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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.
Abstract
Recurrent herpesvirus infections can manifest in different forms of disease, including cold sores, genital herpes, and encephalitis. There is an incomplete understanding of the genetic and immunological factors conferring susceptibility to recurrent herpes simplex virus 2 (HSV2) infection in the central nervous system (CNS). Here, we describe two adult patients with recurrent HSV2 lymphocytic Mollaret’s meningitis that each carry a rare monoallelic variant in the autophagy proteins ATG4A or LC3B2. HSV2-activated autophagy was abrogated in patient primary fibroblasts, which also exhibited significantly increased viral replication and enhanced cell death. HSV2 antigen was captured in autophagosomes of infected cells, and genetic inhibition of autophagy by disruption of autophagy genes, including ATG4A and LC3B2, led to enhanced viral replication and cell death in primary fibroblasts and a neuroblastoma cell line. Activation of autophagy by HSV2 was sensitive to ultraviolet (UV) irradiation of the virus and inhibited in the presence of acyclovir, but HSV2-induced autophagy was independent of the DNA-activated STING pathway. Reconstitution of wild-type ATG4A and LC3B2 expression using lentiviral gene delivery or electroporation of in vitro transcribed mRNA into patient cells restored virus-induced autophagy and the ability to control HSV2 replication. This study describes a previously unknown link between defective autophagy and an inborn error of immunity that can lead to increased susceptibility to HSV2 infection, suggesting an important role for autophagy in antiviral immunity in the CNS.
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