Research ArticleAUTOPHAGY

Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans

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Science Immunology  11 Dec 2020:
Vol. 5, Issue 54, eabc2691
DOI: 10.1126/sciimmunol.abc2691

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Autophagy and susceptibility

Herpes simplex virus 2 (HSV2) infection has been linked to Mollaret’s meningitis, which is a recurrent form of meningitis. Hait et al. characterize rare monoallelic variants in the autophagy proteins ATG4A and LC3B2 in two adult patients with recurrent HSV2 lymphocytic Mollaret’s meningitis. HSV2 infection of primary fibroblasts from these patients revealed defects in autophagy as well as increased viral replication and cell death. In control cells, HSV2 replication was sufficient to induce autophagy, which was independent of the STING pathway, and reconstitution of patient fibroblasts with wild-type ATG4A and LC3B2 restored virus-induced autophagy and curbed infection. These findings describe a role for autophagy in antiviral defense and suggest that defective autophagy represents a rare inborn error of immunity associated with susceptibility to HSV2 CNS infection in humans.

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