Bacteria are able to survive in their environment by developing complex multicellular communities, rather than functioning as individual cells. Communication between cells is essential to facilitate this coordinated activity, and is achieved by the secretion and detection of small-signalling-molecules called autoinducers. The only signalling molecule recognised by both Gram-positive and Gram-negative bacteria is the Autoinducer-2 (AI-2). AI-2 is synthesised by the metabolic enzyme LuxS (S-ribosyl-homocysteine lyase) as a by-product of the conversion of S-ribosyl-homocysteine into homocysteine. The data presented here indicate that in S. pneumoniae, AI-2 accelerates and modulates the progression of disease in mice.
In this study, we determined whether the reduced virulence of a luxS mutant relative to its wild-type parent, D39, could be restored by administrating purified AI-2 in a murine model.
Mice were challenged intranasally with either wild-type D39 or luxS mutant strains and AI-2 was administrated at time zero and 24h post infection. Treatment with AI-2 significantly increased the levels of bacteraemia and lung invasion. Moreover, the rate of survival was dramatically reduced in the mice that received AI-2. Indeed, the virulence of the luxS mutant could be reconstituted to the same level of the wild type strain. To further investigate whether AI-2 could modulate innate immune responses in the host, we performed a RNA-cytokine array. To assess the early host immune response mice were euthanased at 6 h post infection and RNA analysed. We found that only one cytokine was differentially expressed between groups of mice challenged with either wild-type or luxS mutant, and that the expression level of this cytokine could be restored if AI-2 is administrated. These data provide evidence that AI-2 is critical to modulate host immune responses in order to induce systemic disease. Thus, an inhibitor of the universal signal molecule could have therapeutic potential.