with more than 40,000 posts and 3 millions of web interactions. Subsequently I added an Italian Language blog, then discontinued because of very low traffic and interest. I contributed for seven years to a public forum ( in the midst of the Ebola epidemic in West Africa in 2014, I left the site to continue alone my data tracking job.