In vitro analysis of the impact of Kaposi’s sarcoma-associated herpesvirus (KSHV) on experimentally induced necroptosis

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Doctoral Thesis
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Murtadak, Vinay

Apoptosis and necrosis are the two major cell death pathways. Recently a new cell death pathway was discovered termed as necroptosis which is induced by a cellular protein platform denoted ripoptosome, a large protein complex including RIP kinases and caspase-8. Herpesviruses, including Kaposi’s sarcoma-associated herpesvirus (KSHV), have been shown to inhibit apoptosis via various mechanisms; but whether and how KSHV can regulate necroptosis is currently unknown. This thesis therefore aimed at a better understanding of the molecular and cellular mechanisms of necroptosis regulation by KSHV. To this end, the human colorectal cancer cell line HT29 was used as a necroptosis model and infected with recombinant KSHV viruses. It was found that infection with KSHV and supernatant of lytically infected cells inhibited necroptosis in early stages of infection via paracrine mechanisms. This necroptosis inhibitory effect was absent in long-term latently infected cells. Moreover, overexpression of the viral NF-κB activator K13/vFLIP did not protect from but enhanced necroptotic cell death. In addition, infection with recombinant KSHV viruses where the microRNA cluster was deleted in the genomic DNA showed that these latently expressed microRNAs also did not play a role in necroptosis inhibition. This study suggested that during the KSHV lytic replication cycle presently undefined soluble factors are released through respective cells which act in a paracrine fashion to inhibit necroptosis during early infection.

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