Alternative cGAS signaling promotes herpes simplex encephalitis
Abstract
During infection, foreign DNA is sensed by cyclic GMP-AMP synthase (cGAS) leading to the production of cGAMP, STING-dependent type I interferon and proinflammatory cytokine expression, and autophagy. To prevent a response to self-DNA, cGAS activity is tightly regulated. Dysregulation of cGAS underpins interferonopathies, such as Aicardi–Goutières syndrome, as well as Lupus and neurodegenerative diseases like Parkinson’s disease. Thus, cGAS and its product cGAMP are therapeutic targets. However, if cGAS functions independently of cGAMP signaling is undefined. Here, we identified an alternative signaling pathway that cGAS engages independent of cGAMP synthesis. We demonstrate that alternative cGAS signaling promotes hyperexpression of CXCL1 and enhanced neutrophil recruitment that facilitates viral dissemination during herpes simplex encephalitis. Our study reports of an alternative cGAS response independent of cGAMP, highlighting a previously uncharacterized scaffold function for cGAS.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Liraz Shmuel-Galia
Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School
Zhaozhao Jiang
Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School
Laurel Stine
Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School
Sara Cahill
Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School
Sze-Ling Ng
Innate Immunity Research Unit, GlaxoSmithKline
Ruth Wilson
Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School
Richard Kumaran Kandasamy
Centre of Molecular Inflammation Research, and Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology
Evelyn A. Kurt-Jones
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical
Joshi M. Ramanjulu
Innate Immunity Research Unit, GlaxoSmithKline
John Bertin
Immunology and Inflammation Therapeutic Area, Sanofi
Viera Kasparcova
Innate Immunity Research Unit, GlaxoSmithKline
G. Scott Pesiridis
Innate Immunity Research Unit, GlaxoSmithKline
Katherine A. Fitzgerald
Department of Medicine, University of Massachusetts Chan Medical School
Fiachra Humphries