Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP.
The innate immune defence of multicellular organisms against microbial pathogens requires cellular collaboration. Information exchange allowing immune cells to collaborate is generally attributed to soluble protein factors secreted by pathogen-sensing cells. Cytokines, such as type I interferons (IFNs), serve to alert non-infected cells to the possibility of pathogen challenge. Moreover, in conjunction with chemokines they can instruct specialized immune cells to contain and eradicate microbial infection. Several receptors and signalling pathways exist that couple pathogen sensing to the induction of cytokines, whereas cytosolic recognition of nucleic acids seems to be exquisitely important for the activation of type I IFNs, master regulators of antiviral immunity. Cytosolic DNA is sensed by the receptor cyclic GMP-AMP (cGAMP) synthase (cGAS), which catalyses the synthesis of the second messenger cGAMP(2'-5'). This molecule in turn activates the endoplasmic reticulum (ER)-resident receptor STING, thereby inducing an antiviral state and the secretion of type I IFNs. Here we find in murine and human cells that cGAS-synthesized cGAMP(2'-5') is transferred from producing cells to neighbouring cells through gap junctions, where it promotes STING activation and thus antiviral immunity independently of type I IFN signalling. In line with the limited cargo specificity of connexins, the proteins that assemble gap junction channels, most connexins tested were able to confer this bystander immunity, thus indicating a broad physiological relevance of this local immune collaboration. Collectively, these observations identify cGAS-triggered cGAMP(2'-5') transfer as a novel host strategy that serves to rapidly convey antiviral immunity in a transcription-independent, horizontal manner.
Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53127 Bonn, Germany.
Andrea
A
Ablasser
Jonathan L
JL
Schmid-Burgk
Inga
I
Hemmerling
Gabor L
GL
Horvath
Tobias
T
Schmidt
Eicke
E
Latz
Veit
V
Hornung
D000818:Animals; D024201:Bystander Effect / Q000276:immunology*; D002450:Cell Communication; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000378:metabolism; D015290:Second Messenger Systems; D014616:Vaccinia virus / Q000276:immunology; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
D004247:DNA; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase