Editors' ChoiceHost-Pathogen Interactions

Vital Signs

Sci. Signal.  21 Jun 2011:
Vol. 4, Issue 178, pp. ec171
DOI: 10.1126/scisignal.4178ec171

Vaccines that contain live microorganisms elicit more effective immune responses than do those containing killed microorganisms. This is thought to be due to the replication of the live microorganisms and the presence of virulence factors; however, vaccines containing live bacteria that do not produce virulence factors can also induce effective immunity. This led Sander et al. to hypothesize that factors that are associated with live, but not dead, microorganisms [rather than the pathogen-associated molecular patterns (PAMPs) that are associated with both] might be particularly efficient at inducing innate immune responses. Viable and heat-killed forms of a nonreplicating, nonvirulent strain of Escherichia coli induced activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinase signaling to similar extents in infected mouse macrophages; however, live bacteria induced the production of more interferon-β (IFN-β) than did killed bacteria, and only viable bacteria led to production of the proinflammatory cytokine IL-1β, which requires activation of the NLRP3 inflammasome. The enhanced effects of viable bacteria required the Toll-like receptor adaptor protein TRIF, but not MyD88, and the transcription factor IRF3. In vivo studies with inoculated mice showed that viable, but not killed, bacteria induced IL-1β production and that this required TRIF and components of the inflammasome pathway. In mice, bacteria killed with paraformaldehyde, which in contrast to heat, UV irradiation, or ethanol preserves total RNA, induced IL-1β production to a similar extent to that induced by viable bacteria. Finally, addition of total bacterial RNA to heat-killed bacteria restored their ability to induce IL-1β production in macrophages. Thus, the authors suggest that the detection of viability-associated PAMPs (“vita-PAMPS”) by the immune system indicates the heightened threat associated with live, but not dead, bacteria, and that this response might be exploited for the generation of more effective vaccines.

L. E. Sander, M. J. Davis, M. V. Boekschoten, D. Amsen, C. C. Dascher, B. Ryffel, J. A. Swanson, M. Müller, J. M. Blander, Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature 474, 385–389 (2011). [PubMed]