Alternative capture of noncoding RNAs or protein-coding genes by herpesviruses to alter host T cell function

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Herpesvirus saimiri (HVS) is an oncogenic gamma-herpesvirus that infects T-cells.
• Viral noncoding RNAs can regulate host gene expression.
• MicroRNAs (miRNAs) are key regulators of cellular processes, including T-cell function.

Purpose of the Study:

• To investigate the mechanism by which HSUR 1, a viral noncoding RNA from HVS, affects host T-cells.
• To identify the specific host targets regulated by HSUR 1 and its interaction with microRNA-27 (miR-27).
• To understand how different gamma-herpesviruses manipulate host T-cell pathways.

Main Methods:

• High-throughput sequencing of RNA after crosslinking immunoprecipitation (HITS-CLIP) to identify mRNA targets of miR-27.
• Transfection of miR-27 into human T-cells to assess its impact on T-cell receptor (TCR) signaling.
• Analysis of protein levels of miR-27 targets (GRB2, SEMA7A, IFN-γ) upon HSUR 1 manipulation.
• Comparative analysis of viral strategies across different gamma-herpesviruses.

Main Results:

• HSUR 1 directly mediates the degradation of host microRNA-27 (miR-27).
• miR-27 targets mRNAs involved in the T-cell receptor (TCR) signaling pathway, including GRB2.
• miR-27 regulates key T-cell function modulators like SEMA7A and IFN-γ.
• HSUR 1 modulates TCR-induced signaling, MAPK activation, and CD69 induction via miR-27 regulation.

Conclusions:

• Oncogenic gamma-herpesviruses employ diverse strategies to target common host T-cell pathways.
• HVS utilizes HSUR 1 to downregulate miR-27, thereby influencing TCR signaling and T-cell function.
• Understanding these viral strategies provides insights into T-cell biology and pathogenesis.