Department of Medicine, Division of Infectious Diseases and Immunology
Animals; Base Sequence; Carrier Proteins; Caspase 1; DNA, Single-Stranded; Enterohemorrhagic Escherichia coli; Enzyme-Linked Immunosorbent Assay; Escherichia coli Proteins; Hemolytic-Uremic Syndrome; Immunoblotting; Inflammasomes; Interleukin-1beta; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Molecular Sequence Data; RNA; Ribosomal Proteins
Bacteria | Immunity | Immunology and Infectious Disease | Immunology of Infectious Disease | Infectious Disease
Enterohemorrhagic Escherichia coli (EHEC) is an extracellular pathogen that causes hemorrhagic colitis and hemolytic uremic syndrome. The proinflammatory cytokine, interleukin-1beta, has been linked to hemolytic uremic syndrome. Here we identify the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome as an essential mediator of EHEC-induced IL-1beta. Whereas EHEC-specific virulence factors were dispensable for NLRP3 activation, bacterial nucleic acids such as RNA:DNA hybrids and RNA gained cytosolic access and mediated inflammasome-dependent responses. Consistent with a direct role for RNA:DNA hybrids in inflammasome activation, delivery of synthetic EHEC RNA:DNA hybrids into the cytosol triggered NLRP3-dependent responses, and introduction of RNase H, which degrades such hybrids, into infected cells specifically inhibited inflammasome activation. Notably, an E. coli rnhA mutant, which is incapable of producing RNase H and thus harbors increased levels of RNA:DNA hybrid, induced elevated levels of NLRP3-dependent caspase-1 activation and IL-1beta maturation. Collectively, these findings identify RNA:DNA hybrids of bacterial origin as a unique microbial trigger of the NLRP3 inflammasome.
Rights and Permissions
Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.
DOI of Published Version
Proc Natl Acad Sci U S A. 2014 May 27;111(21):7765-70. doi: 10.1073/pnas.1400075111. Epub 2014 May 14. Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America
Vanaja SK, Rathinam VA, Atianand MK, Kalantari P, Skehan BM, Fitzgerald KA, Leong JM. (2014). Bacterial RNA:DNA hybrids are activators of the NLRP3 inflammasome. Infectious Diseases and Immunology Publications. https://doi.org/10.1073/pnas.1400075111. Retrieved from https://escholarship.umassmed.edu/infdis_pp/176