title: Exploitation of the complement system by oncogenic Kaposi's sarcoma-associated herpesvirus for cell survival and persistent infection.
abstract: During evolution, herpesviruses have developed numerous, and often very ingenious, strategies to counteract efficient host immunity. Specifically, Kaposi's sarcoma-associated herpesvirus (KSHV) eludes host immunity by undergoing a dormant stage, called latency wherein it expresses a minimal number of viral proteins to evade host immune activation. Here, we show that during latency, KSHV hijacks the complement pathway to promote cell survival. We detected strong deposition of complement membrane attack complex C5b-9 and the complement component C3 activated product C3b on Kaposi's sarcoma spindle tumor cells, and on human endothelial cells latently infected by KSHV, TIME-KSHV and TIVE-LTC, but not on their respective uninfected control cells, TIME and TIVE. We further showed that complement activation in latently KSHV-infected cells was mediated by the alternative complement pathway through down-regulation of cell surface complement regulatory proteins CD55 and CD59. Interestingly, complement activation caused minimal cell death but promoted the survival of latently KSHV-infected cells grown in medium depleted of growth factors. We found that complement activation increased STAT3 tyrosine phosphorylation (Y705) of KSHV-infected cells, which was required for the enhanced cell survival. Furthermore, overexpression of either CD55 or CD59 in latently KSHV-infected cells was sufficient to inhibit complement activation, prevent STAT3 Y705 phosphorylation and abolish the enhanced survival of cells cultured in growth factor-depleted condition. Together, these results demonstrate a novel mechanism by which an oncogenic virus subverts and exploits the host innate immune system to promote viral persistent infection.
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America; Department of Microbiology and Immunology, Eulji University School of Medicine, Daejeon, Republic of Korea.
authors.forename: Myung-Shin
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Jones
authors.affiliation: Department of Anatomy and Neuroscience, Eulji University School of Medicine, Daejeon, Republic of Korea.
authors.forename: Dae-Yong
authors.initials: DY
authors.lastname: Song
authors.affiliation: Department of Microbiology and Immunology, Eulji University School of Medicine, Daejeon, Republic of Korea.
authors.forename: Jae-Hyuk
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Shou-Jiang
authors.initials: SJ
authors.lastname: Gao
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D003179:Complement C3b / Q000235:genetics / Q000378:metabolism*; D050776:Complement C5b / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology / Q000821:virology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D019288:Herpesvirus 8, Human / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology / Q000473:pathology / Q000821:virology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000821:virology; D009389:Neovascularization, Pathologic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000276:immunology / Q000473:pathology / Q000821:virology*; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017735:Virus Latency
chemical_list: D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D014764:Viral Proteins; D003179:Complement C3b; D050776:Complement C5b