Herpes Simplex Virus 1 (HSV-1) and HSV-2 Mediate Species-Specific Modulations of Programmed Necrosis through the Viral Ribonucleotide Reductase Large Subunit R1.

Abstract

UNLABELLED:

Receptor-interacting protein kinase 3 (RIP3) and its substrate mixed-lineage kinase domain-like protein (MLKL) are core regulators of programmed necrosis. The elimination of pathogen-infected cells by programmed necrosis acts as an important host defense mechanism. Here, we report that human herpes simplex virus 1 (HSV-1) and HSV-2 had opposite impacts on programmed necrosis in human cells versus their impacts in mouse cells. Similar to HSV-1, HSV-2 infection triggered programmed necrosis in mouse cells. However, neither HSV-1 nor HSV-2 infection was able to induce programmed necrosis in human cells. Moreover, HSV-1 or HSV-2 infection in human cells blocked tumor necrosis factor (TNF)-induced necrosis by preventing the induction of an RIP1/RIP3 necrosome. The HSV ribonucleotide reductase large subunit R1 was sufficient to suppress TNF-induced necrosis, and its RIP homotypic interaction motif (RHIM) domain was required to disrupt the RIP1/RIP3 complex in human cells. Therefore, this study provides evidence that HSV has likely evolved strategies to evade the host defense mechanism of programmed necrosis in human cells.

IMPORTANCE:

This study demonstrated that infection with HSV-1 and HSV-2 blocked TNF-induced necrosis in human cells while these viruses directly activated programmed necrosis in mouse cells. Expression of HSV R1 suppressed TNF-induced necrosis of human cells. The RHIM domain of R1 was essential for its association with human RIP3 and RIP1, leading to disruption of the RIP1/RIP3 complex. This study provides new insights into the species-specific modulation of programmed necrosis by HSV.

• Authors: Xiaoliang Yu, Yun Li, Qin Chen, Chenhe Su, Zili Zhang, Chengkui Yang, Zhilin Hu, Jue Hou, Jinying Zhou, Ling Gong, Xuejun Jiang, Chunfu Zheng, Sudan He
• Journal: Journal of virology (J Virol) Vol. 90 Issue 2 Pg. 1088-95 (01 15 2016) ISSN: 1098-5514 [Electronic] United States
• PMID: 26559832 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Tumor Necrosis Factor-alpha
• Ribonucleotide Reductases

Topics

• Animals
• Cell Line
• Herpesvirus 1, Human (immunology, physiology)
• Herpesvirus 2, Human (immunology, physiology)
• Host-Pathogen Interactions
• Humans
• Mice
• Necrosis
• Ribonucleotide Reductases (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)