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So far mast cells (MC) for their role in allergy have been considered “monotasking cells”. However, in the last years increasing evidence points out at the MC to participate in a variety of different immune responses. MC modulate the recruitment of immune cells to inflammation sites and control immune responses by the release of a wide variety of mediators. While new evidence supports the role of MC in the control of bacterial infections, the involvement of these cells in antiviral immune responses is still poorly investigated.
Goal of this project was to investigate the response of mast cells to viral infection by analyzing the gene expression profile induced in these cells upon Newcastle disease virus (NDV), used here as a model for viral infection. Additionally, gene expression analysis showed that the gene rtp4, which codes for the protein receptor transporter protein 4, was the second most upregulated gene. Therefore the second aim of this work was to study the regulation and cellular localization of RTP4 as well as its functional contribution in antiviral immune responses.
Gene expression analysis revealed that BMMC upregulate a wide variety of antiviral genes, as a consequence of the engagement of NDV to PRRs which can be classified as follow: (1.) immediate genes that enable MC to sense viral particles and to activate signaling pathways; (2.) effector genes that regulate and amplify the response and are responsible for the induction of type I interferons (IFN); and (3.) interferon stimulated genes that code for proteins that directly control viral replication, leading to the resolution of the infection.
Expression of rtp4 was shown to be partially dependent on TLR2, TLR3, TLR4, TLR7 and TLR9 as well as the adaptor proteins MyD88 and TRIF. However, type I IFN receptor deficiency, correlates with the lack of rtp4 expression, indicating that type I interferons are responsible for its induction. Additionally, induction of rtp4 in BMMC was triggered by
NDV and influenza A virus (IAV) infection. Fractionation and confocal experiments localized RTP4 in the plasma membranes and in endoplasmic reticulum, early endosomes and lipid bodies, respectively. To investigate the functions of RTP4, knock-out mice were generated. rtp4-/- mice showed no obvious phenotypic abnormalities. Furthermore, gene expression analysis showed that rtp4-/- bone marrow derived MC (BMMC) express a comparable gene pattern to WT BMMC in response to NDV infection. Additionally, functional features of BMMC such as degranulation and cytokine production were similar to their counterpart WT BMMC. This work shows that virally infected MC develop an antiviral program to which the membrane-associated and IFN-induced RTP4 protein belongs.