Detection of prokaryotic mRNA signifies microbial viability and promotes immunity

  • A Corrigendum to this article was published on 21 September 2011


Live vaccines have long been known to trigger far more vigorous immune responses than their killed counterparts1,2,3,4,5,6. This has been attributed to the ability of live microorganisms to replicate and express specialized virulence factors that facilitate invasion and infection of their hosts7. However, protective immunization can often be achieved with a single injection of live, but not dead, attenuated microorganisms stripped of their virulence factors. Pathogen-associated molecular patterns (PAMPs), which are detected by the immune system8,9, are present in both live and killed vaccines, indicating that certain poorly characterized aspects of live microorganisms, not incorporated in dead vaccines, are particularly effective at inducing protective immunity. Here we show that the mammalian innate immune system can directly sense microbial viability through detection of a special class of viability-associated PAMPs (vita-PAMPs). We identify prokaryotic messenger RNA as a vita-PAMP present only in viable bacteria, the recognition of which elicits a unique innate response and a robust adaptive antibody response. Notably, the innate response evoked by viability and prokaryotic mRNA was thus far considered to be reserved for pathogenic bacteria, but we show that even non-pathogenic bacteria in sterile tissues can trigger similar responses, provided that they are alive. Thus, the immune system actively gauges the infectious risk by searching PAMPs for signatures of microbial life and thus infectivity. Detection of vita-PAMPs triggers a state of alert not warranted for dead bacteria. Vaccine formulations that incorporate vita-PAMPs could thus combine the superior protection of live vaccines with the safety of dead vaccines.

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Figure 1: Sensing bacterial viability induces IFN-β and activates the NLRP3 inflammasome in the absence of virulence factors.
Figure 2: The TLR signalling adaptor TRIF controls ‘viability-induced’ responses.
Figure 3: Bacterial RNA is a vita-PAMP that accesses cytosolic receptors during phagocytosis and in the absence of virulence factors.
Figure 4: Bacterial mRNA constitutes an active vita-PAMP.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Affymetrix Microarray data have been deposited with the NCBI Gene Expression Omnibus ( under accession number GSE27960.


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We are grateful to R. Medzhitov and J. C. Kagan for critical reading of the manuscript; C. B. Lopez for Irf3−/− mice; D. M. Monack for Salmonella ΔSpi1ΔSpi2; M. B. Goldberg for Shigella BS103; and D. A. Portnoy for Listeria ΔHlyΔfliC. We thank M. Rivieccio, I. Brodsky, M. Blander, S. J. Blander, J. Sander and Blander laboratory members for insightful discussions, help and support. L.E.S. was supported by Deutsche Forschungsgemeinschaft grant SA-1940/1-1, D.A. by fellowships from the Academic Medical Center and the Landsteiner Foundation for Blood Research, and M.V.B. and M.M. by the Netherlands Nutrigenomics Centre. This work was supported by NIH grant AI080959A and the Kinship Foundation Searle Scholar award to J.M.B.

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L.E.S. and J.M.B. designed experiments and directed the study. L.E.S. performed all experiments. M.J.D. and L.E.S. performed experiments measuring lysosomal leakage. J.A.S. helped with the design and analysis of the lysosomal leakage experiments. M.V.B. performed gene microarray analysis. M.V.B. and M.M. analysed the gene microarray data and helped with data interpretation. D.A. and J.M.B. performed experiments during the development phase of the project, and C.C.D. helped with the design of RNA-related experiments. B.R. provided bone marrow progenitor cells from Nlrp3−/−, Asc−/− and Casp1−/− mice. L.E.S., D.A. and J.M.B. wrote the manuscript. J.M.B. conceived of the study.

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Correspondence to J. Magarian Blander.

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Sander, L., Davis, M., Boekschoten, M. et al. Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature 474, 385–389 (2011).

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