Characterization of innate immune signaling components involved in regulation of TSLP expression in airway cells upon human metapneumovirus infection

Abstract

Viral respiratory tract infections have been linked to development of asthma, which affects approximately 235 million people around the world. Human metapneumovirus (hMPV) is a recently discovered virus recognized as a clinically important respiratory pathogen. Thymic stromal lymphopoietin (TSLP) is an interleukin 7 (IL-7) like cytokine that is expressed mainly by epithelial cells at barrier surfaces and induce immune responses by targeting immune cells that produce T helper 2 (Th2) cytokines. hMPV infection is known to induce TSLP expression in airway epithelial cells and in fibroblasts. Elevated TSLP-directed inflammation in the airways may contribute to respiratory disease and create a Th2-permissive environment that attribute to the development of asthma. How TSLP is regulated in response to hMPV infection in human airway cells is poorly described. Pattern recognition receptor (PRR) components regulating induction of TSLP in response to respiratory syncytial virus (RSV) infection, and IFN-β induction in response to hMPV has previously been assessed, but such characterization of the regulation of TSLP induction in response to hMPV has not previously been done. This study focuses on the regulation of TSLP in response to hMPV subgroup A1 infection in human airway cells. PRR components involved in the regulation of TSLP expression upon hMPV A1 infection in human airway cells were characterized applying siRNA-mediated knockdown method. The results indicate that TSLP is induced in response to hMPV A1 infection in both airway epithelial cells and lung fibroblast. The long form TSLP isoform is predominantly induced upon hMPV infection. The RIG-I-MAVS signaling pathway is suggested to be essential in the induction of TSLP upon hMPV infection. TBK1 seems to be a key component in the lfTSLP induction pathway. Lung fibroblasts seem to be particularly important as a source of TSLP production upon respiratory virus infection.