Toll-like receptor 4 mediates innate immunity to Kaposi sarcoma herpesvirus.
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.
Lagos
Dimitrios
D
Cancer Research UK Viral Oncology Group, UCL Cancer Institute, Paul O'Gorman Building, Huntley Street, University College London, London WC1E 6BT, UK.
Vart
Richard James
RJ
Gratrix
Fiona
F
Westrop
Samantha Jane
SJ
Emuss
Victoria
V
Wong
Ping-Pui
PP
Robey
Rebecca
R
Imami
Nesrina
N
Bower
Mark
M
Gotch
Frances
F
Boshoff
Chris
C
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
D051197:Toll-Like Receptor 4; D014764:Viral Proteins