Severe influenza pneumonitis in children with inherited TLR3 deficiency

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 -, 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-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.

Source: The Journal of Experimental Medicine - September 1, 2019 Category: Internal Medicine Authors: Lim, H. K., Huang, S. X. L., Chen, J., Kerner, G., Gilliaux, O., Bastard, P., Dobbs, K., Hernandez, N., Goudin, N., Hasek, M. L., Garcia Reino, E. J., Lafaille, F. G., Lorenzo, L., Luthra, P., Kochetkov, T., Bigio, B., Boucherit, S., Rozenberg, F., Vedrin Tags: Immunodeficiency, Infectious Disease and Host Defense, Human Disease Genetics Articles Source Type: research