Contents - College of Medical and Dental Sciences - University of ...
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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK<br />
Immunology I Abstract 12<br />
KSHV EVADES INNATE IMMUNITY BY SUPPRESSION OF TLR4 EXPRESSION<br />
Dimitris Lagos 1 , Richard James Vart 1 , Fiona Gratrix 1 , Samantha Jane Westrop 2 , Ping-Pui<br />
Wong 1 , Nesrina Imami 2 , Mark Bower 3 , Frances Gotch 2 <strong>and</strong> Chris Bosh<strong>of</strong>f 1<br />
1<br />
Cancer Research UK Viral Oncology Group, UCL Cancer Institute, Paul O’Gorman<br />
Building, Huntley Street, <strong>University</strong> <strong>College</strong> London, WC1E 6BT, London, U.K.<br />
2<br />
Department <strong>of</strong> Immunology, Chelsea <strong>and</strong> Westminster Hospital, Imperial <strong>College</strong><br />
London, London, U.K.<br />
3<br />
Imperial <strong>College</strong> School <strong>of</strong> Medicine, Chelsea <strong>and</strong> Westminster Hospital, Imperial <strong>College</strong><br />
London, London, UK.<br />
Abstract<br />
Toll-like receptors (TLRs) play a critical role in innate immune responses against invading<br />
pathogens. However, the role <strong>and</strong> regulation <strong>of</strong> TLRs during KSHV infection remain poorly<br />
understood. We demonstrate that TLR4 mediates innate response against KSHV <strong>and</strong> that<br />
KSHV targets TLR4 expression as a mechanism <strong>of</strong> immune evasion. In vitro, mouse<br />
macrophages or human lymphatic endothelial cells lacking TLR4 are more susceptible to<br />
KSHV infection, whereas activation <strong>of</strong> TLR4-mediated signalling with bacterial<br />
lipopolysaccharide protects cells from KSHV infection. In vivo, HIV-1-infected individuals<br />
who carry a non-functional TLR4 allele appear more likely to have multicentric<br />
Castleman’s disease, a lymphoproliferation associated with enhanced KSHV replication.<br />
Furthermore, we show that KSHV has evolved mechanisms to evade the TLR4-mediated<br />
response. The KSHV-encoded vIRF1 <strong>and</strong> vGPCR co-operate to suppress TLR4 expression<br />
in human lymphatic endothelial cells. Notably, ERK activation by vGPCR or by viral<br />
attachment to the cell membrane results in rapid TLR4 down-regulation. Our findings<br />
reveal the first example <strong>of</strong> viral immune evasion through suppression <strong>of</strong> TLR4 expression<br />
<strong>and</strong> suggest the potential use <strong>of</strong> TLR4 agonists for treatment <strong>of</strong> KSHV-related neoplasms.<br />
Presenting author Email: d.lagos@ucl.ac.uk<br />
33