Integrated systems biology analysis of KSHV latent infection reveals viral induction and reliance on peroxisome mediated lipid metabolism

Abstract

Kaposi’s Sarcoma associated Herpesvirus (KSHV), an oncogenic, human gamma-herpesvirus, is the etiological agent of Kaposi’s Sarcoma the most common tumor of AIDS patients world-wide. KSHV is predominantly latent in the main KS tumor cell, the spindle cell, a cell of endothelial origin. KSHV modulates numerous host cell-signaling pathways to activate endothelial cells including major metabolic pathways involved in lipid metabolism. To identify the underlying cellular mechanisms of KSHV alteration of host signaling and endothelial cell activation, we identified changes in the host proteome, phosphoproteome and transcriptome landscape following KSHV infection of endothelial cells. A Steiner forest algorithm was used to integrate the global data sets and, together with transcriptome based predicted transcription factor activity, cellular networks altered by latent KSHV were predicted. Several interesting pathways were identified, including peroxisome biogenesis. To validate the predictions, we showed that KSHV latent infection increases the number of peroxisomes per cell. Additionally, proteins involved in peroxisomal lipid metabolism of very long chain fatty acids, including ABCD3 and ACOX1, are required for the survival of latently infected cells. In summary, novel cellular pathways altered during herpesvirus latency that could not be predicted by a single systems biology platform, were identified by integrated proteomics and transcriptomics data analysis and when correlated with our metabolomics data revealed that peroxisome lipid metabolism is essential for KSHV latent infection of endothelial cells.

Epstein-Barr virus reprograms human B-lymphocytes immediately in the pre-latent phase of infection

“…To our knowledge, only few publications describe global cellular changes after viral infection focusing on the expression and regulation of protein-coding as well as ncRNA genes. A recent report studied the host transcriptome and proteome during KSHV infection and identified global changes in the cellular networks that are essential for virus latency (Sychev et al, 2017). The authors identified alterations in approximately 17 % of the host transcriptome and 13 % of the cellular proteome that includes also dramatic changes in the phosphoproteome 48 hours after KSHV infection.…”

Viral Oncology: Molecular Biology and Pathogenesis

“…Human herpesvirus-8, also known as Kaposi sarcoma-associated herpesvirus, is another member of the herpesviridae family best known for its association with Kaposi sarcoma (KS). HHV-8 has also been implicated in two B-cell lymphoproliferative diseases, multicentric Castleman disease (MCD) and primary effusion lymphoma (PEL) [ 83 ]. Viral transmission occurs via salivary, blood, and sexual contact; mother-to-fetus transmission is rare [ 84 ].…”

Organelle dynamics and viral infections: at cross roads

“…Similarly, the cucumber necrosis virus (CNV) induces the formation of peroxisomal vesicles in which the viral RNA replication occurs in yeast cells [117]. Studies revealed upregulation of peroxisomal biogenesis in endothelial cells upon latent infection of Kaposi's sarcoma associated herpes virus [118]. It was also reported that proteins involved in peroxisomal lipid metabolism were essential for the survival of latently infected human dermal microvascular endothelial cells and lymphatic endothelial cells [118].…”

“…Studies revealed upregulation of peroxisomal biogenesis in endothelial cells upon latent infection of Kaposi's sarcoma associated herpes virus [118]. It was also reported that proteins involved in peroxisomal lipid metabolism were essential for the survival of latently infected human dermal microvascular endothelial cells and lymphatic endothelial cells [118]. Interestingly, HIV infection reduces the number of peroxisomes in infected cells due to upregulation in the levels of microRNAs that inhibit production of peroxisome biogenesis factors [119].…”