title: Toll-like receptor 4 mediates innate immunity to Kaposi sarcoma herpesvirus.
abstract: The involvement of Toll-like receptor 4 (TLR4) in immunity against human herpesviruses has not been previously demonstrated. We show that infection of endothelial cells with Kaposi sarcoma herpesvirus (KSHV), a human oncogenic virus, leads to rapid suppression of TLR4 expression. This is a mechanism of immune escape as TLR4 mediates innate immunity against KSHV. In vitro, cells lacking TLR4 are more susceptible to KSHV infection, whereas activation of TLR4 protects cells from infection. In vivo, HIV-1-infected individuals carrying a mutant TLR4 allele appear more likely to have multicentric Castleman's disease, a lymphoproliferation associated with enhanced KSHV replication. ERK activation by KSHV structural proteins and the KSHV-encoded vGPCR plays a key role in the TLR4 downregulation, whereas the KSHV vIRF1 also contributes to this effect. Our findings reveal a role for TLR4 in innate immunity against herpesviruses and suggest the potential use of TLR4 agonists for the treatment of KSHV-related neoplasms.
authors.affiliation: Cancer Research UK Viral Oncology Group, UCL Cancer Institute, Paul O'Gorman Building, Huntley Street, University College London, London WC1E 6BT, UK.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Lagos
authors.forename: Richard James
authors.initials: RJ
authors.lastname: Vart
authors.forename: Fiona
authors.initials: F
authors.lastname: Gratrix
authors.forename: Samantha Jane
authors.initials: SJ
authors.lastname: Westrop
authors.forename: Victoria
authors.initials: V
authors.lastname: Emuss
authors.forename: Ping-Pui
authors.initials: PP
authors.lastname: Wong
authors.forename: Rebecca
authors.initials: R
authors.lastname: Robey
authors.forename: Nesrina
authors.initials: N
authors.lastname: Imami
authors.forename: Mark
authors.initials: M
authors.lastname: Bower
authors.forename: Frances
authors.initials: F
authors.lastname: Gotch
authors.forename: Chris
authors.initials: C
authors.lastname: Boshoff
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015870:Gene Expression; D015658:HIV Infections / Q000150:complications / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000502:physiology; D019288:Herpesvirus 8, Human / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D020641:Polymorphism, Single Nucleotide; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: D051197:Toll-Like Receptor 4; D014764:Viral Proteins