title: 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: 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.
  
  
  OBJECTIVE
  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.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, and Collaborative Innovation Center of Hematology and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Yu
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, and Collaborative Innovation Center of Hematology and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, and Collaborative Innovation Center of Hematology and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Soochow University, Institutes of Biology and Medical Sciences, Suzhou, China.
authors.forename: Chenhe
authors.initials: C
authors.lastname: Su
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, and Collaborative Innovation Center of Hematology and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Zili
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, and Collaborative Innovation Center of Hematology and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Chengkui
authors.initials: C
authors.lastname: Yang
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, and Collaborative Innovation Center of Hematology and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, and Collaborative Innovation Center of Hematology and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Jue
authors.initials: J
authors.lastname: Hou
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, and Collaborative Innovation Center of Hematology and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Jinying
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, and Collaborative Innovation Center of Hematology and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Gong
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Soochow University, Institutes of Biology and Medical Sciences, Suzhou, China Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada zheng.alan@hotmail.com hesudan@suda.edu.cn.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Zheng
authors.affiliation: Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, and Collaborative Innovation Center of Hematology and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China zheng.alan@hotmail.com hesudan@suda.edu.cn.
authors.forename: Sudan
authors.initials: S
authors.lastname: He
mesh_terms: D000818:Animals; D002460:Cell Line; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000502:physiology*; D018258:Herpesvirus 2, Human / Q000276:immunology* / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D009336:Necrosis; D012264:Ribonucleotide Reductases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D012264:Ribonucleotide Reductases