Abstract
Intracellular Toll-like receptors (TLRs) expressed by dendritic cells recognize nucleic acids derived from pathogens and play an important role in the immune responses against the influenza virus (IAV), a single-stranded RNA sensed by different receptors including TLR7. However, the importance of TLR7 processing in the development of anti-viral immune responses is not known. Here we report that asparagine endopeptidase (AEP) deficient mice are unable to generate a strong anti-IAV response, as demonstrated by reduced inflammation, cross presentation of cell-associated antigens and priming of CD8+ T cells following TLR7-dependent pulmonary infection induced by IAV. Moreover, AEP deficient lung epithelial- or myeloid-cells exhibit impaired TLR7 signaling due to defective processing of this receptor. Indeed, TLR7 requires a proteolytic cleavage by AEP to generate a C-terminal fragment competent for signaling. Thus, AEP activity is critical for TLR7 processing, opening new possibilities for the treatment of influenza and TLR7-dependent inflammatory diseases.
Highlights
Influenza is a common respiratory disease where viral virulence can either cause just a moderate sickness or a severe pathology leading to hospitalisation or even death
Previous data have shown that TLR9 requires proteolysis to be functional but it is unclear whether other intracellular Toll-like receptors (TLRs) (TLR3 and Toll like receptor 7 (TLR7)) are subject to degradation
Inflammation monitored by cytokine release and adaptive immunity measured by cross priming of CD8+ T cells was significantly reduced in infected protease-deficient animals in comparison to control animals
Summary
Influenza is a common respiratory disease where viral virulence can either cause just a moderate sickness or a severe pathology leading to hospitalisation or even death. There are studies demonstrating that IAV infection induces severe and aggressive innate response, manifested with excessive cytokine production by alveolar macrophages and respiratory epithelial cells [1,2]. This innate immune response triggers the activation of professional antigen-presenting cells (APCs) leading to the initiation of adaptive immunity to eradicate the virus. TLR7 senses single-stranded RNA from influenza viruses within the endosomes and has been shown to be essential in the induction of anti-viral immune responses to IAV [1,5,6,7,8]
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