IFNβ responses induced by intracellular bacteria or cytosolic DNA in different human cells do not require ZBP1 (DLM-1/DAI)

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Abstract
Intracellular bacteria and cytosolic stimulation with DNA activate type I IFN responses independently of Toll‐like receptors, most Nod‐like receptors and RIG‐like receptors. A recent study suggested that ZBP1 (DLM‐1/DAI) represents the long anticipated pattern recognition receptor which mediates IFNα/β responses to cytosolic DNA in mice. Here we show that Legionella pneumophila infection, and intracellular challenge with poly(dA‐dT), but not with poly(dG‐dC), induced expression of IFNβ, full‐length hZBP1 and a prominent splice variant lacking the first Zα domain (hZBP1ΔZα) in human cells. Overexpression of hZBP1 but not hZBP1ΔZα slightly amplified poly(dA‐dT)‐stimulated IFNβ reporter activation in HEK293 cells, but had no effect on IFNβ and IL‐8 production induced by bacteria or poly(dA‐dT) in A549 cells. We found that mZBP1 siRNA impaired poly(dA‐dT)‐induced IFNβ responses in mouse L929 fibroblasts at a later time point, while multiple hZBP1 siRNAs did not suppress IFNβ or IL‐8 expression induced by poly(dA‐dT) or bacterial infection in human cells. In contrast, IRF3 siRNA strongly impaired the IFNβ responses to poly(dA‐dT) or bacterial infection. In conclusion, intracellular bacteria and cytosolic poly(dA‐dT) activate IFNβ responses in different human cells without requiring human ZBP1.