RIG-I and TLR3 are both required for maximum interferon induction by influenza virus in human lung alveolar epithelial cells

Abstract

Pattern recognition receptors, such as retinoic acid-inducible protein I (RIG-I), Toll-like receptors 3 and 7 (TLR3 and 7), and nucleotide-binding oligomerization domain containing protein 2 (NOD2), play important roles in the recognition of influenza A virus (IAV), but their role in interferon (IFN) induction is still unclear, particularly in human lung. We investigated IFN induction by IAV in the A549 cell line as well as in primary human alveolar epithelial cells (AEC). TLR3/7, NOD2, RIG-I, and IFN expression levels were measured by qRT-PCR and ELISA in cells infected with IAV PR8. We found that TLR7 and NOD2 were not involved in IFN induction by IAV in these cells. Neither RIG-I nor TLR3 siRNA alone completely blocked IFN induction. However, double knockdown of RIG-I and TLR3 completely inhibited IFN induction by influenza. Thus, signaling through both RIG-I and TLR3 is important for IFN induction by IAV in human lung AEC.

Inflammation induced by influenza virus impairs innate control of human pneumococcal carriage

“…The LAIV carriage+ group showed an enrichment for genes in TLR3 signalling cascade, RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways and IFN-gamma signalling, which is in agreements with the induction of antiviral responses following LAIV vaccination 35 . Moreover, TLR4 signalling was also enriched in this group.…”

IFITM3, TLR3, and CD55 Gene SNPs and Cumulative Genetic Risks for Severe Outcomes in Chinese Patients With H7N9/H1N1pdm09 Influenza

“…Unlike genome-wide association studies, however, our approach had limited the number of candidate genes/SNPs for study, and a more detailed analyses on haplotypes and population substructure are infeasible with this design. The SNPs' effects on protein function, and how this might impact on viral clearance and/ or signaling of proinflammatory responses at different disease stages, would require further elucidation (eg, serial viral load and cytokine/chemokine measurements) [14,15,16,18,19,20,28]. D222G, H275Y, and R292K mutations should have a minimal impact on results because of their reported rarity [25,28,29,31,35].…”

Tyk2 as a target for immune regulation in human viral/bacterial pneumonia

“…In comparison to mouse data showing type I and predominantly type III IFN responses [33], we found that human lung tissue significantly increased members of all IFN types with an emphasis on type II IFN-γ, which was more than 15 times greater. Interestingly, studies on A549 cells, primary human AECs or even human lung tissue found supporting results for type I and III IFN, but unfortunately neglected the measurement of IFN-γ after IAV infection [34][35][36]. Current understanding allocates the cellular source of type II IFN-γ to activated T-lymphocytes and natural killer cells rather than AECs, therefore assuming a role in adaptive immune activation instead of innate antiviral activity [37].…”