Expulsion of nuclear DNA to the cytoplasm after viral entry: A mechanism for activation of the cGAS pathway

Cells respond to viral infection by induction of numerous innate and other host responses to block infection in that cell and surrounding cells. The mechanism(s) by which nuclear replicating DNA viruses and certain RNA viruses elicit responses through the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) cytoplasmic DNA sensor has been elusive. We report here that early events during herpes simplex virus 1 infection induce blebbing of nuclear DNA into the cytoplasm, recruitment of cGAS colocalization with the cytoplasmic DNA, activation of interferon regulatory factor 3, and induction of type 1 human interferon in normal human fibroblasts and keratinocytes. With HSV-1, this is dependent on viral binding and fusion with the surface membrane but independent of transport of the input viral DNA to the nucleus. Infections by herpes simplex virus 2, human cytomegalovirus, or human parainfluenza virus 3 also induce nuclear DNA blebbing, consistent with entry by surface fusion inducing this effect. Extrusion of nuclear DNA through nuclear envelope breaks upon viral entry by fusion represents a mechanism for cells to respond to the physical and/or molecular changes in the infected cell during infection.