Vaccinia tricks Toll
- Rachel Allan
© BioMed Central Ltd 2000
Received: 1 November 2000
Published: 4 December 2000
The first evidence that viruses may subvert signaling pathways from Toll-like receptors within their mammalian hosts has been found.
Significance and context
A search of the vaccinia virus sequences identified two potential TLR homologs, A46R and A52R. Subsequent cloning confirmed that these proteins each contained a putative TIR domain, although they lacked a further conserved set of amino acids known to be important for TLR signaling. The viral homologs could therefore inhibit Toll signaling by competing for a TIR-dependent substrate while failing to recruit downstream components. To explore this possibility, the authors used a reporter gene system to study the effects of A46R and A52R on the Toll-like IL-1 receptor pathway. Expression of A46R and A52R in human cells was found to inhibit NFκB activation following IL-1 stimulation but had no effect on an unrelated pathway. Inhibition was more profound for the A52R protein. A52R was subsequently coexpressed with high levels of various IL-1 signaling intermediates in an attempt to pinpoint its action within the signaling pathway. Upstream components, including MyD88, failed to compensate for the action of A52R, whereas overexpression of downstream IRAK restored NFκB activation. These results indicate that A52R acts at the level of MyD88, consistent with its predicted TIR-dependent mechanism. Similar experiments performed on the IL-8 and TLR-4 systems confirmed that A52R could inhibit multiple TIR-dependent pathways.
The authors conclude that A46R and A52R can effectively inhibit TIR-dependent signaling pathways. These proteins may therefore be useful for defining the importance of TIR-dependent pathways in the host immune response.
The ancient origin of Toll pathways is reflected by their occurrence throughout multicellular organisms - from plants to insects and mammals. Studies of Drosophila Toll proteins have provided valuable insights into the role of these innate pattern-recognition receptors. Thus, we now know that binding of Toll receptors by microbial products such as lipopolysaccharide leads to the activation of appropriate immune defense mechanisms in the host. Cloning by homology has identified several closely related human Toll counterparts whose physiological relevance is now being addressed. For example, recent studies have implicated TLR-2 and TLR-4 in our antibacterial and inflammatory responses. The study of immune evasion mechanisms can provide further insights into the functional importance of immune regulatory molecules in addition to clarifying their physiological roles. If Toll-like pathways are also susceptible to viral subversion, as shown in this paper, then they are likely to be important in a wide range of infections. A common signaling pathway used by multiple innate response proteins would be a particularly suitable target for viral interference.