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The Vaccine Adjuvant Monophosphoryl Lipid A as a TRIF-Biased Agonist of TLR4
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-β (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.
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Citations
Cited by
Signaling to NF-κB by Toll-like receptors
Kawai, T., & Akira, S. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.09.002 · Cited by 2,388
Vaccine Adjuvants: Putting Innate Immunity to Work
Coffman, R. L., Sher, A., & Seder, R. A. (2010) · Immunity · doi:10.1016/j.immuni.2010.10.002 · Cited by 1,924
Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis
Needham, B. D., & Trent, M. S. (2013) · Nature Reviews Microbiology · doi:10.1038/nrmicro3047 · Cited by 565
Kim, E., Erdos, G., Huang, S., Kenniston, T. W., Balmert, S. C., Carey, C. D., Raj, V. S., Epperly, M. W., Klimstra, W. B., Haagmans, B. L., et al. (2020) · eBioMedicine · doi:10.1016/j.ebiom.2020.102743 · Cited by 404
The molecular basis of the host response to lipopolysaccharide
Bryant, C. E., Spring, D. R., Gangloff, M., & Gay, N. J. (2010) · Nature Reviews Microbiology · doi:10.1038/nrmicro2266 · Cited by 391
Metadata
- Authors
- Mata-Haro, V., Cekic, C., Martin, M., Chilton, P. M., Casella, C. R., & Mitchell, T. C.
- Venue
- Science
- Published
- 2007-06-15
- Volume
- 316
- Issue
- 5831
- Pages
- 1628-1632
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2128897591
- Cited by
- 896
- References
- 0
- FWCI
- 14.59
- Type
- journal article
- Language
- en
- Open access
- closed
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- Mata-Haro, V., Cekic, C., Martin, M., Chilton, P. M., Casella, C. R., & Mitchell, T. C. (2007). The Vaccine Adjuvant Monophosphoryl Lipid A as a TRIF-Biased Agonist of TLR4. Science. https://doi.org/10.1126/science.1138963
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