Abstract
BackgroundTLR8 assists in antiviral approach by producing Type 1 INF via MyD88 dependent IRF7 pathway. However, over expression of INFα/β molecule poses threat by developing tolerance in chronic infection cases and enhancing inflammatory response. Here we report a bi-specific siRNA based complex which differentially activates and silences the TLR8 and MYD88 respectively in a negatively regulated fashion.ResultsOuter membrane vesicle from Escherichia coli used for siRNA delivery was observed more efficient when attached with invasive protein Ail along with OmpA (P < 0.001) in HEK293-TLR8 cell line. siRNA complexed with p19 protein was efficient in activating TLR8, confirmed by the increment of INFβ molecules (P < 0.001) in HEK293-TLR8 compared to its counterpart. Fusion of lipid bilayer of endosomal compartment was significant at pH 4.5 when fusogenic peptides (diINF-7) were incubated in membrane vesicle, thus facilitating the escape of siRNA complex to the host cytoplasm in order to silence MyD88 transcript (P < 0.001).ConclusionsWe investigated the activation of TLR8 by bi-specific si-RNA for the production of INFβ. In the same setting we showed that bi-specific si-RNA was able to silence MyD88 transcript in a delayed manner. For the cases of auto immune disease and inflammation where over activation of endosomal TLRs poses serious threat, bi specific siRNA could be used as negative feedback controlled system.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-015-0109-9) contains supplementary material, which is available to authorized users.
Highlights
TLR8 assists in antiviral approach by producing Type 1 INF via Myleoid differentiating factor 88 (MyD88) dependent IRF7 pathway
This study focuses on the administration of silencing RNA (siRNA), as agonist for TLR7/8, which initiates Interferon Stimulating Gene (ISG) expression formerly and simultaneously would silence the MyD88 transcript
Transport of torA-fusion proteins to periplasm of Escherichia coli In order to transport the siRNA, we needed siRNA to be packed in outer membrane vesicle (OMVs), we devised torA fusion system which would efficiently transport the proteins from cytoplasm to periplasm of E.coli
Summary
TLR8 assists in antiviral approach by producing Type 1 INF via MyD88 dependent IRF7 pathway. The role of IFN-I may Adhikari et al BMC Immunology (2015) 16:42 always not be true as mentioned in above instances as in chronic cases like HIV/SIV infection. In these chronic cases, the pattern of IFN mediated antiviral response is dependent upon the amount and duration of IFN molecules administration [15]. The continued IFN treatment can induce IFN-I desensitization and decrease antiviral gene expression, enabling infection with increased SIV reservoir size and accelerated CD4 T-cell loss [15]. Even continued IFN production via TLR7/8 results in decreased Interferon Stimulating Gene (ISG) expression like cGAS, APOBEC3G, MX2, tetherin and TRIM5α in SIV infected models [15]
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