Biased for the Better

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Science  02 Mar 2012:
Vol. 335, Issue 6072, pp. 1021
DOI: 10.1126/science.335.6072.1021-b

Bacterial infections can turn deadly when components of the bacterial membrane, such as lipopolysaccharide (LPS), cause runaway activation of the host immune system. LPS binds to Toll-like receptor 4 (TLR4) on the surface of host cells and activates two major signaling pathways. One, which acts through an adaptor protein known as TRIF, leads to production of interferon and chemokines that beneficially stimulate the adaptive immune system. The problematic side is mediated by the adaptor known as MyD88, which stimulates inflammatory responses that can lead to toxicity. Bowen et al. report that a very small structural change in a mimetic molecule that acts like LPS, analogous to changing just one phosphate group on the lipid A portion of LPS, effectively separates the two signaling pathways. Binding of the mimetic to TLR4 activated TRIF-mediated signals but caused little or no activation of the MyD88-mediated pathway. The results confirm that it may be possible to design therapeutic agents that can harness beneficial signaling from the TLR4—for example, to promote a strong response to vaccination, but avoid the normally concomitant, potentially toxic inflammatory response.

Sci. Signal. 5, ra13 (2012).

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