Editors' ChoiceImmunology

Giving Lipid a Shot

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Science Translational Medicine  30 Jan 2013:
Vol. 5, Issue 170, pp. 170ec20
DOI: 10.1126/scitranslmed.3005775

Many medicines contain adjuvants—agents that can modify the effect of the primary medicine. One critical use of adjuvants is as the “dirty little secret” in vaccines: Adjuvants serve as additional stimulants to improve the vaccination immune response so an immune system can best respond to the pathogen in question. Although immunological adjuvants can work through a variety of mechanisms, the most common adjuvants function by prolonging antigen delivery (for example, aluminum salt). However, new experimental adjuvants are being tested that directly stimulate the innate immune system. Needham et al. now show that bacterial lipopolysaccharide (LPS) can be modified to serve as a biologically derived adjuvant.

The authors began by modifying the Lipid A fraction of LPS from E. coli using combinations of enzymes and subsequently probed for several immunogenic responses. First, two strains of Escherichia coli were altered to produce a homogeneous, bis-phosphorylated Lipid A to use as a starting material. Then, 61 new variations of Lipid A were generated through coexpression of the homogeneous Lipid A with different combinations of six modifying enzymes from other bacterial species. These compounds were then examined for their ability to stimulate the innate immunity toll-like receptor 4 (TLR4) and several humoral immunity indicator cytokines [tumor necrosis factor–α (TNF-α), interleukin-6 (IL-6), IL-1β, and IL-8]. They successfully induced a wide variety of TLR4 agonist activities and cytokine induction responses. Last, Needham et al. tested the ability of these compounds to serve as adjuvants in vivo. Indeed, mice immunized with several of these Lipid A variants produced substantial vaccine-specific immunoglobulin-G (IgG) titers, suggesting that these molecules could function as suitable adjuvants.

This demonstration of reengineering bacterial LPS is very promising. This LPS-modification strategy has the potential to be used for purposes beyond substituting for traditional aluminum-based adjuvants, as demonstrated in this study. Bacteria presenting a modified, less toxic Lipid A could be further modified to target specific tissues, stimulate beneficial immune responses in certain cancers, or negate inflammatory responses that occur with other adjuvants or bacteria.

B. D. Needham et al., Modulating the innate immune response by combinatorial engineering of endotoxin. Proc. Natl. Acad. Sci. U.S.A. 110, 1464–1469 (2013). [Abstract]

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