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Science 316 (5831): 1628-1632

Copyright © 2007 by the American Association for the Advancement of Science

The Vaccine Adjuvant Monophosphoryl Lipid A as a TRIF-Biased Agonist of TLR4

Verónica Mata-Haro,1,2* Caglar Cekic,1,2 Michael Martin,3 Paula M. Chilton,1 Carolyn R. Casella,1 Thomas C. Mitchell1,2{dagger}

Abstract: The inflammatory toxicity of lipopolysaccharide (LPS), a component of bacterial cell walls, is driven by the adaptor proteins myeloid differentiation factor 88 (MyD88) and Toll-interleukin 1 receptor domain–containing adapter inducing interferon-ß (TRIF), which together mediate signaling by the endotoxin receptor Toll-like receptor 4 (TLR4). Monophosphoryl lipid A (MPLA) is a low-toxicity derivative of LPS with useful immunostimulatory properties, which is nearing regulatory approval for use as a human vaccine adjuvant. We report here that, in mice, the low toxicity of MPLA's adjuvant function is associated with a bias toward TRIF signaling, which we suggest is likely caused by the active suppression, rather than passive loss, of proinflammatory activity of this LPS derivative. This finding may have important implications for the development of future vaccine adjuvants.

1 Institute for Cellular Therapeutics, University of Louisville, 570 South Preston Street, Louisville, KY 40202, USA.
2 Department of Microbiology and Immunology, University of Louisville, 319 Abraham Flexner Way, Louisville, KY 40202, USA.
3 Oral Health and Systemic Disease Research Group, University of Louisville, 501 South Preston Street, Louisville, KY 40202, USA.

* Present address: Centro de Investigacion en Alimentacion y Desarrollo, Hermosillo, Sonora, Mexico.

{dagger} To whom correspondence should be addressed. E-mail: tom.mitchell{at}

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