The interplay between the human Herpes simplex virus type 1 and the caspase-8 and NF-kB signalling pathways

Herpes simplex virus-1 (HSV-1) infects epithelial cells and establishes a lifelong latency in neuronal ganglia after primary infection. The ability of HSV-1 to replicate and reactivate from latency is due to several virulence factors by which the virus can evade the host antiviral response and persist for a lifetime. Indeed, despite many vaccines have been developed, the restriction of the infection is made difficult due to the high latency potential of the virus. Moreover, the effectiveness of antiviral therapies is limited by the development of antiviral resistance who is most common in immunocompromised individuals or patients with chronic and/or progressive infections or which have been exposed to prolonged antiviral therapies. In this scenario, a comprehensive understanding of the interaction between the virus and the host immune system as well as the characterization of novel antiviral drugs is of crucial importance. Therefore, the research activity carried out during the PhD program was focused on the study of the immune response pathways mediated by HSV-1 and in parallel on the biological characterization of the antiviral activity of various compounds from natural sources. HSV-1 is known to modulate several intracellular signaling pathways and transcription factors, including the FADD/caspase-8 death-signalling pathways and the nuclear factor-κB (NF-κB) pathway. Caspase-8 is the initiator caspase of the extrinsic apoptosis pathway in mammals. Classically, in response to viral infection, host cells undergo apoptosis to promote the elimination of infected cells and limit the release of progeny virus. Besides its role in apoptosis signalling, several reports showed that, under certain conditions, caspase-8 might direct the signalling toward cell death or pro-survival pathways. However, viral infection also stimulates an NFκB-dependent response which is essential to promote the expression of various anti-apoptotic genes. The balance between pro-apoptotic and pro-survival pathways strongly influences virus-host interaction and viral pathogenesis. Moreover, several host cellular microRNAs (miRNAs) have been reported to manipulate the NFκB-signaling pathway and apoptosis response upon viral infection. On the other side, the viral encoded Us11 protein is known to interfere with the host response to HSV-1 infection that leads to apoptosis. It has been previously shown that Us11 expression increases cell survival and protect the cells against heat and staurosporine-induced apoptosis. Therefore, the aim of the present work was to investigate the role of Us11 in apoptosis signalling and its interaction with caspase-8 during HSV-1 replication, as well as the contribution of miRNA-146a as regulatory factor of the NF-κB pathway during HSV-1 replication. Moreover, the antiviral activity of polyphenol-rich extracts from pistachios kernel (Pistacia vera, L.) and almond skin (Prunus dulcis) was assessed against HSV-1. Indeed, despite the host immune response are usually effective against HSV-1 infections, the use of antiviral drugs is often required for the clearance of the virus. Furthermore, the increasing phenomena of drug-resistance represent a serious public health problem, and thus the discovery of novel antiviral therapies is of fundamental importance. The search for new safe and effective drugs has recently led to the discovery of molecules from natural sources for providing alternative therapeutic solutions to conventional drugs. Natural products are widely used globally for both preventive and therapeutic purposes. In particular, the natural skin of the almond and extracts from pistachios kernels represents a rich source of phenolic compounds, with important health beneficial properties. Therefore, the use of natural products such as flavonoids and polyphenols as antiviral drugs could represent an excellent tool for the development of topical drugs for the treatment of HSV-1 infections.