Tuesday, April 12, 2016

Adjuvant activity of cholera toxin relies on endogenous microbiota-dependent Nod2 activation

Cholera toxin (CT), derived from Vibrio cholerae, is still widely used as a potent mucosal adjuvant in experimental [rodent] immunology. CT binds GM1 ganglioside receptor and activates cyclic AMP (cAMP) production. This mechanism is thought to stimulate TH2-associated cytokines and robust IgG1 production. However, toxicity of CT prevents its implementation in the clinic (it is not uncommon that scientists are studying active molecules that have no clinical use, but all "in hope" that "the mechanisms underlying its [CT's] potent adjuvant activity may lead to the development of nontoxic and effective adjuvants for mucosal vaccination."

This time, new study in Nature Medicine showed that CT's adjuvant activity relied on Nod2 signaling initiated by endogenous microbial flora.

Initially, the authors reported that nasal or oral immunization of germ-free (GF) mice [that harbor no endogenous microbiota] with protein antigen + CT yielded reduced levels of antigen-specific IgG1 and T cell effector differentiation. Similar results were obtained with antibiotic-treated mice.

Effect of endogenous microbiota on CT's adjuvant activity could be replicated in Ripk2 (the adaptor required for Nod1 and Nod2 signaling) or Nod2 deficient mice, but not in MyD88-KO or Nod1-KO mice.

It is known that Nod2 recognizes peptidoglycan molecules that contain muramyl dipeptide (MDP). Indeed, GF mice immunized with a combination of protein Ag + CT + MDP produced high level of antigen-specific IgG1, suggesting the role of MDP in promoting CT's adjuvanticity.

Finally, the authors found that several members of MDP-rich endogenous microbiota (i.e. Staphylococcus sciuri) promoted CT's adjuvant activity in GF mice in a Nod2-dependent manner.

In summary, this study indicates that adjuvanticity of cholera toxin relies on Nod2 signaling triggered by MDP-rich endogenous microbiota.

David Usharauli

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