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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Alon Schneider Hait
  • David Olagnier
  • Vanessa Sancho-Shimizu
  • Kristian Alsbjerg Skipper
  • Marie Helleberg
  • Simon Muller Larsen
  • Chiranjeevi Bodda
  • Liviu Ionut Moldovan
  • Fanghui Ren
  • Nanna-Sophie Brinck Andersen
  • Michelle M Thomsen
  • Mette Ratzer Freytag
  • Sathya Darmalinggam
  • Isobel Parkes
  • Darshana D Kadekar
  • Stine Hess Rahbek
  • Demi van der Horst
  • Lasse Sommer Kristensen
  • Kristina Eriksson
  • Jørgen Kjems
  • Serge Mostowy
  • Mette Christiansen
  • Jacob Giehm Mikkelsen
  • Christian Thomas Brandt
  • Søren R Paludan
  • Trine H Mogensen
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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.

OriginalsprogEngelsk
Artikelnummereabc2691
TidsskriftScience immunology
Vol/bind5
Udgave nummer54
ISSN2470-9468
DOI
StatusUdgivet - 11 dec. 2020

Bibliografisk note

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

ID: 61538437