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. 2025 Jun 3;122(22):e2423873122.
doi: 10.1073/pnas.2423873122. Epub 2025 May 27.

Alternative cGAS signaling promotes herpes simplex encephalitis

Liraz Shmuel-Galia  1 , Zhaozhao Jiang  1 , Laurel Stine  1 , Sara Cahill  1 , Sze-Ling Ng  2 , Ruth Wilson  1 , Richard Kumaran Kandasamy  3 , Evelyn A Kurt-Jones  4 , Joshi M Ramanjulu  2 , John Bertin  5 , Viera Kasparcova  2 , G Scott Pesiridis #  2 , Katherine A Fitzgerald #  1 , Fiachra Humphries #  1
Affiliations

Alternative cGAS signaling promotes herpes simplex encephalitis

Liraz Shmuel-Galia et al. Proc Natl Acad Sci U S A. .

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.

Keywords: HSV; cGAS; infection; mouse model; type I IFN.

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Conflict of interest statement

Competing interests statement:At the time of the study co-authors S.L.-N., J.M.R., J.B., V.K. and G.S.P. were employees of GSK.

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